MLH1, MSH2, MSH6, PMS2, or EPCAM Gene Mutations

Lynch syndrome (LS)

MLH1, MSH2, MSH6, PMS2, AND EPCAM ASSOCIATED CANCER RISKS

 BREASTOVARIANGASTRICCOLORECTALPANCREATICMELANOMAPROSTATEENDOMETRIALOTHER

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Additional Information

MLH1 gene

Associated Syndrome Name: Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MLH1 Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
EndometrialHigh Risk
GastricHigh Risk
OvarianHigh Risk
PancreaticElevated Risk
ProstateElevated Risk
OtherHigh Risk

MLH1 gene Overview

Lynch syndrome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11
  • Individuals with mutations in MLH1 have a condition called Lynch syndrome. This condition is also known as Hereditary Non-Polyposis Colon Cancer (HNPCC).
  • Men and women with Lynch syndrome due to mutations in MLH1 have a high risk of developing colorectal cancer, often at young ages. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress to cancer more quickly than polyps in individuals who do not have Lynch syndrome.
  • Women with Lynch syndrome due to mutations in MLH1 have a high risk for developing endometrial and ovarian cancer, often at young ages.
  • Patients with Lynch syndrome due to mutations in MLH1 also have an increased risk of developing a wide variety of other cancers, including gastric, small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland, and pancreatic. These risks may be more significant in patients with a family history of these cancers. Therefore, the general screening and management recommendations provided below should be modified based on individualized risk assessment and counseling.
  • An increased risk for prostate cancer has been documented in multiple studies of men with Lynch syndrome. Estimates range from an approximately 2 to 5-fold increase in risk, or up to 30%, but the exact increase has not yet been established for men with mutations in MLH1.
  • Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these cancers.
  • Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrial cancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primary colorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and a high risk for other Lynch associated cancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.
  • Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National Comprehensive Cancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with an MLH1 mutation and a diagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with this condition.

MLH1 gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 704, 9, 1252%-82%1.8%
EndometrialTo age 704, 9, 1225%-60%1.7%
Overall cancer risk (Lynch cancers)Risk for a second Lynch-related cancer after a first cancer diagnosis5, 11Increased riskNA
OvarianTo age 704, 9, 124%-12%0.7%
GastricTo age 704, 9, 126%-13%0.4%
Small BowelTo age 704, 9, 123%-6%0.1%
Urinary TractTo age 704, 9, 10, 12, 135%-7%0.7%
PancreaticTo age 704, 8, 9, 121%-6%0.5%
Central Nervous SystemTo age 704, 9, 121%-3%0.4%
ProstateTo age 802, 4, 5, 6, 7, 12Up to 30%10.9%
Hepatobiliary TractTo age 704, 9, 121.4%-4%0.5%
Sebaceous NeoplasmsTo age 704, 9, 121%-9%<1.0%

MLH1 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy3, 4, 1520 to 25 years, or 2 to 5 years younger than the earliest diagnosis in family if it is under age 25Every 1 to 2 years
Colorectal surgical evaluation may be appropriate for some patients4IndividualizedNA
Consider the use of aspirin as a risk-reduction agent3, 4IndividualizedIndividualized
EndometrialPatient education about the importance of quickly seeking attention for endometrial cancer symptoms, such as abnormal bleeding or menstrual cycle irregularities4IndividualizedIndividualized
Consider pelvic examination, endometrial sampling and transvaginal ultrasound.3, 430 to 35 yearsAnnually
Consider hysterectomy.3, 4After completion of childbearingNA
OvarianConsider bilateral salpingo-oophorectomy.3, 4Age 40 or after completion of childbearingNA
Consider transvaginal ultrasound and CA-125 measurement.3, 430 to 35 yearsNA
Consider options for ovarian cancer risk-reduction agents (i.e. oral contraceptives).4, 17IndividualizedNA
Patient education about ovarian cancer symptoms4IndividualizedNA
GastricConsider testing and treating Helicobacter pylori infection.3IndividualizedNA
Consider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry. Consider biopsy of the antrum.3, 4, 15, 1830 to 40 yearsEvery 2 to 5 years
Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history.3, 4, 1530 to 40 yearsEvery 3 to 5 years
Urinary TractConsider urinalysis.3, 430 to 35 yearsAnnually
PancreaticFor patients with a family history of pancreatic cancer, consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in screening for pancreatic cancer, preferably within research protocols.15, 16Age 50, or 10 years younger than the earliest age of pancreatic cancer diagnosis in the familyAnnually
Provide education about ways to reduce pancreatic cancer risk, such as not smoking and losing weight.15, 19IndividualizedIndividualized
Central Nervous SystemPhysical/neurological examination425 to 30 yearsAnnually
ProstateCurrently there are no specific medical management guidelines for prostate cancer risk in mutation carriers. However, the possibility of an increased risk for prostate cancer can be incorporated into the risk and benefit discussion about offering screening with digital rectal examination (DRE) and Prostate Specific Antigen (PSA).4, 2045 years, or youngerIndividualized
Hepatobiliary TractCurrently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers.4NANA
Sebaceous NeoplasmsCurrently there are no specific medical management guidelines for sebaceous neoplasm risk in mutation carriers.NANA
For Patients With A Cancer DiagnosisFor patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (e.g., antibodies to PD-1)14NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the MLH1 gene.

A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.

In rare instances, an individual may inherit mutations in both copies of the MLH1 gene, leading to the condition Constitutional Mismatch Repair-Deficiency syndrome (CMMR-D). Individuals with CMMR-D often have significant complications in childhood, including colorectal polyposis and a high risk for colorectal, small bowel, brain, and hematologic cancers. Individuals with CMMR-D often have café-au-lait spots. The children of this patient are at risk of inheriting CMMR-D only if the other parent is also a carrier of a MLH1 mutation. Screening the other biological parent of any children for MLH1 mutations may be appropriate.9

Parents who are concerned about the possibility of passing on an MLH1 mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).4

References

  1. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626.
  2. Ryan S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014 23:437-49. PMID: 24425144.
  3. Giardiello FM, et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014 109:1159-79. PMID: 25070057.
  4. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 3.2019. Dec 13. Available at http://www.nccn.org.
  5. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731.
  6. Grindedal EM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009 18:2460-7. PMID: 19723918.
  7. Raymond VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 31:1713-8. oi: 10.1200/JCO.2012.44.1238. Epub 2013 Mar 25. PMID: 23530095.
  8. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.
  9. Kohlmann W, Gruber SB. Lynch Syndrome. 2018 Apr 12. In:Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390.
  10. Joost P, et al. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations. Urology. 2015 86:1212-7. PMID: 26385421.
  11. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444.
  12. Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/faststats. (Accessed on 1-2-2017)
  13. M\u00f8ller P, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2017 [Epub ahead of print] PMID: 28754778.
  14. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s031lbl.pdf
  15. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 110:223-62. PMID: 25645574.
  16. Goggins M, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020 69:7-17. PMID: 31672839.
  17. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. V 1.2020. Dec 4. Available at http://www.nccn.org.
  18. Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 4.2019. Dec 20. Available at http://www.nccn.org.
  19. Tempero MA, et al. NCCN Clinical Practice Guidelines in Oncology®: Pancreatic Adenocarcinoma. V 1.2020. Nov 26. Available at http://www.nccn.org.
  20. Carroll PR, et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2019. May 31. Available at http://www.nccn.org.
Last Updated on 10-Dec-2020

MSH2 gene

Associated Syndrome Name: Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MSH2 Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
EndometrialHigh Risk
GastricHigh Risk
OvarianHigh Risk
PancreaticElevated Risk
ProstateElevated Risk
OtherHigh Risk

MSH2 gene Overview

Lynch syndrome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11
  • Individuals with mutations in MSH2 have a condition called Lynch syndrome. This condition is also known as Hereditary Non-Polyposis Colon Cancer (HNPCC).
  • Men and women with Lynch syndrome due to mutations in MSH2 have a high risk of developing colorectal cancer, often at young ages. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress to cancer more quickly than polyps in individuals who do not have Lynch syndrome.
  • Women with Lynch syndrome due to mutations in MSH2 have a high risk for developing endometrial and ovarian cancer, often at young ages.
  • Patients with Lynch syndrome due to mutations in MSH2 also have an increased risk of developing a wide variety of other cancers, including gastric, small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland, and pancreatic. These risks may be more significant in patients with a family history of these cancers. Therefore, the general screening and management recommendations provided below should be modified based on individualized risk assessment and counseling.
  • An increased risk for prostate cancer has been documented in multiple studies of men with Lynch syndrome. Estimates range from an approximately 2 to 5-fold increase in risk, or up to 30%, but the exact increase has not yet been established for men with mutations in MSH2.
  • Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these cancers.
  • Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrial cancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primary colorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and a high risk for other Lynch associated cancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.
  • Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National Comprehensive Cancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with an MSH2 mutation and a diagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with this condition.

MSH2 gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 703, 8, 1252%-82%1.8%
EndometrialTo age 703, 8, 1225%-60%1.7%
Overall cancer risk (Lynch cancers)Risk for a second Lynch-related cancer after a first cancer diagnosis4, 7Increased riskNA
OvarianTo age 703, 8, 124%-12%0.7%
GastricTo age 703, 8, 126%-13%0.4%
Small BowelTo age 703, 8, 123%-6%0.1%
Urinary TractTo age 703, 8, 11, 12, 1311%-21%0.7%
PancreaticTo age 703, 5, 8, 121%-6%0.5%
Central Nervous SystemTo age 703, 8, 121%-3%0.4%
ProstateTo age 801, 2, 3, 7, 9, 12Up to 30%10.9%
Hepatobiliary TractTo age 703, 8, 121.4%-4%0.5%
Sebaceous NeoplasmsTo age 703, 8, 121%-9%<1.0%

MSH2 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy3, 10, 1420 to 25 years, or 2 to 5 years younger than the earliest diagnosis in family if it is under age 25Every 1 to 2 years
Colorectal surgical evaluation may be appropriate for some patients3IndividualizedNA
Consider the use of aspirin as a risk-reduction agent3, 10IndividualizedIndividualized
EndometrialPatient education about the importance of quickly seeking attention for endometrial cancer symptoms, such as abnormal bleeding or menstrual cycle irregularities3IndividualizedIndividualized
Consider pelvic examination, endometrial sampling and transvaginal ultrasound.3, 1030 to 35 yearsAnnually
Consider hysterectomy.3, 10After completion of childbearingNA
OvarianConsider bilateral salpingo-oophorectomy.3, 10Age 40 or after completion of childbearingNA
Consider transvaginal ultrasound and CA-125 measurement.3, 1030 to 35 yearsNA
Consider options for ovarian cancer risk-reduction agents (i.e. oral contraceptives).3, 19IndividualizedNA
Patient education about ovarian cancer symptoms3IndividualizedNA
GastricConsider testing and treating Helicobacter pylori infection.10IndividualizedNA
Consider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry. Consider biopsy of the antrum.3, 10, 14, 1730 to 40 yearsEvery 2 to 5 years
Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history.3, 10, 1430 to 40 yearsEvery 3 to 5 years
Urinary TractConsider urinalysis.3, 1030 to 35 yearsAnnually
PancreaticFor patients with a family history of pancreatic cancer, consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in screening for pancreatic cancer, preferably within research protocols.14, 15Age 50, or 10 years younger than the earliest age of pancreatic cancer diagnosis in the familyAnnually
Provide education about ways to reduce pancreatic cancer risk, such as not smoking and losing weight.14, 20IndividualizedIndividualized
Central Nervous SystemPhysical/neurological examination325 to 30 yearsAnnually
ProstateCurrently there are no specific medical management guidelines for prostate cancer risk in mutation carriers. However, the possibility of an increased risk for prostate cancer can be incorporated into the risk and benefit discussion about offering screening with digital rectal examination (DRE) and Prostate Specific Antigen (PSA).3, 1845 years, or youngerIndividualized
Hepatobiliary TractCurrently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers.3NANA
Sebaceous NeoplasmsCurrently there are no specific medical management guidelines for sebaceous neoplasm risk in mutation carriers.NANA
For Patients With A Cancer DiagnosisFor patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (e.g., antibodies to PD-1)16NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the MSH2 gene.

A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.

In rare instances, an individual may inherit mutations in both copies of the MSH2 gene, leading to the condition Constitutional Mismatch Repair-Deficiency syndrome (CMMR-D). Individuals with CMMR-D often have significant complications in childhood, including colorectal polyposis and a high risk for colorectal, small bowel, brain, and hematologic cancers. Individuals with CMMR-D often have café-au-lait spots. The children of this patient are at risk of inheriting CMMR-D only if the other parent is also a carrier of a MSH2 mutation. Screening the other biological parent of any children for MSH2 mutations may be appropriate.8

Parents who are concerned about the possibility of passing on an MSH2 mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).3

References

  1. Grindedal EM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009 18:2460-7. PMID: 19723918.
  2. Ryan S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014 23:437-49. PMID: 24425144.
  3. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 3.2019. Dec 13. Available at http://www.nccn.org.
  4. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444.
  5. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.
  6. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626.
  7. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731.
  8. Kohlmann W, Gruber SB. Lynch Syndrome. 2018 Apr 12. In:Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390.
  9. Raymond VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 31:1713-8. oi: 10.1200/JCO.2012.44.1238. Epub 2013 Mar 25. PMID: 23530095.
  10. Giardiello FM, et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014 109:1159-79. PMID: 25070057.
  11. Joost P, et al. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations. Urology. 2015 86:1212-7. PMID: 26385421.
  12. Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/faststats. (Accessed on 1-2-2017)
  13. M\u00f8ller P, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2017 [Epub ahead of print] PMID: 28754778.
  14. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 110:223-62. PMID: 25645574.
  15. Goggins M, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020 69:7-17. PMID: 31672839.
  16. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s031lbl.pdf
  17. Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 4.2019. Dec 20. Available at http://www.nccn.org.
  18. Carroll PR, et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2019. May 31. Available at http://www.nccn.org.
  19. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. V 1.2020. Dec 4. Available at http://www.nccn.org.
  20. Tempero MA, et al. NCCN Clinical Practice Guidelines in Oncology®: Pancreatic Adenocarcinoma. V 1.2020. Nov 26. Available at http://www.nccn.org.
Last Updated on 10-Dec-2020

MSH6 gene

Associated Syndrome Name: Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MSH6 Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
EndometrialHigh Risk
GastricElevated Risk
OvarianElevated Risk
PancreaticElevated Risk
ProstateElevated Risk
OtherHigh Risk

MSH6 gene Overview

Lynch syndrome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
  • Individuals with mutations in MSH6 have a condition called Lynch syndrome. This condition is also known as Hereditary Non-Polyposis Colon Cancer (HNPCC).
  • Men and women with Lynch syndrome due to mutations in MSH6 have a high risk of developing colorectal cancer, often at younger ages than seen in the general population. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress to cancer more quickly than polyps in individuals who do not have Lynch syndrome. Colorectal cancer risk may be somewhat lower in women than in men, but there are no differences in the colorectal cancer screening guidelines for men and women.
  • Women with Lynch syndrome due to mutations in MSH6 have a high risk for developing endometrial cancer and an elevated risk for ovarian cancer, often at younger ages than typical in the general population.
  • Patients with Lynch syndrome due to mutations in MSH6 are also believed to have an increased risk of developing a wide variety of other Lynch syndrome associated cancers, including gastric, small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland, and pancreatic. Precise risk estimates are not available because there is less information available for patients with MSH6 mutations compared with patients who have mutations in other Lynch syndrome genes. These risks may be more significant in patients with a family history of these cancers. Therefore, the general screening and management recommendations provided below should be modified based on individualized risk assessment and counseling.
  • An increased risk for prostate cancer has been documented in multiple studies of men with Lynch syndrome. Estimates range from an approximately 2 to 5-fold increase in risk, or up to 30%, but the exact increase has not yet been established for men with mutations in MSH6.
  • Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these cancers.
  • Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrial cancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primary colorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and an increased risk for other Lynch associated cancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.
  • Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National Comprehensive Cancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with an MSH6 mutation and a diagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with this condition.

MSH6 gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
Colorectal (male)To age 705, 6, 8, 1322%-69%2.0%
EndometrialTo age 705, 6, 8, 1316%-71%1.7%
Overall cancer risk (Lynch cancers)Risk for a second Lynch-related cancer after a first cancer diagnosis3, 7Increased riskNA
Colorectal (female)To age 705, 6, 8, 1310%-30%1.5%
ProstateTo age 803, 9, 10, 11, 12, 13Up to 30%10.9%
OvarianTo age 702, 5, 6, 8, 9, 13Elevated risk0.7%
GastricTo age 702, 5, 6, 8, 9, 13Elevated risk0.4%
Small BowelTo age 702, 5, 6, 8, 9, 13Elevated risk0.1%
Urinary TractTo age 702, 5, 6, 8, 9, 13, 144%-7%0.7%
PancreaticTo age 709, 13, 15, 16Elevated risk0.5%
Central Nervous SystemTo age 702, 5, 6, 8, 9, 13Elevated risk0.4%
Hepatobiliary TractTo age 702, 5, 6, 8, 9, 13Elevated risk0.5%
Sebaceous NeoplasmsTo age 702, 5, 6, 8, 9, 13Elevated risk<1.0%

MSH6 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy1, 9, 1720 to 30 years, or 2 to 10 years younger than the earliest diagnosis of colorectal cancer in the familyEvery 1 to 2 years
Colorectal surgical evaluation may be appropriate for some patients9IndividualizedNA
Consider the use of aspirin as a risk-reduction agent1, 9IndividualizedIndividualized
EndometrialPatient education about the importance of quickly seeking attention for endometrial cancer symptoms, such as abnormal bleeding or menstrual cycle irregularities9IndividualizedIndividualized
Consider pelvic examination, endometrial sampling and transvaginal ultrasound.1, 930 to 35 yearsAnnually
Consider hysterectomy.1, 9After completion of childbearingNA
ProstateCurrently there are no specific medical management guidelines for prostate cancer risk in mutation carriers. However, the possibility of an increased risk for prostate cancer can be incorporated into the risk and benefit discussion about offering screening with digital rectal examination (DRE) and Prostate Specific Antigen (PSA).9, 1845 years, or youngerIndividualized
OvarianConsider bilateral salpingo-oophorectomy.1, 9Age 40 or after completion of childbearingNA
Consider transvaginal ultrasound and CA-125 measurement.1, 930 to 35 yearsNA
Consider options for ovarian cancer risk-reduction agents (i.e. oral contraceptives).9, 21IndividualizedNA
Patient education about ovarian cancer symptoms9IndividualizedNA
GastricConsider testing and treating Helicobacter pylori infection.1IndividualizedNA
Consider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry. Consider biopsy of the antrum.1, 9, 17, 1930 to 40 yearsEvery 2 to 5 years
Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history.1, 9, 1730 to 40 yearsEvery 3 to 5 years
Urinary TractConsider urinalysis.1, 930 to 35 yearsAnnually
PancreaticFor patients with a family history of pancreatic cancer, consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in screening for pancreatic cancer, preferably within research protocols.15, 17Age 50, or 10 years younger than the earliest age of pancreatic cancer diagnosis in the familyAnnually
Provide education about ways to reduce pancreatic cancer risk, such as not smoking and losing weight.17, 22IndividualizedIndividualized
Central Nervous SystemPhysical/neurological examination925 to 30 yearsAnnually
Hepatobiliary TractCurrently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers.9NANA
Sebaceous NeoplasmsCurrently there are no specific medical management guidelines for sebaceous neoplasm risk in mutation carriers.NANA
For Patients With A Cancer DiagnosisFor patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (e.g., antibodies to PD-1)20NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the MSH6 gene.

A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.

In rare instances, an individual may inherit mutations in both copies of the MSH6 gene, leading to the condition Constitutional Mismatch Repair-Deficiency syndrome (CMMR-D). Individuals with CMMR-D often have significant complications in childhood, including colorectal polyposis and a high risk for colorectal, small bowel, brain, and hematologic cancers. Individuals with CMMR-D often have café-au-lait spots. The children of this patient are at risk of inheriting CMMR-D only if the other parent is also a carrier of a MSH6 mutation. Screening the other biological parent of any children for MSH6 mutations may be appropriate.2

Parents who are concerned about the possibility of passing on an MSH6 mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).9

References

  1. Giardiello FM, et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014 109:1159-79. PMID: 25070057.
  2. Kohlmann W, Gruber SB. Lynch Syndrome. 2018 Apr 12. In:Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390.
  3. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731.
  4. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626.
  5. Baglietto L, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 102:193-201. PMID: 20028993.
  6. Hendriks YM, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004 127:17-25. PMID: 15236168.
  7. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444.
  8. Bonadona V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011 305:2304-10. PMID: 21642682.
  9. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 3.2019. Dec 13. Available at http://www.nccn.org.
  10. Ryan S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014 23:437-49. PMID: 24425144.
  11. Grindedal EM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009 18:2460-7. PMID: 19723918.
  12. Raymond VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 31:1713-8. oi: 10.1200/JCO.2012.44.1238. Epub 2013 Mar 25. PMID: 23530095.
  13. Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/faststats. (Accessed on 1-2-2017)
  14. M\u00f8ller P, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2017 [Epub ahead of print] PMID: 28754778.
  15. Goggins M, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020 69:7-17. PMID: 31672839.
  16. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.
  17. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 110:223-62. PMID: 25645574.
  18. Carroll PR, et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2019. May 31. Available at http://www.nccn.org.
  19. Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 4.2019. Dec 20. Available at http://www.nccn.org.
  20. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s031lbl.pdf
  21. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. V 1.2020. Dec 4. Available at http://www.nccn.org.
  22. Tempero MA, et al. NCCN Clinical Practice Guidelines in Oncology®: Pancreatic Adenocarcinoma. V 1.2020. Nov 26. Available at http://www.nccn.org.
Last Updated on 10-Dec-2020

PMS2 gene

Associated Syndrome Name: Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

PMS2 Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
EndometrialHigh Risk
GastricElevated Risk
OvarianElevated Risk
PancreaticElevated Risk
ProstateElevated Risk
OtherHigh Risk

PMS2 gene Overview

Lynch syndrome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
  • Individuals with mutations in PMS2 have a condition called Lynch syndrome. This condition is also known as Hereditary Non-Polyposis Colon Cancer (HNPCC).
  • Men and women with Lynch syndrome due to mutations in PMS2 have a high risk of developing colorectal cancer, often at younger ages than seen in the general population. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress to cancer more quickly than polyps in individuals who do not have Lynch syndrome.
  • Women with Lynch syndrome due to mutations in PMS2 have a high risk for developing endometrial cancer and possibly an elevated risk for ovarian cancer, often at younger ages than typical in the general population.
  • Patients with Lynch syndrome due to mutations in PMS2 are also believed to have an increased risk of developing a wide variety of other Lynch syndrome associated cancers, including gastric, small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland, and pancreatic. Precise risk estimates are not available because there is less information available for patients with PMS2 mutations compared with patients who have mutations in other Lynch syndrome genes. These risks may be more significant in patients with a family history of these cancers. Therefore, the general screening and management recommendations provided below should be modified based on individualized risk assessment and counseling.
  • An increased risk for prostate cancer has been documented in multiple studies of men with Lynch syndrome. Estimates range from an approximately 2 to 5-fold increase in risk, but the exact increase has not yet been established for men with mutations in PMS2.
  • Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these cancers.
  • Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrial cancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primary colorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and a high risk for other Lynch associated cancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.
  • Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National Comprehensive Cancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with a PMS2 mutation and a diagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with this condition.

PMS2 gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 704, 11, 12Up to 20%1.8%
EndometrialTo age 704, 11, 12Up to 15%1.7%
Overall cancer risk (Lynch cancers)Risk for a second Lynch-related cancer after a first cancer diagnosis3, 7Increased riskNA
ProstateTo age 803, 5, 8, 9, 12, 13Elevated risk10.9%
OvarianTo age 702, 4, 8, 11, 12Elevated risk0.7%
GastricTo age 702, 4, 8, 11, 12Elevated risk0.4%
Small BowelTo age 702, 4, 8, 11, 12Elevated risk0.1%
Urinary TractTo age 702, 4, 8, 11, 12, 14Elevated risk0.7%
PancreaticTo age 702, 4, 6, 8, 11, 12, 15Elevated risk0.5%
Central Nervous SystemTo age 702, 4, 8, 11, 12Elevated risk0.4%
Hepatobiliary TractTo age 702, 4, 8, 11, 12Elevated risk0.5%
Sebaceous NeoplasmsTo age 702, 4, 8, 11, 12Elevated risk<1.0%

PMS2 Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy1, 8, 1620 to 35 years, or 2 to 10 years younger than the earliest diagnosis of colorectal cancer in the familyEvery 1 to 2 years
Colorectal surgical evaluation may be appropriate for some patients8IndividualizedNA
Consider the use of aspirin as a risk-reduction agent1, 8IndividualizedIndividualized
EndometrialPatient education about the importance of quickly seeking attention for endometrial cancer symptoms, such as abnormal bleeding or menstrual cycle irregularities8IndividualizedIndividualized
Consider pelvic examination, endometrial sampling and transvaginal ultrasound.1, 830 to 35 yearsAnnually
Consider hysterectomy.1, 8After completion of childbearingNA
ProstateCurrently there are no specific medical management guidelines for prostate cancer risk in mutation carriers. However, the possibility of an increased risk for prostate cancer can be incorporated into the risk and benefit discussion about offering screening with digital rectal examination (DRE) and Prostate Specific Antigen (PSA).8, 1845 years, or youngerIndividualized
OvarianConsider bilateral salpingo-oophorectomy.1, 8Age 40 or after completion of childbearingNA
Consider transvaginal ultrasound and CA-125 measurement.1, 830 to 35 yearsNA
Consider options for ovarian cancer risk-reduction agents (i.e. oral contraceptives).8, 20IndividualizedNA
Patient education about ovarian cancer symptoms8IndividualizedNA
GastricConsider testing and treating Helicobacter pylori infection.1IndividualizedNA
Consider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry. Consider biopsy of the antrum.1, 8, 16, 1730 to 40 yearsEvery 2 to 5 years
Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history.1, 8, 1630 to 40 yearsEvery 3 to 5 years
Urinary TractConsider urinalysis.1, 830 to 35 yearsAnnually
PancreaticFor patients with a family history of pancreatic cancer, consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in screening for pancreatic cancer, preferably within research protocols.15, 16Age 50, or 10 years younger than the earliest age of pancreatic cancer diagnosis in the familyAnnually
Provide education about ways to reduce pancreatic cancer risk, such as not smoking and losing weight.16, 21IndividualizedIndividualized
Central Nervous SystemPhysical/neurological examination825 to 30 yearsAnnually
Hepatobiliary TractCurrently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers.8NANA
Sebaceous NeoplasmsCurrently there are no specific medical management guidelines for sebaceous neoplasm risk in mutation carriers.NANA
For Patients With A Cancer DiagnosisFor patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (e.g., antibodies to PD-1)19NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the PMS2 gene.

A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.

In rare instances, an individual may inherit mutations in both copies of the PMS2 gene, leading to the condition Constitutional Mismatch Repair-Deficiency syndrome (CMMR-D). Individuals with CMMR-D often have significant complications in childhood, including colorectal polyposis and a high risk for colorectal, small bowel, brain, and hematologic cancers. Individuals with CMMR-D often have café-au-lait spots. The children of this patient are at risk of inheriting CMMR-D only if the other parent is also a carrier of a PMS2 mutation. Screening the other biological parent of any children for PMS2 mutations may be appropriate.2, 4

Parents who are concerned about the possibility of passing on a PMS2 mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).8

References

  1. Giardiello FM, et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014 109:1159-79. PMID: 25070057.
  2. Kohlmann W, Gruber SB. Lynch Syndrome. 2018 Apr 12. In:Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390.
  3. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731.
  4. Senter L, et al. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations. Gastroenterology. 2008 135419-28. PMID: 18602922.
  5. Raymond VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 31:1713-8. oi: 10.1200/JCO.2012.44.1238. Epub 2013 Mar 25. PMID: 23530095.
  6. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.
  7. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444.
  8. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 3.2019. Dec 13. Available at http://www.nccn.org.
  9. Ryan S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014 23:437-49. PMID: 24425144.
  10. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626.
  11. ten Broeke SW, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015 33:319-25. PMID: 25512458.
  12. Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/faststats. (Accessed on 1-2-2017)
  13. Grindedal EM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009 18:2460-7. PMID: 19723918.
  14. M\u00f8ller P, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2017 [Epub ahead of print] PMID: 28754778.
  15. Goggins M, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020 69:7-17. PMID: 31672839.
  16. Syngal S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 110:223-62. PMID: 25645574.
  17. Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 4.2019. Dec 20. Available at http://www.nccn.org.
  18. Carroll PR, et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2019. May 31. Available at http://www.nccn.org.
  19. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s031lbl.pdf
  20. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic. V 1.2020. Dec 4. Available at http://www.nccn.org.
  21. Tempero MA, et al. NCCN Clinical Practice Guidelines in Oncology®: Pancreatic Adenocarcinoma. V 1.2020. Nov 26. Available at http://www.nccn.org.
Last Updated on 10-Dec-2020

EPCAM gene

Associated Syndrome Name: Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

EPCAM Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalHigh Risk
EndometrialHigh Risk
GastricHigh Risk
OvarianHigh Risk
PancreaticElevated Risk
ProstateElevated Risk
OtherHigh Risk

EPCAM gene Overview

Lynch syndrome 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
  • Individuals with mutations in EPCAM have a condition called Lynch syndrome. This condition is also known as Hereditary Non-Polyposis Colon Cancer (HNPCC).
  • Men and women with Lynch syndrome due to mutations in EPCAM have a high risk of developing colorectal cancer, often at young ages. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress to cancer more quickly than polyps in individuals who do not have Lynch syndrome.
  • Women with Lynch syndrome due to mutations in EPCAM have a high risk for developing endometrial and ovarian cancer, often at young ages.
  • Patients with Lynch syndrome due to mutations in EPCAM are also believed to have an increased risk of developing a wide variety of other cancers, including gastric, small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland, and pancreatic. These risks may be more significant in patients with a family history of these cancers. Therefore, the general screening and management recommendations provided below should be modified based on individualized risk assessment and counseling.
  • An increased risk for prostate cancer has been documented in multiple studies of men with Lynch syndrome. Estimates range from an approximately 2 to 5-fold increase in risk, or up to 30%, but the exact increase has not yet been established for men with mutations in EPCAM.
  • Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medical management guidelines related to these cancers.
  • Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrial cancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primary colorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and a high risk for other Lynch associated cancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.
  • Cancer risks for patients with Lynch syndrome due to mutations in EPCAM are currently estimated to be similar to those for patients with Lynch syndrome due to mutations in MSH2, and medical management guidelines are currently the same for patients with mutations in either gene. However, it is possible that this will change over time as we learn more about the exact risks associated with mutations in EPCAM. There are some early indications that endometrial cancer risk may be much lower for women with certain types of mutations in EPCAM.
  • Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National Comprehensive Cancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with an EPCAM mutation and a diagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with this condition.

EPCAM gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 701, 6, 1352%-82%1.8%
EndometrialTo age 701, 6, 1325%-60%1.7%
Overall cancer risk (Lynch cancers)Risk for a second Lynch-related cancer after a first cancer diagnosis7, 11Increased riskNA
OvarianTo age 701, 6, 134%-12%0.7%
GastricTo age 701, 6, 136%-13%0.4%
Small BowelTo age 701, 6, 133%-6%0.1%
Urinary TractTo age 701, 6, 9, 13, 1411%-21%0.7%
PancreaticTo age 701, 6, 10, 131%-6%0.5%
Central Nervous SystemTo age 701, 6, 131%-3%0.4%
ProstateTo age 801, 2, 4, 5, 7, 13Up to 30%10.9%
Hepatobiliary TractTo age 701, 6, 131.4%-4%0.5%
Sebaceous NeoplasmsTo age 701, 6, 131%-9%<1.0%

EPCAM Cancer Risk Management Table

The overview of medical management options provided is a summary of professional society guidelines. The most recent version of each guideline should be consulted for more detailed and up-to-date information before developing a treatment plan for a particular patient.

This overview is provided for informational purposes only and does not constitute a recommendation. While the medical society guidelines summarized herein provide important and useful information, medical management decisions for any particular patient should be made in consultation between that patient and his or her healthcare provider and may differ from society guidelines based on a complete understanding of the patient’s personal medical history, surgeries and other treatments.

Cancer Type Procedure Age to Begin Frequency
(Unless otherwise indicated by findings)
ColorectalColonoscopy1, 12, 1520 to 25 years, or 2 to 5 years younger than the earliest diagnosis in family if it is under age 25Every 1 to 2 years
Colorectal surgical evaluation may be appropriate for some patients1IndividualizedNA
Consider the use of aspirin as a risk-reduction agent1, 12IndividualizedIndividualized
EndometrialPatient education about the importance of quickly seeking attention for endometrial cancer symptoms, such as abnormal bleeding or menstrual cycle irregularities1IndividualizedIndividualized
Consider pelvic examination, endometrial sampling and transvaginal ultrasound.1, 1230 to 35 yearsAnnually
Consider hysterectomy.1, 12After completion of childbearingNA
OvarianConsider bilateral salpingo-oophorectomy.1, 12Age 40 or after completion of childbearingNA
Consider transvaginal ultrasound and CA-125 measurement.1, 1230 to 35 yearsNA
Consider options for ovarian cancer risk-reduction agents (i.e. oral contraceptives).1, 16IndividualizedNA
Patient education about ovarian cancer symptoms1IndividualizedNA
GastricConsider testing and treating Helicobacter pylori infection.12IndividualizedNA
Consider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry. Consider biopsy of the antrum.1, 12, 15, 2130 to 40 yearsEvery 2 to 5 years
Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history.1, 12, 1530 to 40 yearsEvery 3 to 5 years
Urinary TractConsider urinalysis.1, 1230 to 35 yearsAnnually
PancreaticFor patients with a family history of pancreatic cancer, consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in screening for pancreatic cancer, preferably within research protocols.15, 18Age 50, or 10 years younger than the earliest age of pancreatic cancer diagnosis in the familyAnnually
Provide education about ways to reduce pancreatic cancer risk, such as not smoking and losing weight.15, 17IndividualizedIndividualized
Central Nervous SystemPhysical/neurological examination125 to 30 yearsAnnually
ProstateCurrently there are no specific medical management guidelines for prostate cancer risk in mutation carriers. However, the possibility of an increased risk for prostate cancer can be incorporated into the risk and benefit discussion about offering screening with digital rectal examination (DRE) and Prostate Specific Antigen (PSA).1, 1945 years, or youngerIndividualized
Hepatobiliary TractCurrently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers.1NANA
Sebaceous NeoplasmsCurrently there are no specific medical management guidelines for sebaceous neoplasm risk in mutation carriers.NANA
For Patients With A Cancer DiagnosisFor patients with a gene mutation and a diagnosis of cancer, targeted therapies may be available as a treatment option for certain tumor types (e.g., antibodies to PD-1)20NANA

Information for Family Members

The following information for Family Members will appear as part of the MMT for a patient found to have a mutation in the EPCAM gene.

A major potential benefit of myRisk genetic testing for hereditary cancer risk is the opportunity to prevent cancer in relatives of patients in whom clinically significant mutations are identified. Healthcare providers have an important role in making sure that patients with clinically significant mutations are informed about the risks to relatives, and ways in which genetic testing can guide lifesaving interventions.

Parents who are concerned about the possibility of passing on an EPCAM mutation to a future child may want to discuss options for prenatal testing and assisted reproduction techniques, such as pre-implantation genetic diagnosis (PGD).1

References

  1. Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 3.2019. Dec 13. Available at http://www.nccn.org.
  2. Ryan S, et al. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014 23:437-49. PMID: 24425144.
  3. Kempers MJ, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet. Oncol. 2011 12:49-55. PMID: 21145788.
  4. Grindedal EM, et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev. 2009 18:2460-7. PMID: 19723918.
  5. Raymond VM, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013 31:1713-8. oi: 10.1200/JCO.2012.44.1238. Epub 2013 Mar 25. PMID: 23530095.
  6. Kohlmann W, Gruber SB. Lynch Syndrome. 2018 Apr 12. In:Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390.
  7. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731.
  8. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626.
  9. Joost P, et al. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations. Urology. 2015 86:1212-7. PMID: 26385421.
  10. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.
  11. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444.
  12. Giardiello FM, et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014 109:1159-79. PMID: 25070057.
  13. Fast Stats: An interactive tool for access to SEER cancer statistics. Surveillance Research Program, National Cancer Institute. https://seer.cancer.gov/faststats. (Accessed on 1-2-2017)
  14. M\u00f8ller P, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2017 [Epub ahead of print] PMID: 28754778.
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Last Updated on 10-Dec-2020