NTHL1 Gene Mutations

NTHL1 ASSOCIATED CANCER RISKS

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Additional Information

NTHL1 Monoallelic gene

Associated Syndrome Name: Carrier Status for NTHL1-associated Cancer Risk

NTHL1 Monoallelic gene Overview

Carrier Status for NTHL1-associated Cancer Risk 1, 2, 3, 4
  • Individuals with a mutation in only one copy of the NTHL1 gene (a monoallelic mutation) are not believed to have any increased risk for cancer over people in the general population.
  • Individuals with mutations in both of their copies of the NTHL1 gene (biallelic mutations) have a condition known as NTHL1-associated cancer risk, which is believed to result in large numbers of colorectal polyps and an increased risk for colorectal cancer, as well as possible increased risks for other cancers. This patient does not have a diagnosis of NTHL1-associated cancer risk, but may have relatives who are at risk for this condition. Please see the Information for Family Members section below for details.
  • Currently there are no medical management guidelines for patients with a single NTHL1 mutation. However, this may change as we learn more, and therefore patients with monoallelic NTHL1 mutations may benefit from consultation with healthcare providers who have expertise in medical genetics and the care of patients with hereditary cancer syndromes.

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 NTHL1 Monoallelic 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.

This patient carries a single NTHL1 mutation (monoallelic). This patient's relatives are at risk for carrying a single NTHL1 mutation, or mutations in both copies of NTHL1 (biallelic). Relatives who have inherited mutations in both copies of NTHL1 have an increased risk for colorectal and possibly other cancers. Genetic testing may be appropriate for close family members to determine whether they are at an increased risk for colorectal and other cancers.

References

  1. Kuiper RP, et al. NTHL1 defines novel cancer syndrome. Oncotarget. 2015 6:34069-70. PMID: 26431160.
  2. 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.
  3. Weren RD, et al. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018 244:135-142. PMID: 29105096
  4. Belhadj S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin Gastroenterol Hepatol. 2017 15:461-462. PMID: 27720914.
Last Updated on 10-Dec-2020

NTHL1 Biallelic gene

Associated Syndrome Name: NTHL1-associated Cancer Risk

NTHL1 Biallelic Summary Cancer Risk Table

Cancer Genetic Cancer Risk
ColorectalElevated Risk
Female BreastElevated Risk

NTHL1 Biallelic gene Overview

NTHL1-associated Cancer Risk 1, 2, 3, 4, 5
  • Mutations in both copies of the NTHL1 gene (biallelic mutations) have been found in individuals with approximately 10 to 50 colorectal polyps. These polyps are mostly adenomas, which are associated with an increased risk for colorectal cancer. Although there are as yet no precise estimates of the colorectal cancer risk associated with biallelic NTHL1 mutations, it is believed that this risk is significantly increased over that in the general population.
  • Recent studies have found that women with biallelic mutations in NTHL1 have an increased risk for breast cancer, including a possibly increased risk for multiple primary diagnoses. Although there are as yet no precise estimates of this risk, it may be significantly increased over the risk for women in the general population.
  • The small number of individuals identified to date with biallelic NTHL1 mutations have often been diagnosed with other types of cancer as well as colorectal and breast cancer. However, more studies are needed to determine the types of cancer associated with biallelic NTHL1 mutations and the exact size of the risks. At this time there are no professional society guidelines for the management of these additional possible cancer risks.
  • Although there are increased risks for cancer in individuals with biallelic NTHL1 mutations, it may be possible to reduce these risks with appropriate medical management. Guidelines for the medical management of individuals with biallelic NTHL1 mutations have been developed by the National Comprehensive Cancer Network (NCCN). These are listed below. These guidelines will evolve as we learn more, and it is recommended that patients with biallelic NTHL1 mutations be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with hereditary cancer syndromes.

NTHL1 Biallelic gene Cancer Risk Table

Cancer Type Age Range Cancer Risk Risk for General Population
ColorectalTo age 801, 2, 6Elevated risk3.0%
Female BreastTo age 804, 6Elevated risk10.2%

NTHL1 Biallelic 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)
ColorectalColonoscopy325 to 30 yearsEvery 2 to 3 years
Colorectal surgical evaluation and counseling.3Based on cancer diagnosis and/or polyp number, size and histologyNA
Female BreastCurrently there are no specific medical management guidelines for female breast cancer risk in biallelic mutation carriers. However, the possibility of an increased risk for breast cancer warrants consideration of individualized breast cancer risk-reduction strategies, such as the modification of standard population screening recommendations by starting screening at younger ages and/or performing screenings at greater frequency.7, 8NANA

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 NTHL1 Biallelic 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.

Since this patient has mutations in both copies of the NTHL1 gene, it is almost certain each of their parents and all of their children carry at least one of these NTHL1 mutations. Brothers and sisters are at very high risk for carrying either one or two NTHL1 mutations. The cancer risk table that follows provides cancer risks for men and women with mutations in both copies (biallelic) of the NTHL1 gene. These risks do not apply to relatives who have inherited only a single NTHL1 mutation (monoallelic).

References

  1. Kuiper RP, et al. NTHL1 defines novel cancer syndrome. Oncotarget. 2015 6:34069-70. PMID: 26431160.
  2. Belhadj S, et al. Delineating the Phenotypic Spectrum of the NTHL1-Associated Polyposis. Clin Gastroenterol Hepatol. 2017 15:461-462. PMID: 27720914.
  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. Grolleman JE, et al. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. Cancer Cell. 2019 35:256-266. PMID: 30753826.
  5. Weren RD, et al. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018 244:135-142. PMID: 29105096
  6. 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)
  7. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 1.2019. May 17. Available at http://www.nccn.org.
  8. 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.
Last Updated on 10-Dec-2020