PROFESSIONAL

67 Hereditary Cancer-related Genes and Cancer Risk

When multiple cases of cancer occur in a family, it is necessary to consider whether the family members are exposed to a shared intrinsic risk factor due to the inheritance of cancer-related gene mutations.

What are Hereditary Cancers?

Approximately 5–10% of cancers are caused by inherited genetic mutations.¹ In addition to BRCA1/2 mutations, which are widely known to increase the risk of breast, ovarian, pancreatic and prostate cancer, mutations in many other hereditary cancer-related genes also increase the lifetime risk of cancer by up to 90 times as compared to the general population (Figure 1).^2-5

Although hereditary cancers constitute a small proportion of all cancer cases, they should not be overlooked. Many of the cancer-stricken families carry susceptibility or predisposing genes which are passed down in the family across multiple generations. Based on the penetrance rate, these genes can be classi?ed as either high penetrance, moderate penetrance, or low penetrance.⁶ Patients with moderate-to-high penetrance genes have a signi?cantly higher risk of developing cancer. Therefore, in accordance with the recommendations of the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guideline, cancer screening, monitoring, and intervention need to be performed early. Indeed, a study in 2017 found that the incidence of colorectal cancer could be reduced if patients with these susceptibility gene (e.g., MLH1, MSH2, MSH6, PMS2) mutations underwent regular colonoscopy and polyps removal, which were found to decrease the mortality rate by a staggering 65%.⁷

How are cancer susceptibility genes inherited?

Patients with a hereditary cancer usually have a family history of cancer. Therefore, it is important to consider both the paternal and maternal lines of inheritance. Using hereditary breast and ovarian cancer syndrome (HBOCS) as an example, BRCA1 mutations are inherited in an autosomal dominant fashion (Figure 2). As such, each of the siblings or children would have a 50% chance of carrying the mutant BRCA1 gene from the parent, which predisposes them to the development of hereditary cancers. Therefore, the occurrence rate of these cancers in the affected family would be comparatively higher than others. The onset of these cancers may also be earlier compared to the average age of onset of the respective cancers. Since each hereditary cancer has different characteristics, it is highly recommended that genetic counselling is conducted by a trained professional before and after the tests.

 

References

1. NIH, Genetic Testing for Inherited Cancer Susceptibility Syndromes

2. Kuchenbaecker, KB, et al. JAMA. 2017;317(23):2402–2416.

3. NCCN Guidelines: Genetic/Familial High-Risk Assessment: Colorectal (2019. V3)

4. NCCN Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian (2020. V1)

5. NCCN Guidelines: Gastric Cancer (2017. V3)

6. Semin Oncol. 2016 Oct;43(5):528-535

7. Emma Steel, et al. Hered Cancer Clin Pract. 2017;15:1