Hereditary Cancers: How to Improve Your Odds in This Game of Roulette

Several hereditary mutations have been identified since we noticed the relationship between genetic alteration and cancer formation. Knowing the type of genetic alteration involved will assist in making a wise risk-management choice. However, some questions remain. For example, should everyone receive genetic testing? How should one interpret the testing results?

Hereditary Cancer and Cancer Predisposition Genes

Cancer is a multifaceted disease that is influenced by genetic and environmental factors. The forms of cancer can be divided into three broad categories. First, hereditary cancer, which accounts for 5–10% of all cancer types, is caused by a germline mutation. Germline mutations occur in a reproductive cell (egg or sperm) and can be passed from parent to offspring so that every cell of the offspring will be affected. It is typical with hereditary cancer to see a recurring pattern across two to three generations, such as multiple individuals being diagnosed with the same type of cancer. Second, familial cancer, which accounts for 10–20% of all cancer types, refers to similar cancer that appears in the family arising from shared factors, such as environment and lifestyle, but no specific mutations have been linked to such cancers. Third, sporadic cancer, which accounts for 70–85% of all cancer types, is caused by a somatic mutation that occurs in a single somatic cell and which can neither be inherited nor passed on; that is, only the individual possessing the mutated cell is affected. Several factors, such as ageing, lifestyle, or environmental exposure, may contribute to the development of sporadic cancer.^1,2

Many cancer-predisposing traits are inherited in an autosomal dominant fashion; that is, cancer susceptibility occurs when only one copy of the altered gene is inherited. As such, each of the siblings or children would have a 50% chance of carrying the mutation from the parent, which predisposes them to the development of hereditary cancers.

Currently, genetic mutations have been associated with more than 50 hereditary cancer syndromes, which are disorders that may predispose individuals to develop certain cancers (Table 1).³ Individuals with genetic mutations are at higher risk of developing certain types of cancer and having earlier-onset cancer compared with the general population. For example, people who carry BRCA mutations have a higher risk of developing breast, pancreatic, and ovarian cancer compared with the general population (Figure 1). Others, such as CDH1- and MMR-related gene mutations, are closely associated with gastric and colorectal cancer risk, respectively, and CDK4/CDKN2A mutations cause an increased risk of developing melanoma. Hence, genetic testing can help to identify whether an individual harbours pathogenic mutations, and, based on the result, can be used to provide clinical implications such as disease surveillance and clinical management. Moreover, the information can also help family members to plan for their health management in the future.

Although hereditary cancers constitute a small proportion of all cancer cases, they should not be overlooked. Many factors influence whether an individual with the mutated gene will develop cancer. One factor is the penetrance of the mutated gene, which can be used for further classification into high, moderate, and low-risk genes to reveal the relative risk of developing cancer. High-penetrance genes, such as BRCA1/2, TP53, and PTEN, confer a high relative risk for cancer development (greater than four times that of the general population). Moderate-penetrance genes, such as ATM, CHEK2, and RAD51C, increase the risk of cancer development by two to four times compared with that of the general population. Low-penetrance genes, such as RAD50, MRE11, and XRCC2, are related to a less than double the risk of cancer development.⁴ High- and moderate-penetrance genes are currently proposed for cancer predisposition testing and specific clinical management recommendations for patients.^5,6

Following the recommendations of the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines, cancer screening, monitoring, and intervention for different cancers need to be performed early to reduce the risk of cancer. To further illustrate this information, we will focus on two major hereditary cancer types in the following sections.

BRCA1- and BRCA2-Related Cancers

The risk of breast cancer in the general population is nearly 7%. However, a female individual who harbours either a germline BRCA1 or BRCA2 mutation has an 85% chance of developing breast cancer during her lifetime.⁵ Additionally, the BRCA1/2 mutation also results in higher lifetime risk of ovarian cancer. In contrast to the 0.7% chance for ovarian cancer in the general population, the chance of developing ovarian cancer for BRCA1 and BRCA2 mutation carriers is 63% and 27%, respectively.

Moreover, breast cancer patients with the BRCA mutation also have a higher risk of second primary cancers in the other breast and ovary when compared with those without the BRCA mutation. The likelihood for a carrier of a BRCA1/2 mutation to develop second primary breast cancer increases from 5–10% to 10–30% within the first ten years after the initial breast cancer diagnosis.⁷ Similarly, if a breast cancer patient harbours a BRCA1 or BRCA2 mutation, she has a 12.7% or 6.3% chance of another primary cancer in the ovary within ten years.⁸ This risk is significantly higher than the general breast cancer population. Taken together, inherited BRCA1 and BRCA2 mutations are closely associated with the development of hereditary breast and ovarian cancer in women.

Because of the higher risk of having breast cancer and ovarian cancer, individuals with the BRCA1/2 mutation may require enhanced medical management, such as a higher frequency of surveillance and even a risk-reducing surgery. Certain cancer risk management strategies have been demonstrated to prevent cancer occurrence and significantly reduce mortality. For carriers of the BRCA1 mutation who choose no intervention, which means no routine breast screening, no prophylactic mastectomy (PM), and no prophylactic oophorectomy (PO), the likelihood of survival to age 70 is 53%.⁹ However, the survival is dramatically increased to 79% with PM at age 25 and PO at age 40. Additionally, breast screening from ages 25 to 69 plus PO at age 40 also demonstrated a gain in survival probability of 21% compared with no intervention (that is, 74% vs. 53%). Likewise, those risk-reducing interventions also enhanced the survival probability of carriers with inherited BRCA2 mutations. The survival probability for no intervention, PM at age 25 plus PO at age 40, and breast screening plus PO at age 40 is 71%, 83%, and 80%, respectively. Therefore, carriers of the BRCA mutation would have similar survival as the general population once they have the right interventions.

Lynch Syndrome

Lynch Syndrome is mainly caused by heredity mutations in DNA mismatch repair (MMR)-related genes, which include MSH2, MSH6, MLH1, and PMS2. As a result, carriers of LS have a much higher lifetime risk of colorectal cancer (60–80% for men; 40–60% for women) and endometrial cancer (up to 71%) compared with the general population (3–5% for both cancer types).^6,10 Among the MMR genes, MSH2 and MLH1 mutations have substantial effects on cancer risk. Additionally, LS elevates the risk of ovarian cancer (10–15%). A cancer patient with LS is also at increased risk of developing a second primary cancer. The likelihood increases up to 50% within 15 years after the first diagnosis of cancer, whereas the risk of developing a second cancer is only approximately 5% in the general population.¹¹

Because carriers of LS have a higher risk of certain cancers, frequent surveillance may help in the early detection of LS-associated cancers and enhance the survival rate. A previous study has demonstrated that colonoscopic and gynaecological surveillance performed at two-year intervals or more frequently for early diagnosis of cancer resulted in excellent post-diagnosis survival for LS patients.¹² The 10-year survival by cancer type is 91%, 98%, and 89% for colorectal, endometrial, and breast cancer, respectively. Despite not significantly increasing the survival rate, a risk-reducing surgery, such as hysterectomy and bilateral salpingo-oophorectomy, resulted in a decreased risk for developing endometrial cancer and ovarian cancer in LS patients.¹³ If a risk-reducing hysterectomy is performed by age 40, the risk of endometrial cancer before age 70 would be reduced by 34%, 45%, 40%, and 13% in patients with a hereditary mutation in MLH1, MSH2, MSH6, and PMS2, respectively. Likewise, performing bilateral salpingo-oophorectomy by age 40 reduces the risk of ovarian cancer before age 70. The risk prevention is 9% for patients with an MLH1 mutation, 16% for those with an MSH2 mutation, 9% for those with an MSH6 mutation, and 3% for those with a PMS2 mutation. Accordingly, cancer surveillance and risk-reducing surgery would benefit LS patients.

Who Should Be Tested and How to Interpret the Test Results

Although cancer predisposition genes are closely correlated to cancer risk, not everyone needs to evaluate their genetic risk. Specific scenarios are suggested by the NCCN guidelines.^5,6 The highlights for who should determine their risk are as follows:

• Those with multiple family members who have cancer;
• Those with a family member who has multiple cancers, early-onset cancer, or rare cancer;
• Any individual who is concerned about the inherent risk of hereditary cancers and cancer syndromes.

With regards to the test results, not all the tested individuals will have a hereditary genetic mutation even though they both meet the hereditary genetic testing criteria. Although the test outcomes will differ by populations and the selected gene list, there are only three possible testing results: a positive result, a negative result, or a variant of uncertain significance (VUS). Positive results (a pathogenic/likely pathogenic variant has been identified) account for 6–22% of all testing reports, which indicates an increased risk of developing a particular cancer in the future and guides future risk management.^14,15 In contrast, VUS accounts for 28–35%, indicating unknown effects on gene function and is typically not considered when making healthcare decisions. Lastly, 40–65% of cases are negative for mutations in any of the cancer predisposition genes tested.

How to Perform Hereditary Genetic Testing and Cancer Risk Assessment (Figure 2)¹⁶

Conclusion

Based on the information provided above, hereditary genetic alterations are closely associated with the risk of developing several types of cancer. However, not all individuals require genetic testing. A comprehensive pre-test evaluation is essential for individuals who intend to have genetic testing. Moreover, post-test counselling is necessary for the unaffected/affected individuals and even their families. Once everything is prepared, hereditary genetic testing helps people understand any hereditary genetic alteration they have and improve their risk management strategy. [APBN]

References

1. Nagy, R. et al. (2004) Highly penetrant hereditary cancer syndromes. Oncogene, 23(38), 6445-70. DOI: 10.1038/sj.onc.1207714.
2. Rahner, N. et al. (2008) Hereditary cancer syndromes. Dtsch Arztebl Int, 105(41), 706-14. DOI: 10.3238/arztebl.2008.0706.
3. NIH: Genetic Testing for Inherited Cancer Susceptibility Syndromes.
4. Tsaousis, G.N. et al. (2019) Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer, 19(1), 535. DOI: 10.1186/s12885-019-5756-4.
5. National Comprehensive Cancer Network. (2021) Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 2. 2021). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf.
6. National Comprehensive Cancer Network. (2021) Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal (Version 1. 2021). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf.
7. Kuchenbaecker, K.B. et al. (2017) Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA, 317(23), 2402-2416. DOI: 10.1001/jama.2017.7112.
8. Schilder, R.J. et al. (2005) Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol, 96(1), 103-7. DOI: 10.1016/j.ygyno.2004.09.027.
9. Kurian, A.W. et al. (2010) Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol, 28(2), 222-31. DOI: 10.1200/JCO.2009.22.7991.
10. Mehta A. & Gupta G. (2018) Lynch syndrome—It’s time we start detecting it. J Curr Oncol, 1, 55-60. DOI: 10.4103/JCO.JCO_26_18.
11. Strafford J.C. (2012) Genetic Testing for Lynch Syndrome, an Inherited Cancer of the Bowel, Endometrium, and Ovary. Rev Obstet Gynecol, 5(1), 42-49.
12. Møller, P. et al. (2017). Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut, 66(3), 464-472. DOI: 10.1136/gutjnl-2015-309675.
13. Dominguez-Valentin, M. et al. (2021). Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report. Genet Med, 23(4), 705-712. DOI: 10.1038/s41436-020-01029-1.
14. Rosenthal, E.T. et al. (2017). Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer genetics, 218-219, 58–68. DOI: 10.1016/j.cancergen.2017.09.003.
15. Tsaousis, G.N. et al. (2019). Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC cancer, 19(1), 535. DOI: 10.1186/s12885-019-5756-4.
16. NIH: Cancer Genetics Risk Assessment and Counseling.

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About the Authors

Dr. Chi-Jui Liu, Assistant Manager, Medical Affairs, ACT Genomics

 

 

 

Hsiao Yun Lu, Scientist, Medical Information Division, ACT Genomics