Germline Testing for the Evaluation of Hereditary Cancer Predisposition

Significance of Hereditary Cancer Predisposition Testing

Hereditary predisposition to develop solid tumors or hematologic malignancies has been considered to have a modest contribution to cancer incidence overall. 13141516 These estimates have long been biased because of the selection of individuals at high risk of having a hereditary cancer predisposition syndrome based on their clinical and family histories. In recent years, widening the pretest selection criteria led to the identification of cancer predisposition in individuals who do not meet current testing criteria, revealing that hereditary cancer predisposition is more prevalent than previously anticipated. 123 ^, 56789 ^, 11 , 12 Germline pathogenic variants that confer high to moderate cancer risk have been identified in 3% to 12% of adult and 8.5% to 10% of pediatric patients with a range of tumor types. 345 ^, 8 , 12

Determining whether an individual has a germline defect that increases their cancer risk and identifying the causative pathogenic variants have important implications for both patients and their family members. ^17 , 18 First, discovering at-risk individuals can allow timely screening and interventions to reduce future cancer risk. Second, certain gene defects are associated with treatment implications, such as increased toxicity to radiation therapy in TP53 carriers, ^19 , 20 or predicting response to targeted therapies, such as PARP inhibitors in BRCA1/BRCA2 carriers ²¹ or immune-checkpoint inhibitor therapies in carriers of mismatch repair pathway gene defects. ^22 , 23 In a recent cohort of patients who have cancer with high-penetrance pathogenic germline variants, 28.2% had clinically actionable management changes indicated by their germline variant. ⁹ Another recent universal genetic testing approach uncovered a germline variant with therapeutic actionability in 8% of patients with advanced cancer, ¹⁰ suggesting that germline testing may be highly informative to guide treatment strategies for patients with cancer. Third, identification of germline variants that predispose to cancer necessitates testing of potential donors for patients with hematologic malignancies to avoid inadvertently selecting an affected family member. ¹⁸ Finally, patients and family members can receive appropriate genetic counseling for reproductive planning.

Genetic Testing Criteria

In current practice, patients are selected for hereditary cancer predisposition testing in a guideline-based manner. Only individuals who meet established criteria from national medical organizations are offered genetic testing based on their cancer type, age of onset, and other clinical and/or family histories. ^17 , 18 , 242526 These guidelines are not static and are updated periodically as new data becomes available regarding the utility and expected yield of genetic testing for different patient groups. Of note, many cancer predisposition genes have incomplete penetrance and variable expressivity with a wide age of onset range, which poses challenges in identifying at risk individuals before testing, as their personal or family histories may not be significant. Most genes are associated with risk for cancer only. Although certain genes such as TSC2 and FANCA underlie syndromic presentations that may include developmental anomalies in addition to predisposition to cancer, carriers of such genes may have mild presentations that may be missed clinically. Therefore, universal testing strategies without pretest selection of patients have the potential to uncover hereditary cancer predisposition in individuals who do not meet current testing criteria.