The Role of Genetic Counseling in Familial and Sporadic Cancer: Considerations, Challenges, and Collaboration

Traditionally, genetic testing for inherited cancer risk has been limited to germline analysis for specific hereditary cancer syndromes (HCSs), such as BRCA1/2 testing for suspected hereditary breast or ovarian cancer syndrome and DNA mismatch repair (MMR) gene testing for suspected Lynch syndrome. With increasing capability and affordability of next-generation sequencing technology, commercial laboratories now offer an array of multigene panels that can analyze many cancer susceptibility genes in parallel (1). Further, precision medicine efforts in oncology are uncovering inherited mutations when tumor (somatic) sequencing is performed to identify mutational drug targets, and germline alterations themselves are increasingly being considered as therapeutic targets (2). Genetic counseling for inherited cancer risk is evolving rapidly to keep pace with these discoveries and improved technology. Classic HCS Evaluation Genetic counseling involves the comprehensive collection of a patient's personal and family medical history, tumor pathologic and molecular features, and prior genetic test results to determine the pretest probability of an HCS and guide confirmatory germline testing. A traditional counseling session involves discussion of cancer inheritance; genetic test options; risks, benefits, and limitations of testing; types of test results (pathogenic variant or mutation, variant of uncertain significance, or no mutation or variants); and potential consequences of identifying a pathogenic variant (for example, financial and reproductive implications) so that patients can make an informed decision about whether to proceed with testing (3). Identification of a pathogenic variant can provide information on additional cancer risks for which heightened screening or other risk-reduction measures may be considered. For example, pathogenic germline BRCA1 and BRCA2 variants increase risk for cancer of the breast, ovary, pancreas, and prostate and possibly melanoma, necessitating a discussion of screening strategies and specialist referrals. Affected persons with advanced cancer may have targeted therapeutic options, such as poly adenosine diphosphateribose polymerase inhibitors in BRCA1/2-associated cancer (4). A negative result in a patient from a family with no mutation identified is considered indeterminate or uninformative. Because other untested inherited factors cannot be completely ruled out, recommendations for cancer prevention and screening are typically based on personal and family history. Variants of uncertain significance are also reported to patients but currently have no management implications. However, because these variants can be reclassified as pathogenic or benign over time, patients should maintain contact with their cancer genetics program for updates as new information emerges. Because these considerations apply to each gene tested, multigene testing has considerably increased the complexity of genetic counseling. Molecular Testing Although clinical history, such as young age at cancer diagnosis or family history, can suggest inherited cancer risk, phenotypic and molecular features of tumors themselves often provide valuable clues about the presence of an underlying HCS. The most noteworthy example is Lynch syndrome, which is one of the most common HCSs in the general population and accounts for 3% of colorectal and 2% of endometrial cancer cases (5). Lynch syndrome is characterized by pathogenic germline alterations in 1 of the DNA MMR genes. Cancer in persons with this syndrome classically lacks effective DNA MMR function, resulting in marked accumulation of small insertion or deletion events at repetitive DNA sequences (primarily mono- and dinucleotide repeated sequences, such as An and [CA]n) throughout the tumor genome, which is a distinctive mutational fingerprint known as microsatellite instability (MSI) (6). Although MSI and MMR deficiency (MMR-D) can be found in many non-Lynch cancer cases, virtually all cases of Lynch syndromeassociated cancer have MSI and MMR-D. Therefore, routine tumor testing for MSI and MMR-D is highly sensitive for detecting underlying Lynch syndrome. Studies have consistently found that universal screening of patients with colorectal cancer using polymerase chain reactionbased MSI testing or immunohistochemistry for MMR-D is efficient, feasible, cost-effective, and markedly more sensitive than clinical history for identifying Lynch syndrome (5). Such universal tumor testing is also now being widely implemented to screen patients with endometrial cancer for Lynch syndrome (7). For persons with colorectal, endometrial, or other cancer found to have MSI or MMR-D, germline testing for underlying Lynch syndrome is typically recommended, unless the tumor specimen has other molecular features that indicate a non-Lynch cause (for example, somatic hypermethylation of the MLH1 promoter) (5). Intriguingly, recent data have shown that characteristic insertion or deletion events associated with MSI result in an abundance of immunogenic neopeptides in these tumors. This has led to the discovery that MSI and MMR-D status strongly predicts therapeutic benefit from immune checkpoint inhibitors, regardless of whether Lynch syndrome is present (8). The use of mutational signatures to both identify an underlying HCS and guide targeted therapeutics is expanding into BRCA1/2-associated cancer and other forms of inherited cancer susceptibility (9). Precision Medicine Recently, many academic and commercial laboratories have begun offering tumor DNA sequencing to identify somatic variants that may be targeted with approved or investigational agents. Most laboratories sequence a tumor sample alone, although a few simultaneously sequence a matched normal (that is, germline) sample. When only the tumor is tested, inherited genetic variants will necessarily be reflected in the DNA sequence. Mutations detected in tumors could therefore represent germline mutations, which may have implications for patients' families and possibly the patients themselves. Clinicians ordering tumor sequencing must decide whether identified variants are likely to represent germline mutations that should be confirmed in a separate sample of normal DNA. Although allelic fraction and phenotype concordance may help the clinician make that determination, recent studies suggest that nearly 10% of patients with advanced cancer may have pathogenic, actionable germline variants that would not have been identified under existing guidelines for clinical testing (10). Many, and perhaps most, patients with pathogenic variants identified on tumor sequencing should therefore be referred to genetic specialists for germline testing. This workflow can be avoided by routine secondary testing of a normal DNA sample if the laboratory does tumor-normal sequencing. However, this creates logistic challenges in obtaining appropriate pretest consent and posttest follow-up in all patients because, to date, the primary purpose of tumor sequencing has been to direct treatment rather than to identify cancer susceptibility. The distinction is blurring with the advent of poly adenosine diphosphateribose polymerase inhibitors as therapy for patients with germline defects in BRCA1, BRCA2, and other genes involved in homologous recombination DNA damage repair, providing a further argument for routine secondary germline sequencing (4). Conclusion Internists play a critical role in identifying patients who may be predisposed to cancer and could benefit from genetic consultation. Key features that might indicate an inherited cancer predisposition include young age at cancer diagnosis, several types of cancer in 1 person, or clustering of cancer types in a family. Close collaboration between internists and cancer genetics programs is vital to provide genetic evaluation and tailored screening and management options for the benefit of patients and their families.