Genetics and Genomics in Oncology Flashcards

A 34-year-old woman is found to carry a BRCA1 pathogenic variant. Which of the following risk-reduction surgical interventions has the strongest evidence for reducing ovarian cancer mortality in BRCA1 carriers?

Answer: Risk-reducing salpingo-oophorectomy (RRSO) after completion of childbearing

RRSO significantly reduces ovarian cancer risk by approximately 80–96% in BRCA1 carriers and is the most effective risk-reduction strategy recommended after childbearing is complete. Surveillance alone has not been shown to reduce mortality. Hysterectomy without oophorectomy does not address ovarian cancer risk. Oral contraceptives reduce risk modestly but are not a substitute for surgical intervention in high-risk carriers.

Which hereditary cancer syndrome is characterized by mismatch repair (MMR) gene mutations and confers a markedly elevated lifetime risk of colorectal and endometrial cancers?

Answer: Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Lynch syndrome is caused by germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) and accounts for the most common hereditary colorectal cancer syndrome. Lifetime colorectal cancer risk can reach 80% and endometrial cancer risk 40–60%. FAP involves APC mutations and thousands of polyps. Li-Fraumeni involves TP53. Cowden involves PTEN and thyroid/breast risk.

When reviewing a solid tumor's comprehensive genomic profiling (CGP) report, which finding would most directly guide selection of a PARP inhibitor as targeted therapy?

Answer: Homologous recombination deficiency (HRD) or BRCA1/2 somatic mutation

PARP inhibitors exploit synthetic lethality in tumors with defective homologous recombination repair, most commonly caused by BRCA1/2 mutations or HRD. TMB-H and MSI-H guide immunotherapy selection (pembrolizumab). High PD-L1 also guides checkpoint inhibitor use. HRD/BRCA mutation status is the biomarker predictive of PARP inhibitor response.

A patient with newly diagnosed colorectal cancer has a tumor showing loss of MLH1 protein expression on immunohistochemistry. What is the most appropriate next step to determine if this is due to a hereditary cause?

Answer: Test the tumor for BRAF V600E mutation and MLH1 promoter hypermethylation first

Isolated MLH1 loss on IHC is most often caused by somatic MLH1 promoter hypermethylation (sporadic) rather than a germline mutation. Testing the tumor for BRAF V600E and/or MLH1 methylation first differentiates sporadic from hereditary cases, avoiding unnecessary germline testing in the majority of patients. If methylation is absent and BRAF is wild-type, germline testing is then indicated.

When counseling a patient about germline genetic testing results, which element of informed consent is most critical to address specifically in the oncology genetics context?

Answer: Implications for at-risk biological relatives and potential psychosocial impact

A unique feature of germline genetic testing is that results have direct implications for the patient's biological relatives (family members share 50% of DNA). Pre-test counseling must explicitly address the hereditary nature of results, the duty to disclose to at-risk relatives, and potential psychosocial distress. While cost and accreditation matter, they are not the most distinguishing ethical element of genetics counseling.

A patient's tumor molecular profile shows an NTRK fusion. Which class of targeted therapy is specifically approved based on this tumor-agnostic biomarker, regardless of histology?

Answer: TRK inhibitors (e.g., larotrectinib, entrectinib)

Larotrectinib and entrectinib are FDA-approved as tumor-agnostic therapies for any solid tumor harboring an NTRK gene fusion, regardless of where the cancer originated. This represents a paradigm shift toward biomarker-driven, histology-independent treatment. CDK4/6 inhibitors target cell cycle in hormone-receptor-positive breast cancer. Bevacizumab targets angiogenesis. MEK inhibitors target the MAPK pathway.