Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy

Abstract

PURPOSE Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

A one‐stop approach to diagnosing hereditary colorectal cancer in the Chinese population

“…These findings indicate that the existing guidelines and consensus could miss those patients who have an HCRC. The results were consistent with previous studies indicating that following clinical guidelines would miss more than half of germline variants based on pan‐cancer analysis 14,15 …”

“…However, whether CRC tumors without matched normal tissue/WBCs could be used to predict germline variants and diagnose HCRC using next‐generation sequencing (NGS) remains elusive. Several previous studies have demonstrated that guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes 14,15 . A pan‐cancer study has indicated that more than 50% of cancer patients harbor P/LP germline variants without a family history or phenotype 14 .…”

Identification of germline cancer predisposition variants during clinical ctDNA testing

“…Tumor next generation sequencing (NGS) has become commonplace in routine clinical practice for patients with a variety of malignancies to help identify potential drug targets. We, and others, have demonstrated that in the process of tumor NGS approximately 3–13% of patients are found to harbor incidental germline pathogenic variants 1 – 7 . While not the goal of tumor NGS, these findings can have major implications for healthy family members 8 .…”

Ordering and Interpreting Precision Oncology Studies for Adults With Advanced Solid Tumors: A Primer

“…Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration. 4,5 Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations.…”