Detecting likely germline variants during tumor-based molecular profiling
Diana Jaber, Jessica Zhang, Lucy A. Godley
Diana Jaber, Jessica Zhang, Lucy A. Godley
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Review

Detecting likely germline variants during tumor-based molecular profiling

Abstract

As the use of molecular profiling of tumors expands, cancer diagnosis, prognosis, and treatment planning increasingly rely on the information it provides. Although primarily designed to detect somatic variants, next-generation sequencing (NGS) tumor-based profiling also identifies germline DNA alterations, necessitating careful clinical interpretation of the data. Traditionally, germline risk testing has depended on prioritizing individuals based on physical exam findings consistent with known hereditary cancer syndromes, tumor-specific features, age at diagnosis, personal history, and family history. As NGS-based molecular profiling is used increasingly to diagnose, prognosticate, and follow cancer progression, DNA variants that are likely to be of germline origin are identified with increased frequency. Because pathogenic/likely pathogenic germline variants are critical biomarkers for risk stratification and treatment planning, consensus guidelines are expanding to recommend comprehensive germline testing for more cancer patients. This Review highlights the nuances of identifying DNA variants of potential germline origin incidentally at the time of NGS-based molecular profiling and emphasizes key differences between comprehensive germline versus tumor-based platforms, sample types, and analytical methodologies. In the growing era of precision oncology, clinicians should be adept at navigating these distinctions to optimize testing strategies and leverage insights regarding germline cancer risk surveillance and management for all people with cancer.

Authors

Diana Jaber, Jessica Zhang, Lucy A. Godley

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Figure 1

DNA repair pathways and additional mechanisms underlying hereditary cancer risk.

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DNA repair pathways and additional mechanisms underlying hereditary canc...
(A) Defects in the homologous recombination repair (HRR) genes BRCA1 and BRCA2 impair the accurate repair of double-strand DNA breaks, resulting in error-prone mechanisms like single-strand annealing, alternative end joining, and non-homologous end joining, leading to increased genomic instability and the accumulation of somatic variants. HRR deficiency is associated with several tumor types, including breast, ovarian, prostate, and pancreatic cancers. (B) Defects in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 impair the repair of DNA replication errors, leading to microsatellite instability and genome-wide hypermutation. MMR deficiency is commonly associated with Lynch syndrome, predisposing individuals to a variety of cancers, including colorectal, endometrial, and ovarian cancers. Similar to HRR defects, MMR defects result in a mutator phenotype that drives tumorigenesis by allowing the accumulation of somatic variants. (C) Additional pathways implicated in hereditary cancer risk are shown, highlighting commonly altered cancer susceptibility genes recommended for further germline evaluation by the ACMG and the ESMO PMWG when identified on tumor-based profiling. Corresponding clinical phenotypes and penetrance estimates are detailed in Table 1.