A Case-Based Approach to Understanding Complex Genetic Information in an Evolving Landscape

Abstract

The rapid integration of highly sensitive next-generation sequencing technologies into clinical oncology care has led to unparalleled progress, and yet these technological advances have also made genetic information considerably more complex. For instance, accurate interpretation of genetic testing for germline/inherited cancer predisposition syndromes and somatic/acquired pathogenic variants now requires a more nuanced understanding of the presence and incidence of clonal hematopoiesis and circulating tumor cells, with careful evaluation of pathogenic variants occurring at low variant allele frequency required. The interplay between somatic and germline pathogenic variants and awareness of distinct genotype-phenotype manifestations in various inherited cancer syndromes are now increasingly appreciated and can impact patient management. Through a case-based approach, we focus on three areas of particular relevance to the treating clinician oncologist: (1) understanding clonal hematopoiesis and somatic mosaicism, which can be detected on germline sequencing and lead to considerable confusion in clinical interpretation; (2) implications of the detection of a potentially germline pathogenic variant in a high-penetrance cancer susceptibility gene during routine tumor testing; and (3) a review of gene-specific risks and surveillance recommendations in Lynch syndrome. A discussion on the availability and difficulties often associated with direct-to-consumer genetic testing is also provided.