Tumor-Based Genetic Testing and Familial Cancer Risk

Abstract

As genetic testing on somatic tumor tissue becomes a more routine part of personalized cancer treatment, a growing opportunity arises to identify hereditary germline variants within those results. These germline results can affect future cancer screening for both patients and their family members. Finding this germline information can be complicated as a result of differences between somatic and germline testing processes, nomenclature, and outcome goals (e.g., treatment impact). The goal of this review is to highlight differences between somatic and germline testing and outline a potential guide to allow for appropriate clinical interpretation of somatic testing results in order to better facilitate genetic counseling referrals and confirmatory germline testing.

Germline evaluation of patients undergoing tumor genomic profiling: An academic cancer center’s experience with implementing a germline review protocol

“…As previously described, our protocol was developed using published medical literature and did evolve with practice. Therefore, our GRP reflects similarities to several proposed processes that have been published (DeLeonardis et al, 2019;Forman & Sotelo, 2020;Li et al, 2020). However, several challenges were raised when implementing into clinical practice.…”

“…However, the VAF was not provided on FoundationOne® reports; therefore, it was not always available at the time of GRP review. When used, VAF of 40%-60% was highly suspicious of germline origin but no specific cutoffs were set as VAF is influenced by tumor heterogeneity, which can skew the VAF outside the expected range for heterozygosity (Forman & Sotelo, 2020;Li et al, 2020;Meric-Bernstam et al, 2016). Therefore, supplementary information was needed to make a final recommendation on whether an individual variant warranted a referral for GC.…”

“…When comparing the GRP to other proposed processes that were published after the GRP was developed, several of the same considerations were applied when reviewing TGP results. The GRP and other proposed processes all included review of the patient's personal and family history (DeLeonardis et al, 2019;Forman & Sotelo, 2020;Li et al, 2020). As previously reported, there are limitations and differences in methodology utilized to perform TGP, which can result in a germline P/LP variant being missed (Forman & Sotelo, 2020;Li et al, 2020).…”

“…The GRP and other proposed processes all included review of the patient's personal and family history (DeLeonardis et al, 2019;Forman & Sotelo, 2020;Li et al, 2020). As previously reported, there are limitations and differences in methodology utilized to perform TGP, which can result in a germline P/LP variant being missed (Forman & Sotelo, 2020;Li et al, 2020). Reasons a germline P/LP variant can be missed on TGP include germline variant filtering, differences in nomenclature, differences in the genes tested, differences in depth of sequencing, differences in coverage of genes analyzed, tumor heterogeneity, and acquired changes in the tumor (Forman & Sotelo, 2020;Li et al, 2020;Mroz & Rocco, 2016).…”

“…Currently, there are no formal consensus guidelines on how to identify patients who should be offered GT based on their TGP results. Several reviews and opinions on approaches have been written but little original research has been published on how the suggested process and points to consider are being put into clinical practice (DeLeonardis et al, 2019;Forman & Sotelo, 2020;Li et al, 2020).…”