Abstract
BackgroundMatched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. We report patient preferences for the return of additional germline results, and describe various gMAV scenarios delivered through a clinical genetics service.MethodsTumor profiling was offered to 1960 advanced cancer patients, of which 1556 underwent tumor-normal sequencing with multigene hotspot panels containing 20 cancer predisposition genes. All patients were provided with an IRB-approved consent for return of additional gMAVs.ResultsOf the whole cohort 94% of patients consented to be informed of additional germline results and 5% declined, with no statistically significant differences based on age, sex, race or prior genetic testing. Eight patients were found to have gMAVs in a cancer predisposition gene. Five had previously unidentified gMAVs: three in TP53 (only one fulfilled Chompret’s Revised criteria for Li-Fraumeni Syndrome), one in SMARCB1 in the absence of schwannomatosis features and one a TP53 variant at low allele frequency suggesting an acquired event in blood.ConclusionInterest in germline findings is high among patients who undergo tumor profiling. Disclosure of previously unidentified gMAVs present multiple challenges, thus supporting the involvement of a clinical genetics service in all tumor profiling programs.
Highlights
Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants in cancer predisposition genes
Here, we describe the integration of a clinical genetics service in a tumor profiling program not designed to actively seek nor comprehensively analyze germline medically actionable variants
The normal DNA analysis resulted in a variety of returnable additional findings, disclosed through the incorporation of a clinical genetics service within the research study and into the clinical care of these families
Summary
Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. Tumor profiling through generation sequencing (NGS) has facilitated precision cancer therapies by identification of actionable tumor variants to guide cancer patient management [1]. Genetic analysis of tumor tissue can detect both acquired (somatic) aberrations found exclusively in the cancer cells, and inherited (germline, constitutional) variants. Stjepanovic et al BMC Medical Genomics (2018) 11:65 tumor profiling programs have reported additional germline findings in actionable cancer predisposition genes with the frequency ranging between 4.3 and 17.5% of patients tested [8,9,10,11]. Tumor profiling programs may provide a new avenue to identify individuals with a cancer predisposition syndrome with implications on their clinical management and families
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