CIViC is an expert-crowdsourced knowledgebase for Clinical Interpretation of Variants in Cancer describing the therapeutic, prognostic, diagnostic and predisposing relevance of inherited and somatic variants of all types. CIViC is committed to open-source code, open-access content, public application programming interfaces (APIs) and provenance of supporting evidence to allow for the transparent creation of current and accurate variant interpretations for use in cancer precision medicine.
Clinical response to immune checkpoint inhibitors (ICIs) varies significantly and the majority of studies into their effectiveness are focused on primary tumours of single histologies. This retrospective study utilises whole genome and transcriptome analysis (WGTA) to examine a pan-cancer cohort of advanced and previously treated patients which are currently underrepresented in the field, yet encompass a large proportion of cancer patients routinely seen in clinics. Our results reveal that tumour mutation burden and immune expression signatures are efficient at stratifying patients in this context, but suggest that PD-L1 testing may not be the most appropriate clinical biomarker for these patients. This study also demonstrates the benefit of measuring multiple markers simultaneously, highlighting the clinical utility of WGTA in selecting patients most likely to benefit from ICIs. Research.
We report a case of early-onset pancreatic ductal adenocarcinoma in a patient harboring biallelic
MUTYH
germline mutations, whose tumor featured somatic mutational signatures consistent with defective
MUTYH
-mediated base excision repair and the associated driver
KRAS
transversion mutation p.Gly12Cys. Analysis of an additional 730 advanced cancer cases (
N
= 731) was undertaken to determine whether the mutational signatures were also present in tumors from germline
MUTYH
heterozygote carriers or if instead the signatures were only seen in those with biallelic loss of function. We identified two patients with breast cancer each carrying a pathogenic germline
MUTYH
variant with a somatic
MUTYH
copy loss leading to the germline variant being homozygous in the tumor and demonstrating the same somatic signatures. Our results suggest that monoallelic inactivation of
MUTYH
is not sufficient for C:G>A:T transversion signatures previously linked to
MUTYH
deficiency to arise (
N
= 9), but that biallelic complete loss of
MUTYH
function can cause such signatures to arise even in tumors not classically seen in
MUTYH
-associated polyposis (
N
= 3). Although defective
MUTYH
is not the only determinant of these signatures,
MUTYH
germline variants may be present in a subset of patients with tumors demonstrating elevated somatic signatures possibly suggestive of
MUTYH
deficiency (e.g., COSMIC Signature 18, SigProfiler SBS18/SBS36, SignatureAnalyzer SBS18/SBS36).
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