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Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
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Journal Article
Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
2020
Overview
Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in
CDKN2A
,
CDK4
,
ATM
,
POLH
,
MRE11A
,
RECQL4
and
XPC
, affecting 7/44 patients. These mutations were associated with poor OS (
p
= 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (
p
= 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (
p
= 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb;
p
= 0.0034) and BRAF
p
.V600 mutation (
p
= 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (
p
= 0.0155). This was confirmed in the TCGA (n = 443,
p
= 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).
Publisher
Nature Publishing Group UK
Subject
