期刊
SCIENTIFIC REPORTS
卷 10, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-020-74956-3
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资金
- National Health and Medical Research Council of Australia (NHMRC) Early Career Fellowship [APP1109048]
- NHMRC Senior Research Fellowship [APP1139071]
- 2017 Priority-driven Collaborative Cancer Research Scheme
- Cure Cancer Australia
- Cancer Australia [1144639]
- Gallipoli Medical Research Foundation
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).
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