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Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients
- Source :
- Scientific Reports, Vol 10, Iss 1, Pp 1-11 (2020), Scientific Reports
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- 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 (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).
- Subjects :
- Adult
Male
Proto-Oncogene Proteins B-raf
Oncology
medicine.medical_specialty
Skin Neoplasms
lcsh:Medicine
Article
Germline
Tumour biomarkers
Germline mutation
CDKN2A
Internal medicine
Cancer genomics
Biomarkers, Tumor
medicine
Humans
Prospective Studies
lcsh:Science
Adverse effect
Cancer genetics
Melanoma
Germ-Line Mutation
Aged
Aged, 80 and over
Multidisciplinary
business.industry
lcsh:R
Middle Aged
Prognosis
medicine.disease
Survival Analysis
MRE11A
Cohort
Cutaneous melanoma
Female
lcsh:Q
business
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....95476bc3fa79b822027b0d80d93826da