Abstract
Abstract
Background
Acral and mucosal melanomas are aggressive subtypes of melanoma, which have a significantly lower burden of somatic mutations than cutaneous melanomas, but more frequent copy number variations, focused gene amplifications, and structural alterations. The landscapes of their genomic alterations remain to be fully characterized.
Methods
We compiled sequencing data of 240 human acral and mucosal melanoma samples from 11 previously published studies and applied a uniform pipeline to call tumor cell content, ploidy, somatic and germline mutations, as well as CNVs, LOH, and SVs. We identified genes that are significantly mutated or recurrently affected by CNVs and implicated in oncogenesis. We further examined the difference in the frequency of recurrent pathogenic alterations between the two melanoma subtypes, correlation between pathogenic alterations, and their association with clinical features.
Results
We nominated PTPRJ, mutated and homozygously deleted in 3.8% (9/240) and 0.8% (2/240) of samples, respectively, as a probable tumor suppressor gene, and FER and SKP2, amplified in 3.8% and 11.7% of samples, respectively, as probable oncogenes. We further identified a long tail of infrequent pathogenic alterations, involving genes such as CIC and LZTR1. Pathogenic germline mutations were observed on MITF, PTEN, ATM, and PRKN. We found BRAF V600E mutations in acral melanomas with fewer structural variations, suggesting that they are distinct and related to cutaneous melanomas. Amplifications of PAK1 and GAB2 were more commonly observed in acral melanomas, whereas SF3B1 R625 codon mutations were unique to mucosal melanomas (12.9%). Amplifications at 11q13-14 were frequently accompanied by fusion to a region on chromosome 6q12, revealing a recurrent novel structural rearrangement whose role remains to be elucidated.
Conclusions
Our meta-analysis expands the catalog of driver mutations in acral and mucosal melanomas, sheds new light on their pathogenesis and broadens the catalog of therapeutic targets for these difficult-to-treat cancers.
Funder
National Cancer Institute
Melanoma Research Alliance
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Cited by
16 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献