Integrated genomic analyses of acral and mucosal melanomas nominate novel driver genes

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.

The genetic evolution of acral melanoma

“…The genomic regions affected by hailstorms were not randomly distributed across the genome but frequently involved chromosomes 5p (including TERT , RICTOR and SKP2 ), 11q (including CCND1 , PAK1 , GAB2 and YAP1 ), 12q (including CDK4 and MDM2 ) and 22q (including CRKL , SOX10 and EP300 ) ( Figs. 1b and S2 ), in line with prior genetic analyses of acral melanoma 6,7,17,18 . The non-random distribution of hailstorms with amplifications recurrently targeting known melanoma oncogenes indicates that these alterations are under positive selection.…”

“…A UV radiation signature, almost universally present in cutaneous melanomas, has been reported in a few instances of acral melanoma 7,18 . In our cohort, five melanomas showed evidence of mutational signature SBS7, characteristic of UV radiation.…”

Identifying new driver genes for castration resistance for prostate cancer based on protein mass spectrometry and transcriptome big data

“…Meta analysis and data mining on public papers, clinical reports etc. were widely used for identifying new driver gene searching as well as using transcriptome data and single cell sequencing for less studied elds [46][47][48][49][50][51][52] . While however, driver gene searching using integrated method of transcriptome big data, public information and protein mass spectrometry results simultaneously was not reported to our knowledge.…”

Activated Akt expression is associated with the recurrence of primary melanomas and further refines the prognostic and predictive values for relapse in acral melanomas

“…Acral melanomas arise at the palms and soles and have characteristic genomic aberrations such as CCND1 amplification (Consortium, 2020). Those genomic aberrations are clearly different from those of Low‐ cumulative sun damage (CSD) melanomas, which are characterized by a high mutational burden with an ultraviolet (UV) mutational signature (Alexandrov et al, 2020; Wang et al, 2022).…”