Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations

Abstract

Purpose: Unlike advances in the genomics-driven precision treatment of cutaneous melanomas, the current poor understanding of the molecular basis of mucosal melanomas (MM) has hindered such progress for MM patients. Thus, we sought to characterize the genomic landscape of MM to identify genomic alterations with prognostic and/or therapeutic implications. Experimental Design: Whole-genome sequencing (WGS) was performed on 65 MM samples, including 63 paired tumor blood samples and 2 matched lymph node metastases, with a further droplet digital PCR-based validation study of an independent MM cohort (n ¼ 80). Guided by these molecular insights, the FDA-approved CDK4/6 inhibitor palbociclib was tested in an MM patient-derived xenograft (PDX) trial. Results: Besides the identification of well-recognized driver mutations of BRAF (3.1%), RAS family (6.2%), NF1 (7.8%), and KIT (23.1%) in MMs, our study also found that (i) mutations and amplifications in the transmembrane nucleoporin gene POM121 (30.8%) defined a patient subgroup with higher tumor proliferation rates; (ii) enrichment of structural variations between chromosomes 5 and 12 defined a patient subgroup with significantly worse clinical outcomes; (iii) over 50% of the MM patients harbored recurrent focal amplification of several oncogenes (CDK4, MDM2, and AGAP2) at 12q13-15, and this co-occurred significantly with amplification of TERT at 5p15, which was verified in the validation cohort; (iv) the PDX trial demonstrated robust antitumor effects of palbociclib in MMs harboring CDK4 amplification. Conclusions: Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution and identifies genomic aberrations that could facilitate the delivery of precision cancer treatments.

Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling

“…On the focal level, KIT, CCND1, CDK4, NOTCH2 amplification, CDKN2A/2B, and PTEN deletion were recurrently seen, in line with previous findings reported by others (Newell et al, ; Zhou et al, ). Noteworthy, amplification of CDK4/CCND1 was also more frequent in patients lacking common driver mutations in cutaneous melanomas (Cancer Genome Atlas, ).…”

“…In addition, we did not observe the concurrence of NOTCH2 and NRAS amplification as previously reported (Garman et al, ) despite the fact that both genes are located nearby on 1p. Lastly, NOTCH2 amplification was exclusive to acral melanomas in our data, although it has previously been reported in mucosal melanomas (Newell et al, ; Zhou et al, ), which may be attributed to the limited cohort size.…”

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

“…Malignant tumors are characterized by uncontrolled cell growth, which is mainly due to the dysregulated expression of cancer driver genes that regulate cell proliferation and differentiation. This includes gain of function mutations of oncogenes and functional deletion alterations of tumor-suppressor genes, or disabling of genome maintenance genes (Masuda and Kuwano, 2019;Zhou et al, 2019). Many studies have reported that RBPs show dysregulated expression in various human cancers (Dong et al, 2019;Soni et al, 2019;Velasco et al, 2019).…”

Canine tumor mutation rate is positively correlated with TP53 mutation across cancer types and breeds

“…We used 601 cases with WES data [11][12][13][15][16][17] for discovery, and 18 with WES data 18,23 and 91 with WGS data [18][19][20][21][22] for validation. We also compared our canine findings to those published for the corresponding human cancers 3,4,[24][25][26][27] . The study is described below.…”