Whole-genome Landscape of Mucosal Melanoma Reveals Diverse Drivers and Therapeutic Targets

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jul 20

PMID 31320640

Citations 124

Authors

Felicity Newell

Yan Kong

James S Wilmott

Peter A Johansson

Peter M Ferguson

Chuanliang Cui

Zhongwu Li

Stephen H Kazakoff

Hazel Burke

Tristan J Dodds

Ann-Marie Patch

Katia Nones

Varsha Tembe

Ping Shang

Louise van der Weyden

Kim Wong

Oliver Holmes

Serigne Lo

Conrad Leonard

Scott Wood

QinYing Xu

Robert V Rawson

Pamela Mukhopadhyay

Reinhard Dummer

Mitchell P Levesque

Goran Jonsson

Xuan Wang

Iwei Yeh

Hong Wu

Nancy Joseph

Boris C Bastian

Georgina V Long

Andrew J Spillane

Kerwin F Shannon

John F Thompson

Robyn P M Saw

David J Adams

Lu Si

John V Pearson

Nicholas K Hayward

Nicola Waddell

Graham J Mann

Jun Guo

Richard A Scolyer

Affiliations

Soon will be listed here.

Abstract

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

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