Abstract 2895: MBD4 inactivation results in an alternative evolutionary route in uveal melanoma
Authors: Rodrigues Manuel , Mobuchon Lenha , Houy Alexandre , Alsafadi Samar , Gardrat Sophie , Piperno-Neumann Sophie , Cassoux Nathalie , Pierron Gaelle , Roman-Roman Sergio , Mariani Pascale , Stern Marc-Henri 
Published: August 2019

Abstract
Introduction
Uveal melanomas (UM) are chemoresistant tumors that carry few copy number variations (CNV) and a low mutation burden. Genomics of UM metastases have been scarcely described. We assessed genetic heterogeneity in UM at primary and metastatic stages, in order to evaluate if tumor heterogeneity may explain this chemoresistance.
Methods
Whole-exome sequencing of primary and metastatic UM tumors.
Results
We obtained 97 tumor samples from 26 patients (16 samples from 15 primary tumors and 81 samples from 50 metastases). MBD4 was inactivated in two cases (MBD4-deficient; MBD4def). All samples presented high variant allelic frequencies of UM driver mutations (Gαq pathway mutations, BAP1, SF3B1 and EIF1AX). Indeed, mutational statuses of these genes were identical between primary tumors and metastases, except for one MBD4def case that carried both SF3B1 and BAP1 mutations in the primary tumor, while the metastasis only carried a different BAP1 mutation. MBD4-proficient (MBD4pro) primary tumors presented a median of 11.5 single nucleotide variants (SNV; range 5-22); while MBD4pro metastases carried a median of 14 SNV (range 6-23) with a very high genetic homogeneity between samples. No mutation was recurrently acquired during the metastatic process. Metastases presented a higher number of copy number variations (CNV; median = 11; range 2-25) than matched primary (median = 5; range 2-18). Metastases-associated CNV were similar to that usually associated with UM primary tumors, including 8q gain, 1p loss, 1q gain, 6q loss and isodisomy 3. MBD4def samples were hypermutated with at least 266 mutations/sample (&gt;20-fold increase compared to MBD4pro) with &gt;70% of CpG&gt;TpG. MBD4def cases presented a higher heterogeneity with less than 60% of common SNV concordance between tumors in a given patient. No major difference in CNV profiles was observed between MBD4def and MBD4pro samples.
Conclusion
MBD4pro are homogeneous diseases that evolve as metastases with few non-recurrent SNV and recurrent UM-typical CNV. These characteristics lead to simple evolutionary trees with a limited number of short clades and branches, supporting a punctuated evolutionary process. Genetic heterogeneity thus cannot explain the resistance to chemotherapy. In contrast, MBD4 inactivation in UM results in genetic heterogeneity, subclonality and risk of secondary resistance to anticancer drugs.
Citation Format: Manuel Rodrigues, Lenha Mobuchon, Alexandre Houy, Samar Alsafadi, Sophie Gardrat, Sophie Piperno-Neumann, Nathalie Cassoux, Gaelle Pierron, Sergio Roman-Roman, Pascale Mariani, Marc-Henri Stern. MBD4 inactivation results in an alternative evolutionary route in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2895.