Loss of Chromosome Y Leads to Down Regulation of KDM5D and KDM6C Epigenetic Modifiers in Clear Cell Renal Cell Carcinoma

Overview

Journal Sci Rep

Specialty Science

Date 2017 Mar 24

PMID 28332632

Citations 33

Authors

Madeleine Arseneault

Jean Monlong

Naveen S Vasudev

Ruhina S Laskar

Maryam Safisamghabadi

Patricia Harnden

Lars Egevad

Nazanin Nourbehesht

Pudchalaluck Panichnantakul

Ivana Holcatova

Antonin Brisuda

Vladimir Janout

Helena Kollarova

Lenka Foretova

Marie Navratilova

Dana Mates

Viorel Jinga

David Zaridze

Anush Mukeria

Pouria Jandaghi

Paul Brennan

Alvis Brazma

Jorg Tost

Ghislaine Scelo

Rosamonde E Banks

Mark Lathrop

Guillaume Bourque

Yasser Riazalhosseini

Affiliations

Soon will be listed here.

Abstract

Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.

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