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Single CpG hypermethylation, allele methylation errors, and decreased expression of multiple tumor suppressor genes in normal body cells of mutation‐negative early‐onset and high‐risk breast cancer patients
Author(s) -
Böck Julia,
Appenzeller Silke,
Haertle Larissa,
Schneider Tamara,
Gehrig Andrea,
Schröder Jörg,
Rost Simone,
Wolf Beat,
Bartram Claus R.,
Sutter Christian,
Haaf Thomas
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31526
Subject(s) - epigenetics , dna methylation , mlh1 , methylation , cpg site , bisulfite sequencing , biology , breast cancer , cancer , cancer research , allele , germline mutation , pten , gene , microbiology and biotechnology , genetics , mutation , gene expression , dna mismatch repair , pi3k/akt/mtor pathway , apoptosis , colorectal cancer
To evaluate the role of constitutive epigenetic changes in normal body cells of BRCA1 / BRCA2 ‐mutation negative patients, we have developed a deep bisulfite sequencing assay targeting the promoter regions of 8 tumor suppressor (TS) genes ( BRCA1 , BRCA2 , RAD51C , ATM , PTEN , TP53 , MLH1 , RB1 ) and the estrogene receptor gene ( ESR1 ), which plays a role in tumor progression. We analyzed blood samples of two breast cancer (BC) cohorts with early onset (EO) and high risk (HR) for a heterozygous mutation, respectively, along with age‐matched controls. Methylation analysis of up to 50,000 individual DNA molecules per gene and sample allowed quantification of epimutations (alleles with >50% methylated CpGs), which are associated with epigenetic silencing. Compared to ESR1 , which is representative for an average promoter, TS genes were characterized by a very low (< 1%) average methylation level and a very low mean epimutation rate (EMR; < 0.0001% to 0.1%). With exception of BRCA1 , which showed an increased EMR in BC (0.31% vs. 0.06%), there was no significant difference between patients and controls. One of 36 HR BC patients exhibited a dramatically increased EMR (14.7%) in BRCA1 , consistent with a disease‐causing epimutation. Approximately one third (15 of 44) EO BC patients exhibited increased rates of single CpG methylation errors in multiple TS genes. Both EO and HR BC patients exhibited global underexpression of blood TS genes. We propose that epigenetic abnormalities in normal body cells are indicative of disturbed mechanisms for maintaining low methylation and appropriate expression levels and may be associated with an increased BC risk.