AUTHOR=Dobre Maria , Salvi Alessandro , Pelisenco Iulia Andreea , Vasilescu Florina , De Petro Giuseppina , Herlea Vlad , Milanesi Elena 

TITLE=Crosstalk Between DNA Methylation and Gene Mutations in Colorectal Cancer

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.697409

DOI=10.3389/fonc.2021.697409

ISSN=2234-943X

ABSTRACT=<p>Colorectal cancer (CRC) is often characterized by mutations and aberrant DNA methylation within the promoters of tumor suppressor genes and proto-oncogenes. The most frequent somatic mutations occur within <italic>KRAS</italic> and <italic>BRAF</italic> genes. Mutations of the <italic>KRAS</italic> gene have been detected in approximately 40% of patients, while mutations in <italic>BRAF</italic> have been detected less frequently at a rate of 10%. In this study, the DNA methylation levels of 22 candidate genes were evaluated in three types of tissue: mucosal tumoral tissue from 18 CRC patients, normal adjacent tissues from 10 CRC patients who underwent surgical resection, and tissue from a control group of six individuals with normal colonoscopies. A differential methylation profile of nine genes (<italic>RUNX3</italic>, <italic>SFRP1</italic>, <italic>WIF1</italic>, <italic>PCDH10</italic>, <italic>DKK2</italic>, <italic>DKK3</italic>, <italic>TMEFF2</italic>, <italic>OPCML</italic>, and <italic>SFRP2</italic>) presenting high methylation levels in tumoral compared to normal tissues was identified. <italic>KRAS</italic> mutations (codons 12 or 13) were detected in eight CRC cases, and <italic>BRAF</italic> mutations (codon 600) in four cases. One of the CRC patients presented concomitant mutations in <italic>KRAS</italic> codon 12 and <italic>BRAF</italic>, whereas seven patients did not present these mutations (WT). When comparing the methylation profile according to mutation status, we found that six genes (<italic>SFRP2</italic>, <italic>DKK2</italic>, <italic>PCDH10</italic>, <italic>TMEFF2</italic>, <italic>SFRP1</italic>, <italic>HS3ST2</italic>) showed a methylation level higher in <italic>BRAF</italic> positive cases than <italic>BRAF</italic> negative cases. The molecular sub-classification of CRC according to mutations and epigenetic modifications may help to identify epigenetic biomarkers useful in designing personalized strategies to improve patient outcomes.</p>