Crosstalk Between DNA Methylation and Gene Mutations in Colorectal Cancer

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

doi:10.3389/fonc.2021.697409

Crosstalk Between DNA Methylation and Gene Mutations in Colorectal Cancer

Front Oncol. 2021 Jul 1:11:697409. doi: 10.3389/fonc.2021.697409. eCollection 2021.

Authors

Maria Dobre¹, Alessandro Salvi², Iulia Andreea Pelisenco³, Florina Vasilescu¹, Giuseppina De Petro², Vlad Herlea⁴, Elena Milanesi⁵

Affiliations

¹ Laboratory of Histopathology and Immunohistochemistry, Victor Babes National Institute of Pathology, Bucharest, Romania.
² Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
³ Faculty of Biology, University of Bucharest, Bucharest, Romania.
⁴ Department of Pathology, Fundeni Clinical Institute, Bucharest, Romania.
⁵ Laboratory of Radiobiology, Victor Babes National Institute of Pathology, Bucharest, Romania.

Abstract

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 KRAS and BRAF genes. Mutations of the KRAS gene have been detected in approximately 40% of patients, while mutations in BRAF 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 (RUNX3, SFRP1, WIF1, PCDH10, DKK2, DKK3, TMEFF2, OPCML, and SFRP2) presenting high methylation levels in tumoral compared to normal tissues was identified. KRAS mutations (codons 12 or 13) were detected in eight CRC cases, and BRAF mutations (codon 600) in four cases. One of the CRC patients presented concomitant mutations in KRAS codon 12 and BRAF, whereas seven patients did not present these mutations (WT). When comparing the methylation profile according to mutation status, we found that six genes (SFRP2, DKK2, PCDH10, TMEFF2, SFRP1, HS3ST2) showed a methylation level higher in BRAF positive cases than BRAF 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.

Keywords: BRAF; DNA methylation; KRAS; colorectal cancer; mutations.