AbstractsMedical & Health Science

The interplay between genetics and epigenetics in cancer development

by Joice Kuroiwa Trzmielina




Institution: University of New South Wales
Department: Clinical School - Prince of Wales Hospital
Year: 2014
Keywords: Colorectal cancer; Familial cancer; Breast cancer; Epigenetics; Cancer; Variant; DNA methylation; Constitutional methylation; Epimutation; BRCA1; BRCA2; MGMT; SNP
Record ID: 1048700
Full text PDF: http://handle.unsw.edu.au/1959.4/53917


Abstract

Cancer is caused by genetic and epigenetic changes resulting in altered patterns of gene expression. This study explored how somatic epigenetic events may predispose to the development of cancer and how genetic variation can underlie these events. Firstly, the role of constitutional methylation of the BRCA1 and BRCA2 genes in breast cancer development was investigated in BRCA-mutation negative cases of familial and early-onset breast cancer. No BRCA2 methylation was detected. Low level BRCA1 methylation was seen in 5/266 (2%) familial cases, 4/20 (20%) early-onset and 5/252 (2%) controls. No underlying sequence variants were found in regulatory regions of BRCA1 in methylation-positive cases. One familial case had two affected cousins who showed methylation (1-13%) – they all shared the same BRCA1 haplotype, suggesting a genetic basis for the epimutation. In another familial case, methylation detected in buccal cells (5%) was elevated in a cerebral metastasis (17%), suggesting a causative role in tumourigenesis in that case. However, methylation was found at similar low levels soma-wide and in the primary breast carcinoma in an early-onset case. Secondly, the role of the minor (T) allele of the MGMT enhancer rs16906252 C>T SNP, which correlates with MGMT promoter methylation, was studied in colorectal cancer (CRC). In a case-control study, the T allele was associated with increased risk of CRC showing MGMT-methylation, but not of developing CRC. Monoallelic methylation, mostly of the T allele, was observed in MGMT-methylated tumours retaining protein expression, producing discordant methylation and protein expression profiles. In peripheral blood and normal colorectal mucosa (NCM) of CRC cases and controls, low-level MGMT methylation was linked to the T allele. Allele quantification in NCM transcripts from cases and controls revealed a two-fold reduction in expression of the T compared to the C allele, possibly predisposing the T allele to methylation via altered interaction with transcription factors. These findings revealed a genetic-epigenetic interaction at this locus, which may predispose to the development of MGMT-methylated CRC. This study has advanced knowledge regarding genetic-epigenetic interactions and their role in cancer susceptibility. These findings may impact on strategies for cancer prevention, early-detection and targeted surveillance.