Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category
Open Access
- 15 June 2008
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (12), 4597-4605
- https://doi.org/10.1158/0008-5472.can-07-6645
Abstract
Tumor suppressor genes (TSG) may be inactivated by methylation of critical CpG sites in their promoter regions, providing targets for early detection and prevention. Although sporadic cancers, especially colorectal carcinoma (CRC), have been characterized for epigenetic changes extensively, such information in familial/hereditary cancer is limited. We studied 108 CRCs and 63 endometrial carcinomas (EC) occurring as part of hereditary nonpolyposis CRC, as separate familial site-specific entities or sporadically, for promoter methylation of 24 TSGs. Eleven genes in CRC and 6 in EC were methylated in at least 15% of tumors and together accounted for 89% and 82% of promoter methylation events in CRC and EC, respectively. Some genes (e.g., CDH13, APC, GSTP1, and TIMP3) showed frequent methylation in both cancers, whereas promoter methylation of ESR1, CHFR, and RARB was typical of CRC and that of RASSF1(A) characterized EC. Among CRCs, sets of genes with methylation characteristic of familial versus sporadic tumors appeared. A TSG methylator phenotype (methylation of at least 5 of 24 genes) occurred in 37% of CRC and 18% of EC (P = 0.013), and the presence versus absence of MLH1 methylation divided the tumors into high versus low methylation groups. In conclusion, inactivation of TSGs by promoter methylation followed patterns characteristic of tumor type (CRC versus EC) and family category and was strongly influenced by MLH1 promoter methylation status in all categories. Paired normal tissues or blood displayed negligible methylation arguing against a constitutional methylation abnormality in familial cases. [Cancer Res 2008;68(12):4597–605]Keywords
Other Versions
This publication has 42 references indexed in Scilit:
- Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic studyGut, 2007
- Patterns of PIK3CA alterations in familial colorectal and endometrial carcinomaInternational Journal of Cancer, 2007
- Cancer genetics of epigenetic genesHuman Molecular Genetics, 2007
- The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal CancerGastroenterology, 2007
- CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancerNature Genetics, 2006
- The epigenetic progenitor origin of human cancerNature Reviews Genetics, 2006
- The power and the promise of DNA methylation markersNature Reviews Cancer, 2003
- Aberrant CpG-island methylation has non-random and tumour-type–specific patternsNature Genetics, 2000
- hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial TumorigenesisThe American Journal of Pathology, 1999
- Mutation sharing, predominant involvement of the MLH1 gene and description of four novel mutations in hereditary nonpolyposis colorectal cancerHuman Mutation, 1998