Two subtypes of colorectal tumor with distinct molecular features in familial adenomatous polyposis
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Kiyoko Takane1,2, Keisuke Matsusaka1, Satoshi Ota3, Masaki Fukuyo1, Yao Yue4, Motoi Nishimura4, Eiji Sakai1,7, Kazuyuki Matsushita4, Hideaki Miyauchi5, Hiroyuki Aburatani8, Yukio Nakatani3,6, Tadatoshi Takayama2, Hisahiro Matsubara5, Kiwamu Akagi9 and Atsushi Kaneda1,8
1 Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
2 Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
3 Department of Pathology, Chiba University Hospital, Chiba, Japan
4 Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
5 Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
6 Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
7 Department of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan
8 Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
9 Division of Molecular Diagnosis, Saitama Cancer Center, Saitama, Japan
Atsushi Kaneda, email:
Keywords: CIMP, colorectal cancer, DNA methylation, familial adenomatous polyposis (FAP), KRAS
Received: July 02, 2016 Accepted: August 17, 2016 Published: August 22, 2016
While sporadic colorectal cancer (CRC) is classified into several molecular subtypes, stratification of familial colorectal tumors is yet to be well investigated. We previously established two groups of methylation markers through genome-wide DNA methylation analysis, which classified sporadic CRC and adenoma into three distinct subgroups: high-, intermediate-, and low-methylation epigenotypes. Here, we investigated familial adenomatous polyposis (FAP), through quantitative methylation analysis of 127 samples (16 cancers, 96 adenomas, and 15 benign mucosa from 14 patients with FAP) using six Group-1 and 14 Group-2 methylation markers, APC, BRAF, and KRAS mutation analysis, and CTNNB1 and TP53 immunohistochemical analysis. All the 14 patients presented with APC germline mutation. Three were from the same family and presented the same APC mutation. FAP tumors lacked BRAF-mutation(+) high-methylation epigenotype and were classified into two methylation epigenotypes. While 24 of 112 tumor samples showed intermediate-methylation epigenotype significantly correlating with KRAS-mutation(+) (P=3×10-4), 88 tumor samples showed low-methylation epigenotype correlating with the absence of KRAS- and BRAF-mutations. Similar to sporadic CRC, CTNNB1 was frequently activated at the adenoma stage, and TP53 mutation occurred during cancer development from adenoma. Whereas some patients showed a single epigenotype in all tumors throughout the colon, tumors with two distinct epigenotypes developed within a family with the same APC mutation or even within one patient. Methylation accumulation significantly correlated with proximal location and older age. These results indicate that there are at least two distinct molecular subtypes of FAP tumors, resembling sporadic CRC and independent from the APC germline mutation status.
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