Colorectal advanced neoplasms occur through dual carcinogenesis pathways in individuals with coexisting serrated polyps.
BACKGROUND
Individuals with serrated polyps (SP) are at higher risk for synchronous colorectal advanced neoplasms (AN) and cancers. However, it remains unclear whether there is a unique involvement of the serrated pathway and/or the classical adenoma-carcinoma sequence in this setting.


METHODS
Colorectal ANs, which include tubular adenomas ≥ 10 mm, adenomas with villous histology, high-grade intraepithelial neoplasms, and cancers, were collected retrospectively. The groups included ANs with (AN+SP) or without (AN-only) coexisting SPs. Clinicopathological findings were compared between groups. BRAF and KRAS mutations in ANs and SPs, and methylation levels at long interspersed element-1 (LINE-1) in adjacent mucosa were determined by pyrosequencing.


RESULTS
Seventy-five ANs from 40 patients in the AN+SP group, and 179 ANs from 119 patients in the AN-only group were analyzed. There were no significant differences in clinicopathological findings between the two groups, except that intraepithelial neoplasia in the AN+SP group was more likely to be located in the right colon (P=0.018). BRAF mutations were significantly more frequent in the AN+SP group (P=0.003), while KRAS mutations showed no significant differences between groups (P=0.142). The majority of high-grade intraepithelial neoplasms in both groups showed a contiguous component of conventional adenoma. Individuals with large and right-sided SPs had significantly more conventional adenomas compared to those without such SPs (P=0.027 and P=0.031, respectively). Adjacent mucosa from individuals with multiple and large SPs showed significantly lower methylation levels at LINE-1 compared to individuals without such associated SPs (P=0.049 and P=0.015, respectively).


CONCLUSIONS
Our data suggest that both the adenoma-carcinoma sequence and the serrated pathway are operational in individuals with coexisting ANs and SPs. The reduced methylation levels at LINE-1 in the background mucosa suggest the possibility of an underlying 'field defect'.
Gastrointestinal Cancer Research Laboratory, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Atsushi
A
Yamada
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
Sachiko
S
Minamiguchi
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yoshiharu
Y
Sakai
Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital, Kyoto, Japan.
Takahiro
T
Horimatsu
Department of Therapeutic Oncology, Kyoto University Hospital, Kyoto, Japan.
Manabu
M
Muto
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tsutomu
T
Chiba
Gastrointestinal Cancer Research Laboratory, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America.
C Richard
CR
Boland
Gastrointestinal Cancer Research Laboratory, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States of America.
Ajay
A
Goel
D000236:Adenoma / Q000150:complications / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis; D003111:Colonic Polyps / Q000150:complications*; D015179:Colorectal Neoplasms / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins