Yamada Atsushi, Minamiguchi Sachiko, Sakai Yoshiharu, Horimatsu Takahiro, Muto Manabu, Chiba Tsutomu, Boland C Richard, Goel Ajay
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.
Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
PLoS One. 2014 May 21;9(5):e98059. doi: 10.1371/journal.pone.0098059. eCollection 2014.
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.
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.
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).
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'.
患有锯齿状息肉（SP）的个体发生同步性结直肠高级别肿瘤（AN）和癌症的风险更高。然而，在这种情况下，锯齿状途径和/或经典腺瘤-癌序列是否有独特的参与仍不清楚。
回顾性收集包括直径≥10mm的管状腺瘤、具有绒毛组织学的腺瘤、高级别上皮内瘤变和癌症在内的结直肠AN。这些组包括伴有（AN+SP）或不伴有（仅AN）共存SP的AN。比较两组之间的临床病理结果。通过焦磷酸测序确定AN和SP中的BRAF和KRAS突变，以及相邻黏膜中长散在核元件-1（LINE-1）的甲基化水平。
分析了AN+SP组40例患者的75个AN和仅AN组119例患者的179个AN。两组之间的临床病理结果没有显著差异，除了AN+SP组的上皮内瘤变更可能位于右半结肠（P=0.018）。BRAF突变在AN+SP组中显著更频繁（P=0.003），而KRAS突变在两组之间没有显著差异（P=0.142）。两组中的大多数高级别上皮内瘤变都显示出传统腺瘤的连续成分。与没有此类SP的个体相比，患有大的和右侧SP的个体有明显更多的传统腺瘤（分别为P=0.027和P=0.031）。与没有此类相关SP的个体相比，患有多个大SP的个体的相邻黏膜在LINE-1处的甲基化水平显著降低（分别为P=0.049和P=0.015）。
我们的数据表明，腺瘤-癌序列和锯齿状途径在共存AN和SP的个体中都起作用。背景黏膜中LINE-1甲基化水平的降低提示存在潜在“场缺陷”的可能性。
