Do Molecular Features of Colorectal Cancers Change Abruptly at Splenic Flexure?
Shuji Ogino, Mai Yamauchi, Teppei Morikawa, Charles Fuchs. Brigham and Women's Hospital, Boston; Dana-Farber Cancer Institute, Boston
Background: Colorectal cancer is typically classified into rectal, distal colon, and proximal colon cancer. Tumor molecular features in each of these locations have been shown to be different from those in the other sites. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, we hypothesized tumor molecular features might gradually change along the bowel, rather than abruptly change at splenic flexure.
Design: We used 1443 colorectal cancers, and examined the frequencies of molecular features [CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and BRAF and KRAS mutations] along the bowel segments. Linearity and non-linearity of molecular relations along the bowel were statistically tested by multivariate logistic regression models, adjusting for potential confounders.
Results: The frequencies of CIMP-high, MSI-high, and BRAF mutation gradually increased from rectum (<2.3%) to ascending colon (36-40%), followed by falls in the cecum (12-22%).
By linearity tests, these molecular relations were significantly linear along the bowel subsites from rectum to ascending colon (p<0.0001), and there was no evidence for non-linearity (p>0.12 by likelihood ratio tests). Notably, cecal cancers showed the highest frequency of KRAS mutations (52% in cecum vs. 27-35% in the other sites from rectum to ascending colon; p<0.0001).
Conclusions: The frequencies of CIMP-high, MSI-high, and BRAF mutation in colorectal cancer increased gradually along the bowel from rectum to ascending colon. Our novel data challenge the common conception of discrete molecular features of proximal vs. distal colorectal cancers, and have substantial impact on pathological, translational, and epidemiology research, which has typically been performed with dichotomous classification of proximal vs. distal tumors.
Monday, March 19, 2012 9:00 AM
Platform Session: Section D, Monday Morning