title: Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum.
abstract: OBJECTIVE
  Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.
  
  
  METHODS
  Utilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.
  
  
  RESULTS
  The frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36-40%), followed by falls in the caecum (12-22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27-35% in other sites; p<0.0001).
  
  
  CONCLUSIONS
  The frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kuchiba
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.forename: Levi
authors.initials: L
authors.lastname: Waldron
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Charles
authors.initials: C
authors.lastname: Fuchs
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
mesh_terms: D000368:Aged; D002430:Cecal Neoplasms / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D059645:Mutation Rate; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012004:Rectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012811:Sigmoid Neoplasms / Q000235:genetics / Q000473:pathology; D018631:ras Proteins / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins