Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum
- PMID: 22427238
- PMCID: PMC3345105
- DOI: 10.1136/gutjnl-2011-300865
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.
Design: 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.
Conflict of interest statement
Figures


Similar articles
-
Prognostic implication of the CpG island methylator phenotype in colorectal cancers depends on tumour location.Br J Cancer. 2013 Aug 20;109(4):1004-12. doi: 10.1038/bjc.2013.430. Epub 2013 Jul 30. Br J Cancer. 2013. PMID: 23900220 Free PMC article.
-
Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.Mol Cancer. 2014 May 31;13:135. doi: 10.1186/1476-4598-13-135. Mol Cancer. 2014. PMID: 24885062 Free PMC article.
-
TGFBR2 and BAX mononucleotide tract mutations, microsatellite instability, and prognosis in 1072 colorectal cancers.PLoS One. 2011;6(9):e25062. doi: 10.1371/journal.pone.0025062. Epub 2011 Sep 20. PLoS One. 2011. PMID: 21949851 Free PMC article.
-
Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer.World J Gastroenterol. 2014 Apr 21;20(15):4230-43. doi: 10.3748/wjg.v20.i15.4230. World J Gastroenterol. 2014. PMID: 24764661 Free PMC article. Review.
-
Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes.Eur J Cancer. 2017 Oct;84:69-80. doi: 10.1016/j.ejca.2017.07.016. Epub 2017 Aug 5. Eur J Cancer. 2017. PMID: 28787661 Free PMC article. Review.
Cited by
-
Anatomic subsite of primary colorectal cancer and subsequent risk and distribution of second cancers.Cancer. 2013 Sep 1;119(17):3140-7. doi: 10.1002/cncr.28076. Epub 2013 Jul 15. Cancer. 2013. PMID: 23856984 Free PMC article.
-
Expression changes of cell-cell adhesion-related genes in colorectal tumors.Oncol Lett. 2015 Jun;9(6):2463-2470. doi: 10.3892/ol.2015.3107. Epub 2015 Apr 8. Oncol Lett. 2015. PMID: 26137091 Free PMC article.
-
Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803.Clin Cancer Res. 2012 Feb 1;18(3):890-900. doi: 10.1158/1078-0432.CCR-11-2246. Epub 2011 Dec 6. Clin Cancer Res. 2012. PMID: 22147942 Free PMC article. Clinical Trial.
-
How many diseases are colorectal cancer?Gastroenterol Res Pract. 2012;2012:564741. doi: 10.1155/2012/564741. Epub 2012 Sep 9. Gastroenterol Res Pract. 2012. PMID: 22991509 Free PMC article.
-
Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.Nat Commun. 2024 Feb 15;15(1):1384. doi: 10.1038/s41467-024-45605-4. Nat Commun. 2024. PMID: 38360902 Free PMC article.
References
-
- Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113:779–88. - PubMed
-
- Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002;101:403–8. - PubMed
-
- Gervaz P, Bucher P, Morel P. Two colons-two cancers: paradigm shift and clinical implications. J Surg Oncol. 2004;88:261–6. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- P01CA87969/CA/NCI NIH HHS/United States
- P01 CA087969-10/CA/NCI NIH HHS/United States
- P01 CA055075-17/CA/NCI NIH HHS/United States
- P30 DK043351/DK/NIDDK NIH HHS/United States
- R01 CA137178/CA/NCI NIH HHS/United States
- P50 CA127003-04/CA/NCI NIH HHS/United States
- R01CA137178/CA/NCI NIH HHS/United States
- P50CA127003/CA/NCI NIH HHS/United States
- R01CA151993/CA/NCI NIH HHS/United States
- R01 CA151993-02/CA/NCI NIH HHS/United States
- P50 CA127003/CA/NCI NIH HHS/United States
- R01 CA137178-03/CA/NCI NIH HHS/United States
- P01CA55075/CA/NCI NIH HHS/United States
- P01 CA087969/CA/NCI NIH HHS/United States
- P01 CA055075/CA/NCI NIH HHS/United States
- R01 CA151993/CA/NCI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous