Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer death in the United States,1 with heterogeneous outcomes and diverse underlying pathobiologic and molecular characteristics. Accordingly, epidemiologic and histologic differences in proximal and distal CRCs have been observed: patients with right-sided CRCs are more likely to be women, be older, and have mucinous, undifferentiated, or signet-ring cell histology compared with those with left-sided CRCs.2–5 There are also different frequencies of metastasis to different organs, with right-sided CRCs more likely to metastasize to the peritoneum and left-sided CRCs more likely to metastasize to the thorax or, less commonly, bone.6 The primary tumor site likely serves as a surrogate for underlying biology, including differential pathways of carcinogenesis and varying molecular features.7 With the availability of genomic platforms capable of broadly surveying gene expression and methylation, as evidenced by The Cancer Genome Atlas,8 we can now identify genomic subtypes of CRCs that are also differentially distributed between proximal and distal CRCs. This review describes the key molecular and genomic differences between proximal (right-sided) and distal (left-sided) CRCs, shedding light on the heterogeneity of clinical outcomes observed between right- and left-sided CRCs.
The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Kopetz has receiving funding from University of Texas MD Anderson Moon Shot Program, R01 CA 172670, and R01 CA184843. Dr. Lee has received funding from K12 CA 120780.
Howlader N, Noone A, Krapcho M et al.. SEER Cancer Statistics Review, 1975-2011. Vol. 2014. Bethesda, MD: National Cancer Institute; 2014.
Benedix F, Kube R, Meyer F et al.. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 2010;53:57–64.
Gonzalez EC, Roetzheim RG, Ferrante JM, Campbell R. Predictors of proximal vs. distal colorectal cancers. Dis Colon Rectum 2001;44:251–258.
Missiaglia E, Jacobs B, D'Ario G et al.. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 2014;25:1995–2001.
Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990;113:779–788.
The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337.
Meguid RA, Slidell MB, Wolfgang CL et al.. Is there a difference in survival between right- versus left-sided colon cancers? Ann Surg Oncol 2008;15:2388–2394.
Weiss JM, Pfau PR, O'Connor ES et al.. Mortality by stage for right- versus left-sided colon cancer: analysis of surveillance, epidemiology, and end results—Medicare data. J Clin Oncol 2011;29:4401–4409.
Schoenwolf GC, Bleyl SB, Brauer PR, Francis-West PH. Larsen's Human Embryology, 5th edition. Philadelphia, PA: Churchill Livingstone; 2015.
Raghav KP, Shetty AV, Kazmi SM et al.. Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. Oncologist 2013;18:1270–1277.
Raghav K, Overman MJ. Small bowel adenocarcinomas—existing evidence and evolving paradigms. Nat Rev Clin Oncol 2013;10:534–544.
Venook AP, Niedzwiecki D, Innocenti F et al.. Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance) [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 3504.
- Search Google Scholar
- Export Citation
. Venook AP Niedzwiecki D Innocenti F Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance) [abstract]. J Clin Oncol 2016; 34( Suppl): Abstract 3504.
Brule SY, Jonker DJ, Karapetis CS et al.. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer 2015;51:1405–1414.
Venook A, Niedzwiecki D, Ou F-S et al.. Impact of primary tumor location on overall survival and progression free survival in patients with metastatic colorectal cancer: analysis of all RAS wt subgroup on CALGB/SWOG 80405 (Alliance). Presented at the European Society for Medical Oncology 2016 Congress; October 7–11, 2016; Copenhagen, Denmark.
- Search Google Scholar
- Export Citation
. Impact of primary tumor location on overall survival and progression free survival in patients with metastatic colorectal cancer: analysis of all RAS wt subgroup on CALGB/SWOG 80405 (Alliance). Venook A Niedzwiecki D Ou F-S Presented at the European Society for Medical Oncology 2016 Congress; October 7–11, 2016; Copenhagen, Denmark.
Schrag D, Weng S, Brooks G et al.. The relationship between primary tumor sidedness and prognosis in colorectal cancer [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 3505.
Yamauchi M, Morikawa T, Kuchiba A et al.. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 2012;61:847–854.
Fu M, Tam PK, Sham MH, Lui VC. Embryonic development of the ganglion plexuses and the concentric layer structure of human gut: a topographical study. Anat Embryol (Berl) 2004;208:33–41.
Castellarin M, Warren RL, Freeman JD et al.. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012;22:299–306.
Kostic AD, Gevers D, Pedamallu CS et al.. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 2012;22:292–298.
Toprak NU, Yagci A, Gulluoglu BM et al.. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin Microbiol Infect 2006;12:782–786.
Winters MD, Schlinke TL, Joyce WA et al.. Prospective case-cohort study of intestinal colonization with enterococci that produce extracellular superoxide and the risk for colorectal adenomas or cancer. Am J Gastroenterol 1998;93:2491–2500.
Lepage P, Seksik P, Sutren M et al.. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD. Inflamm Bowel Dis 2005;11:473–480.
Flemer B, Lynch DB, Brown JM et al.. Tumour-associated and non-tumour-associated microbiota in colorectal cancer [published online ahead of print March 18, 2016]. Gut 2016; doi: 10.1136/gutjnl-2015-309595.
Dejea CM, Wick EC, Hechenbleikner EM et al.. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A 2014;111:18321–18326.
Venturi M, Hambly RJ, Glinghammar B et al.. Genotoxic activity in human faecal water and the role of bile acids: a study using the alkaline comet assay. Carcinogenesis 1997;18:2353–2359.
Reddy BS, Hedges AR, Laakso K, Wynder EL. Metabolic epidemiology of large bowel cancer: fecal bulk and constituents of high-risk North American and low-risk Finnish population. Cancer 1978;42:2832–2838.
Hill MJ, Taylor AJ, Thompson MH, Wait R. Fecal steroids and urinary volatile phenols in four Scandinavian populations. Nutr Cancer 1982;4:67–73.
Bernstein C, Holubec H, Bhattacharyya AK et al.. Carcinogenicity of deoxycholate, a secondary bile acid. Arch Toxicol 2011;85:863–871.
Thomas LA, Veysey MJ, French G et al.. Bile acid metabolism by fresh human colonic contents: a comparison of caecal versus faecal samples. Gut 2001;49:835–842.
Glebov OK, Rodriguez LM, Nakahara K et al.. Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev 2003;12:755–762.
Kaz AM, Wong CJ, Dzieciatkowski S et al.. Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age. Epigenetics 2014;9:492–502.
Menigatti M, Truninger K, Gebbers JO et al.. Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters. Oncogene 2009;28:899–909.
Gupta S, Balasubramanian BA, Fu T et al.. Polyps with advanced neoplasia are smaller in the right than in the left colon: implications for colorectal cancer screening. Clin Gastroenterol Hepatol 2012;10:1395–1401, e1392.
Nishihara R, Wu K, Lochhead P et al.. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 2013;369:1095–1105.
Brenner H, Hoffmeister M, Arndt V et al.. Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 2010;102:89–95.
Cheng YW, Pincas H, Bacolod MD et al.. CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer. Clin Cancer Res 2008;14:6005–6013.
Goel A, Nagasaka T, Arnold CN et al.. The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 2007;132:127–138.
Kane MF, Loda M, Gaida GM et al.. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997;57:808–811.
Toyota M, Ahuja N, Ohe-Toyota M et al.. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 1999;96:8681–8686.
Lee MS, McGuffey EJ, Morris JS et al.. Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer. Br J Cancer 2016;114:1352–1361.
Shen L, Catalano PJ, Benson AB III et al.. Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res 2007;13:6093–6098.
Juo YY, Johnston FM, Zhang DY et al.. Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis. Ann Oncol 2014;25:2314–2327.
Cha Y, Kim KJ, Han SW et al.. Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer. Br J Cancer 2016;115:164–171.
Dahlin AM, Palmqvist R, Henriksson ML et al.. The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res 2010;16:1845–1855.
Samowitz WS, Curtin K, Ma KN et al.. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 2001;10:917–923.
Benatti P, Gafa R, Barana D et al.. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 2005;11:8332–8340.
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–618.
Koopman M, Kortman GA, Mekenkamp L et al.. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009;100:266–273.
Tran B, Kopetz S, Tie J et al.. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer 2011;117:4623–4632.
Lochhead P, Kuchiba A, Imamura Y et al.. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013;105:1151–1156.
Gonsalves WI, Mahoney MR, Sargent DJ et al.. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147 [published corrections appears in J Natl Cancer Inst 2014;106:dju228]. J Natl Cancer Inst 2014;106:dju106.
Schell MJ, Yang M, Teer JK et al.. A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat Commun 2016;7:11743.
Budinska E, Popovici V, Tejpar S et al.. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol 2013;231:63–76.
De Sousa E, Melo F, Wang X, Jansen M et al.. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 2013;19:614–618.
Marisa L, de Reynies A, Duval A et al.. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 2013;10:e1001453.
Roepman P, Schlicker A, Tabernero J et al.. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer 2014;134:552–562.
Sadanandam A, Lyssiotis CA, Homicsko K et al.. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013;19:619–625.
Schlicker A, Beran G, Chresta CM et al.. Subtypes of primary colorectal tumors correlate with response to targeted treatment in colorectal cell lines. BMC Med Genomics 2012;5:66.
Giannakis M, Mu XJ, Shukla SA et al.. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep 2016;17:1206.
Calon A, Lonardo E, Berenguer-Llergo A et al.. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet 2015;47:320–329.
Dunne PD, McArt DG, Bradley CA et al.. Challenging the cancer molecular stratification dogma: intratumoral heterogeneity undermines consensus molecular subtypes and potential diagnostic value in colorectal cancer. Clin Cancer Res 2016;22:4095–4104.
Morris JS, Kopetz S. Tumor microenvironment in gene signatures: critical biology or confounding noise? Clin Cancer Res 2016;22:3989–3991.
Khambata-Ford S, Garrett CR, Meropol NJ et al.. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 2007;25:3230–3237.
Jacobs B, De Roock W, Piessevaux H et al.. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 2009;27:5068–5074.
Seligmann JF, Elliott F, Richman SD et al.. Combined epiregulin and amphiregulin expression levels as a predictive biomarker for panitumumab therapy benefit or lack of benefit in patients with RAS wild-type advanced colorectal cancer [published online ahead of print February 11, 2016]. JAMA Oncol, doi: 10.1001/jamaoncol.2015.6065.
- Search Google Scholar
- Export Citation
. Seligmann JF Elliott F Richman SD Combined epiregulin and amphiregulin expression levels as a predictive biomarker for panitumumab therapy benefit or lack of benefit in patients with RAS wild-type advanced colorectal cancer [published online ahead of print February 11, 2016]. JAMA Oncol, doi: 10.1001/jamaoncol.2015.6065.
Adams RA, Fisher D, Farragher S et al.. Use of epiregulin (EREG) and amphiregulin (AREG) gene expression to predict response to cetuximab (cet) in combination with oxaliplatin (Ox) and 5FU in the first-line treatment of advanced colorectal cancer (aCRC) [abstract]. J Clin Oncol 2012;30(Suppl):Abstract 32.
- Search Google Scholar
- Export Citation
. Adams RA Fisher D Farragher S Use of epiregulin (EREG) and amphiregulin (AREG) gene expression to predict response to cetuximab (cet) in combination with oxaliplatin (Ox) and 5FU in the first-line treatment of advanced colorectal cancer (aCRC) [abstract]. J Clin Oncol 2012; 30( Suppl): Abstract 32.
Sinicrope FA, Mahoney MR, Smyrk TC et al.. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol 2013;31:3664–3672.
Loupakis F, Yang D, Yau L et al.. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst 2015;107:dju427.
Moretto R, Cremolini C, Rossini D et al.. Location of primary tumor and benefit from anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF wild-type metastatic colorectal cancer. Oncologist 2016;21:988–994.
Tejpar S, Stintzing S, Ciardiello F et al.. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials [published online ahead of print October 10, 2016]. JAMA Oncol, doi:10.1001/jamaoncol.2016.3797.
- Search Google Scholar
- Export Citation
. Tejpar S Stintzing S Ciardiello F Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials [published online ahead of print October 10, 2016]. JAMA Oncol, doi:10.1001/jamaoncol.2016.3797.