Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer

Kwangmin Kim; Ernes John T. Castro; Hongjin Shim; John Vincent G. Advincula; Young-Wan Kim

doi:10.3393/ac.2018.12.17

Articles

Page Path: HOME > Ann Coloproctol > Volume 34(6); 2018 > Article

Review Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer: Kwangmin Kim^1,2, Ernes John T. Castro³, Hongjin Shim⁴, John Vincent G. Advincula⁵, Young-Wan Kim^1,6; Annals of Coloproctology 2018;34(6):280-285.
DOI: https://doi.org/10.3393/ac.2018.12.17
Published online: December 31, 2018

¹Big Data Research Group, Yonsei University Wonju College of Medicine, Wonju, Korea

²Division of Acute Care Surgery, Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea

³Department of Surgery, The Medical City, Pasig, Philippines

⁴Division of Trauma Surgery and Surgical Critical Care, Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea

⁵Department of Surgery, Amang Memorial Rodriguez Medical Center, Marikina City, hilippines

⁶Division of Colorectal Surgery, Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea

Correspondence to: Young-Wan Kim, M.D. Department of Surgery, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea Tel: +82-33-741-0573, Fax: +82-33-742-0574 E-mail: youngwkim@yonsei.ac.kr

• Received: October 19, 2018 • Accepted: December 17, 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next

7,757 Views
266 Download
41 Web of Science
39 Crossref
46 Scopus

Full Article

Download PDF

Abstract
INTRODUCTION
DIFFERENT MOLECULAR FEATURES
RIGHT VERSUS LEFT: DIFFERENT MOLECULAR CHARACTERISTICS
CRC gene expression profiling (CMS classification)
CRC subtype classification using key molecular features
DIFFERENCES IN GUT MICROBIOTA
ONCOLOGIC OUTCOMES
CONCLUSIONS
ARTICLE INFORMATION
Acknowledgments
REFERENCES

Abstract

For many years, developmental and physiological differences have been known to exist between anatomic segments of the colorectum. Because of different outcomes, prognoses, and clinical responses to chemotherapy, the distinction between right colon cancer (RCC) and left colon cancer (LCC) has gained attention. Furthermore, variations in the molecular features and gut microbiota between right and LCCs have recently been a hot research topic. CpG island methylator phenotype-high, microsatellite instability-high colorectal cancers are more likely to occur on the right side whereas tumors with chromosomal instability have been detected in approximately 75% of LCC patients and 30% of RCC patients. The mutation rates of oncogenes and tumor suppressor genes also differ between RCC and LCC patients. Biofilm is more abundant in RCC patients than LLC patients, as are Prevotella, Selenomonas, and Peptostreptococcus. Conversely, Fusobacterium, Escherichia/Shigella, and Leptotrichia are more abundant in LCC patients compared to RCC patients. Distinctive characteristics are apparent in terms of molecular features and gut microbiota between right and LCC. However, how or to what extent these differences influence diverging oncologic outcomes remains unclear. Further clinical and translational studies are needed to elucidate the causative relationship between primary tumor location and prognosis.
Keywords: Colonic neoplasms; Molecular subtype; Gastrointestinal microbiome; Treatment outcome

INTRODUCTION

Colorectal cancer (CRC) can be characterized by the location of the primary tumor in the colorectum. For many years, developmental and physiological differences have been known to exist between anatomic segments of the colorectum, and CRCs have been known to occur with distinctly different frequencies at different subsites [1]. The proximal and the distal colon have different embryologic origins. The distal duodenum to the proximal two-thirds of the transverse colon is derived from the midgut whereas the distal third of the transverse colon to the upper two-thirds of the anorectal canal is derived from the hindgut [2]. In addition, they have different physiological functions: the water and electrolyte absorption capacity of the distal colon differs from that of the proximal colon. The main location for water absorption is the proximal colon whereas the main function of the distal colon is the passage of bowel contents.

Recently, the different outcomes, prognoses, and clinical responses to chemotherapy observed between right colon cancer (RCC) and left colon cancer (LCC) have attracted attention. Some trials in terms of metastatic CRC showed that outcomes for patients with left-sided tumors were superior to those for patients with right-sided tumors [3, 4]. With regard to patients who received a curative resection for nonmetastatic colon cancer, the prognostic role of the primary tumor’s location is still being debated [5]. In fact, several recent studies have indicated that the sidedness of the primary tumor may be prognostic and predictive of the response to antiepidermal growth factor receptor (EGFR) therapy in metastatic CRC. Trials using cetuximab as an anti-EGFR therapy, including CRYSTAL and FIRE-3, showed that the outcomes for patients with left-sided tumors were superior to those for patients with right-sided tumors [4].

The aim of this review is to describe the differences regarding the molecular features and gut microbiota between right and LCCs based on current evidence. This review article is exempt from the requirement for approval by the Ethics Committee.

DIFFERENT MOLECULAR FEATURES

CRCs exhibit variable genetic signatures and develop through at least three major pathways: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) (Fig. 1).

Chromosomal instability

Of the three major pathways leading to CRC, CIN was the first pathway to be described and is the most commonly seen in 65%–70% of sporadic CRCs [6-8]. Although CIN is one of the most described pathways, its mechanism is still not clear. Several mechanisms leading to CIN include chromosome segregation defects (either defects in mitotic arrest deficient and budding uninhibited by benzimidazoles genes, which are mitotic checkpoints, or abnormal centrosome function or number), telomere dysfunction (either shortened telomeres, often seen in early carcinogenesis, or elongated telomeres due to increased telomerase activity, often seen in advanced stages of CRC), errors in DNA damage repair response affecting TP53 and APC genes, and lastly, loss of heterozygosity (either from mitotic nondisjunction, recombination of chromosomes, or chromosome deletion) [7]. In karyotypic studies, CIN shows a gain or loss of chromosomes. Furthermore, these chromosomes show losses in heterozygosity, i.e., loss of a maternal or paternal allele and gain of the opposite (often abnormal) allele [9]. Loss of heterozygosity is a hallmark feature in CIN-positive tumors, with at least 25%–30% alleles being lost in these tumors [7]. CIN-positive tumors also feature extensive somatic copy number alterations (SCNA) in the genome, giving rise to aneuoploid tumors from asymmetric mitosis [8].

Microsatellite instability

A microsatellite is defined as a part of DNA that repeats 1 to 6 short nucleotide sequences. MSI is a genetic instability in short nucleotide repeats (microsatellite) due to a high mutation rate as a result of abnormal DNA mismatch repair. The National Cancer Institute suggested panel markers, such as mononucleotide marker (BAT26, BAT25) and dinucleotide marker (D5S346, D2S123, and D17S250), in CRCs. Tumors with MSI show instability in 2 or more markers whilst tumors with microsatellite stability (MSS) show instability in no more than one marker [10]. According to a Bethesda guideline, MSI-High is defined as having instability of 40% or more, MSI-Low as less than 40%, and MSS as less instability. However, in general, MSI-L (instability <40% of markers) CRCs are classified in the same subtype as MSS CRCs. MSI is a characteristic seen in patients with hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC, also called Lynch syndrome, occurs in about 1% to 6% of all CRCs. Patients with Lynch syndrome have an increased risk for a number of extracolonic cancers, including carcinomas of the endometrium, ovary, renal pelvis and ureter, small intestine, stomach, and hepatobiliary tract. HNPCC is characterized by extensive MSI-H, which is due to germ-line mutation of mismatch repair genes [11]. MSI is reported in about 10%–15% of sporadic CRCs. MSI in sporadic CRCs is mainly due to transcriptional silencing by acquired promoter hypermethylation of the hMLH1 gene [12].

In general, MSI CRCs are clinically characterized by poorly differentiated tumors in the proximal colon of older females that exhibit mucinous or signet-ring cell histology. MSI CRCs are clinically characterized as having a favorable prognosis. In addition, MSI is a potential sensitive marker for 5-fluorouracil (5-FU) therapy. Recent studies suggest that MSI is a marker of good response to 5-FU treatment, particularly when accompanied by large deletions in HSPH1 (HSP110) [13, 14].

CpG island methylator phenotype

Epigenetic changes are physiological mechanisms that regulate gene expression without altering the DNA sequence. An example of an epigenetic change is methylation of gene promoters, as seen in methylation in a CpG dinucleotide context [15]. CIMP changes in CRC are often defined as excessive methylation of genetic loci that contain CpG islands, usually a promoter of a tumor-suppressor gene, which leads to inhibition of transcription of that gene and promotion of carcinogenesis [8, 15]. The CIMP definition criteria vary among studies, with some using at least three loci methylated from 5 to 15 marker panels and different cutoff values to group them as either CIMP-positive (which is further grouped as CIMP-high and CIMP-low) or CIMP-negative [8, 16]. The CIMP definition criteria and CRC prognosis due to high heterogeneity in the CIMP definitions are still serious issues; however, a CIMP-positive or a CIMP-high CRC may be an independent prognostic factor for poor survival compared to CIMP-negative CRC [16]. CRCs diagnosed within five years postcolonoscopy are usually CIMP-positive [17]. The association of CIMP with MSI showed poorer survival in patients with CRC [8, 16]. The results of predicting responses to therapies by using CIMP definitions are still inconsistent [16]. CIMP-positivity may be seen in sessile serrated lesions (SSL) in 15%–30% of patients with CRC [15].

RIGHT VERSUS LEFT: DIFFERENT MOLECULAR CHARACTERISTICS

Traditionally, primary tumors arising from the left and the right sides of the colon have distinct chromosomal and molecular characteristics. CIMP-high, MSI-high CRCs are more likely to occur on the right side [18, 19] whereas tumors with CIN have been detected in approximately 75% of patients with LCC and 30% of those with RCC [20]. The mutation rates of oncogenes and tumor suppressor genes also differ between RCC and LCC. Hypermethylation is more common in RCC than LCC [21], and RCCs have also been associated with an increase in RAS and phosphoinositide 3-kinase pathway mutations and a higher frequency of transforming growth factor (TGF)-βR2 mutations and BRAF mutations [22]. Mutations in the APC, SMAD4, and TP53 genes occur more often in LCC than in RCC [23]. Overexpression of the EGFR ligands epiregulin (EREG) and amphiregulin (AREG) and amplifications of EGFR and human EGFR2 are associated with LCC [18, 21]. High expressions of EREG and AREG in tumors are associated with better response rates and improved outcomes to anti-EGFR antibody therapy in patients with KRAS and NRAS wild type (wt) metastatic CRCs [24]. The expression of vascular endothelial growth factor 1 is also significantly higher in LCC than in RCC [25]. Therefore, variable treatment options should be provided because mutations and genomic patterns are variable.

CRC gene expression profiling (CMS classification)

Recently, several studies performed gene expression profiling to categorize CRCs into subtypes and identify associations with genes and clinicopathological features. Members of the Colorectal Cancer Subtyping Consortium combined genomic datasets for a total of 4,151 samples to perform consensus molecular subtyping (CMS) by applying unsupervised clustering techniques [26]. Extensive labor established four CMSs. CMS1 (MSI immune, 14%) is characterized as presenting with MSI and an activated immune system; the tumors are CIMP-positive and SCNA-low, harbor BRAF mutations, and occur in the proximal colon of older female patients. CMS2 (canonical, 37%) is characterized as showing MSS, CIN, and WNT/MYC pathway activation; the tumors are CIMP-negative and SCNA-high with APC and TP53 mutations and occur in the distal colon to rectum. This subtype shows good survival after relapse. CMS3 (metabolic, 13%) is characterized as showing MSS, having a CIMP-low and SCNA-intermediate phenotype, showing KRAS and APC mutations, and exhibiting an epithelial signature and metabolic dysregulation. CMS4 (mesenchymal, 23%) is characterized as showing MSS, having a CIMP-negative and SCNA-high phenotype and occurring at advanced stages. This subtype shows poorer overall survival and signatures of TGF-β activation, stromal infiltration, epithelial-mesenchymal transition activation, matrix remodeling, and angiogenesis. Although, this CMS classification system was not a therapeutic aim, it facilitated a better understanding of the broad biological groups in the overall category of CRCs.

CRC subtype classification using key molecular features

The categorization of CRCs using multiple key molecular features might provide insights regarding various clinical outcomes, although the classification of CRCs is complex because CRCs are heterogeneous. Sinicrope et al. [27] categorized colon cancers into five subtypes with distinct clinicopathological features, including clinical outcomes. This categorization combined KRAS and BRAF^V600E mutations with DNA MMR (mismatch repair) status as key molecular features. In addition, it used a cohort of patients with stage III colon cancer in an adjuvant chemotherapy trial. MMR-proficient tumors with BRAF or KRAS mutations (42% of all cases) showed higher mortality rates than those without this phenotype. MMR-proficient tumors with BRAF wt and KRAS wt (49%) were the most prevalent subtype in the cohort and were associated with better survival than tumors lacking this phenotype [27, 28].

Phipps et al. [29] suggested that the combination of MSI and CIMP status and BRAF and KRAS mutations divided CRCs into 5 categories with distinct clinicopathological features. Type 1 CRCs (7% of all cases) were characterized as having MSI and BRAF mutations, were KRAS wt- and CIMP-positive, and occurred in the proximal colon of older female patients. Type 2 CRCs (4%) had the highest mortality rate and were defined as having MSS and BRAF mutations, as well as being KRAS wt- and CIMP-positive. Type 4 CRCs (47%), defined as being MSS-, BRAF wt-, KRAS wt-, and CIMP-negative, represented the most common subtype, were characterized by canonical APC mutations and occurred in the distal colon to rectum of male patients. Type 5 CRCs (7%), defined as being MSI-, BRAF wt-, KRAS wt- and CIMP-negative, showed the lowest mortality rates and were characterized clinically based on occurrence in the proximal colon of relatively young patients.

Another study reported that CIMP might be used as a molecular marker to determine the poor prognosis of CRC patients with MSS and BRAF mutations [30]. This corresponds to type 2 CRCs in the study by Phipps et al. [29].

DIFFERENCES IN GUT MICROBIOTA

CRCs have multiple causes, one of which is the gut microbiome. One study [31] suggested that the gut microbiome may influence not only the initiating events of carcinogenesis but also its progression (Table 1).

How bacteria influence CRC initiation

Two major theories have emerged for how bacteria might initiate CRCs [32, 33]. The first and perhaps most direct is that certain bacteria have DNA mutagenesis capabilities and/or interfere with host DNA repair machinery, which has been observed in enterotoxigenic Bacteroides fragilis that express B. fragilis toxin (BFT), superoxide-producing E. faecalis, and the polyketide synthase (pks)-expressing clade of Escherichia coli. The second theory considers that many implicated bacteria, including the above three species, as well as Fusobacterium nucleatum, share the ability to enhance Wnt-mediated signaling pathways or other proinflammatory pathways that are commonly mutated and/or overexpressed in CRC. However, that a single organism is responsible for all CRCs is highly unlikely.

An emerging concept in the role of microbiota in CRC initiation is that both the composition of the microbiota and the complex community structures they form, such as bacterial biofilms, also dramatically alter both host and microbial functions in CRCs. Bacterial biofilms along the colorectal axis are present in approximately 15% of healthy patients upon colonoscopy [34], but were recently shown to be a feature in nearly 100% of patients with right-sided CRC [35]. However, the reason bacteria preferentially form biofilms on RCC is still not fully understood. In healthy individuals, approximately 15% exhibit thin biofilms, although they are not specific to the proximal colon [35]. Thus, other environmental influences, such as diet and smoking, may affect biofilm development [36].

Biofilms are defined as massive bacterial invasions of the mucus layer that are encased in a polymeric matrix. However, why or how microbiota form biofilms in the colon is still not clear. One hypothesis is that biofilm formation is a microbiota defense mechanism against the host [37]. Approximately 100 species of bacteria can exist as biofilms; the predominant species is bacteroidetes (encompassing Bacterides and Prevotella). Biofilms in CRC patients tend to be thicker and more continuous than those in healthy controls [35, 38]. Tissues underlying the biofilms in CRC patients showed decreased or altered E-cadherin and enhanced interleukin-6 and Ki67 expression in the tumor host, as well as phospho-Stat3, suggesting that the biofilms elicited a pro-carcinogenic effect [35]. This finding is perhaps unsurprising given that a feature of biofilms is the invasion of the mucus layer by bacteria, allowing bacteria to directly interact with colonocytes and potentially trigger inflammatory responses, as well as oncogenic changes, in the colonic epithelial cell layer. Conversely, colonic epithelial cells and/or leukocytes have been observed invading the biofilms, again suggesting that the biofilms are immunogenic and involve highly dynamic bacteria-host interactions [35].

How bacteria influence CRC progression

Observational studies on patient outcomes have provided clues as to which microbes are associated with CRC progression. Boleij et al. [39] showed that BFT was more often observed in advanced CRC cases than in early-stage CRCs. Basically, some studies suggested that Fusobacterium was abundant in right-side colon cancer and might be linked to the worse prognosis [40, 41]. Another study by Castellarin et al. [42] demonstrated that a high level of F. nucleatum DNA in tumor tissue was associated with an increased number of lymph node metastases. In addition, Mima et al. [43] showed that F. nucleatum was associated with a decrease in CD3+ T cells within CRC tumors, a feature that is typically associated with MSS status and poorer patient outcomes [44].

Prevotella, Selenomonas, and Peptostreptococcus were identified in relatively higher abundances in RCC than in LCC. Conversely, Fusobacterium, Escherichia/Shigella, and Leptotrichia were relatively abundant in LCC compared to RCC [45]. A recent study showed that these CRC-associated microbiota profiles were linked to distinct mucosal gene expression profiles [31]. Furthermore, analysis of CRC microbiomes and their relation to tumor CMSs showed enriched levels of Fusobacteria and Bacteroidetes and decreased levels of Firmicutes and Proteobacteria in CMS1. CMS2 was enriched for Selenomonas and Prevotella species whereas CMS3 showed few significant associations [46]. In addition, a prospective cohort study found that prudent diets rich in whole grains and dietary fiber were associated with a lower risk of F. nucleatum-negative cancer, supporting a potential role for intestinal microbiota in mediating the association between diet and CRC [47].

ONCOLOGIC OUTCOMES

Growing evidence indicates that primary tumor location and tumor stage are prognostic factors for patients with CRCs. However, the difference in outcome is related to not only the location of the primary tumor but also its molecular profile. Recently, in K-RAS wt metastatic CRC patients receiving anti-EGFR therapy, the molecular characteristics considered typical of RCC more frequently overlapped with CMS1 (MSI immune) whereas CMS3 and CMS4 were recurrent in LCC [18]. The study also showed a correlation between the different molecular characteristics investigated and survival, confirming a consistent link between molecular features and clinical outcome.

CONCLUSIONS

Distinctive aspects regarding the molecular features and gut microbiota exist between RCCs and LCCs. However, how and the extent to which these differences influence divergent oncologic outcomes is still unclear. Thus, further clinical and translational studies are needed to elucidate the causative relationship between primary tumor location and prognosis.

ARTICLE INFORMATION

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education (NRF-2017R1D1A3B03032301).

Fig. 1.

Molecular features of right and left colon cancers. AREG, amphiregulin; CIMP, CpG island methylator phenotype; SCNA, somatic copy number alterations; EGFR, epidermal growth factor receptor; EREG, epiregulin; MSI, microsatellite instability; VEGF-1, vascular endothelial growth factor 1.

Table 1.

Different clinical features and gut microbiota between right and left colon cancers

Feature	Right	Left
Age at diagnosis	Older	Younger
Sex	More women	More men
Tumor size	Larger	Smaller
Tumor condition at diagnosis	More advanced	Less advanced
Differentiation	Poor	Well
Prognosis	Poor	Good
Biofilm	Abundant	Less abundant
Microbiome	Prevotella	Fusobacterium
	-	Escherichia/Shigella
	Selenomonas	Leptotrichia
	Peptostreptococcus	-
Bile salt	Abundant	Less abundant
Association with Western dietary pattern	Less	More

REFERENCES

1. Jensen OM. Different age and sex relationship for cancer of subsites of the large bowel. Br J Cancer 1984;50:825–9.Article PubMed PMC PDF
2. Mik M, Berut M, Dziki L, Trzcinski R, Dziki A. Right- and left-sided colon cancer - clinical and pathological differences of the disease entity in one organ. Arch Med Sci 2017;13:157–62.Article PubMed
3. Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, et al. CALGB 80403 (Alliance)/E1206: a randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol 2016;34:2736–42.Article PubMed PMC
4. Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier 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. JAMA Oncol; 2016.
5. Jung MK, Shin US, Ki YJ, Kim YB, Moon SM, Sung SJ. Is the Location of the tumor another prognostic factor for patients with colon cancer? Ann Coloproctol 2017;33:210–8.Article PubMed PMC PDF
6. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–7.Article PubMed PMC
7. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 2010;138:2059–72.Article PubMed PMC
8. Carethers JM, Jung BH. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology 2015;149:1177–90. e3.Article PubMed PMC
9. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396:643–9.Article PubMed PDF
10. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248–57.PubMed
11. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816–9.Article PubMed
12. Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 1998;58:1713–8.PubMed
13. Collura A, Lagrange A, Svrcek M, Marisa L, Buhard O, Guilloux A, et al. Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy. Gastroenterology 2014;146:401–11.e1. e1.Article PubMed
14. Dorard C, de Thonel A, Collura A, Marisa L, Svrcek M, Lagrange A, et al. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nat Med 2011;17:1283–9.Article PubMed PDF
15. East JE, Atkin WS, Bateman AC, Clark SK, Dolwani S, Ket SN, et al. British Society of Gastroenterology position statement on serrated polyps in the colon and rectum. Gut 2017;66:1181–96.Article PubMed PMC
16. Jia M, Gao X, Zhang Y, Hoffmeister M, Brenner H. Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review. Clin Epigenetics 2016;8:25. Article PubMed PMC
17. Nishihara R, Wu K, Lochhead P, Morikawa T, Liao X, Qian ZR, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 2013;369:1095–105.Article PubMed
18. Lee MS, McGuffey EJ, Morris JS, Manyam G, Baladandayuthapani V, Wei W, et al. Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer. Br J Cancer 2016;114:1352–61.Article PubMed PMC PDF
19. Ang PW, Loh M, Liem N, Lim PL, Grieu F, Vaithilingam A, et al. Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features. BMC Cancer 2010;10:227. Article PubMed PMC PDF
20. Shen H, Yang J, Huang Q, Jiang MJ, Tan YN, Fu JF, et al. Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J Gastroenterol 2015;21:6470–8.Article PubMed PMC
21. Missiaglia E, Jacobs B, D’Ario G, Di Narzo AF, Soneson C, Budinska E, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol 2014;25:1995–2001.Article PubMed
22. Lan YT, Jen-Kou L, Lin CH, Yang SH, Lin CC, Wang HS, et al. Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers. J Surg Oncol 2015;111:905–10.Article PubMed PMC
23. Rowan A, Halford S, Gaasenbeek M, Kemp Z, Sieber O, Volikos E, et al. Refining molecular analysis in the pathways of colorectal carcinogenesis. Clin Gastroenterol Hepatol 2005;3:1115–23.Article PubMed PMC
24. Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 2009;27:5068–74.Article PubMed PMC
25. Bendardaf R, Buhmeida A, Hilska M, Laato M, Syrjänen S, Syrjänen K, et al. VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res 2008;28:3865–70.PubMed
26. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21:1350–6.Article PubMed PMC PDF
27. Sinicrope FA, Shi Q, Smyrk TC, Thibodeau SN, Dienstmann R, Guinney J, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology 2015;148:88–99.Article PubMed PMC
28. Inamura K. Colorectal cancers: an update on their molecular pathology. Cancers (Basel) 2018;10.Article
29. Phipps AI, Limburg PJ, Baron JA, Burnett-Hartman AN, Weisenberger DJ, Laird PW, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology 2015;148:77–87.e2.Article PubMed
30. Vedeld HM, Merok M, Jeanmougin M, Danielsen SA, Honne H, Presthus GK, et al. CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers. Int J Cancer 2017;141:967–76.Article PubMed PMC
31. Flemer B, Lynch DB, Brown JM, Jeffery IB, Ryan FJ, Claesson MJ, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut 2017;66:633–43.Article PubMed
32. Irrazábal T, Belcheva A, Girardin SE, Martin A, Philpott DJ. The multifaceted role of the intestinal microbiota in colon cancer. Mol Cell 2014;54:309–20.Article PubMed
33. Sears CL, Garrett WS. Microbes, microbiota, and colon cancer. Cell Host Microbe 2014;15:317–28.Article PubMed PMC
34. Swidsinski A, Loening-Baucke V, Herber A. Mucosal flora in Crohn’s disease and ulcerative colitis - an overview. J Physiol Pharmacol 2009;60 Suppl 6:61–71.PubMed
35. Dejea CM, Wick EC, Hechenbleikner EM, White JR, Mark Welch JL, Rossetti BJ, et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A 2014;111:18321–6.Article PubMed PMC
36. Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H, 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.Article PubMed
37. Drewes JL, Housseau F, Sears CL. Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy. Br J Cancer 2016;115:273–80.Article PubMed PMC PDF
38. Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol 2005;43:3380–9.Article PubMed PMC
39. Boleij A, Hechenbleikner EM, Goodwin AC, Badani R, Stein EM, Lazarev MG, et al. The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients. Clin Infect Dis 2015;60:208–15.Article PubMed
40. Karakas Y, Dizdar O. Tumor sidedness and prognosis in colorectal cancer: is microbiome the missing link? JAMA Oncol 2017;3:1000. Article
41. Mima K, Cao Y, Chan AT, Qian ZR, Nowak JA, Masugi Y, et al. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location. Clin Transl Gastroenterol 2016;7:e200.Article PubMed PMC PDF
42. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012;22:299–306.Article PubMed PMC
43. Mima K, Sukawa Y, Nishihara R, Qian ZR, Yamauchi M, Inamura K, et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol 2015;1:653–61.Article PubMed PMC
44. Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol 2015;16:30. Article PubMed PMC
45. Gao R, Kong C, Huang L, Li H, Qu X, Liu Z, et al. Mucosa-associated microbiota signature in colorectal cancer. Eur J Clin Microbiol Infect Dis 2017;36:2073–83.Article PubMed PDF
46. Purcell RV, Visnovska M, Biggs PJ, Schmeier S, Frizelle FA. Distinct gut microbiome patterns associate with consensus molecular subtypes of colorectal cancer. Sci Rep 2017;7:11590. Article PubMed PMC PDF
47. Mehta RS, Nishihara R, Cao Y, Song M, Mima K, Qian ZR, et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol 2017;3:921–7.Article PubMed PMC

Figure & Data

References

Citations

Citations to this article as recorded by

Integrating E-cadherin expression levels with TNM staging for enhanced prognostic prediction in colorectal cancer patients
Jae-Ghi Lee, Ilkyu Park, Hannah Lee, Seungyoon Nam, Jisup Kim, Won-Suk Lee, Myunghee Kang, Jung Ho Kim
BMC Cancer.2025;[Epub] CrossRef
The Gut Microbiota and Colorectal Cancer: Understanding the Link and Exploring Therapeutic Interventions
Imen Zalila-Kolsi, Dhoha Dhieb, Hussam A. Osman, Hadjer Mekideche
Biology.2025; 14(3): 251. CrossRef
The gut microbiota and its biogeography
Giselle McCallum, Carolina Tropini
Nature Reviews Microbiology.2024; 22(2): 105. CrossRef
The role of gut microbiota and probiotics in preventing, treating, and boosting the immune system in colorectal cancer
Forough Masheghati, Mohammad Reza Asgharzadeh, Abbas Jafari, Naser Masoudi, Hadi Maleki-Kakelar
Life Sciences.2024; 344: 122529. CrossRef
Diet-mediated gut microbial community modulation and signature metabolites as potential biomarkers for early diagnosis, prognosis, prevention and stage-specific treatment of colorectal cancer
Mutebi John Kenneth, Hsin-Chi Tsai, Chuan-Yin Fang, Bashir Hussain, Yi-Chou Chiu, Bing-Mu Hsu
Journal of Advanced Research.2023; 52: 45. CrossRef
Microbiome and metabolic features of tissues and feces reveal diagnostic biomarkers for colorectal cancer
Jiahui Feng, Zhizhong Gong, Zhangran Sun, Juan Li, Na Xu, Rick F. Thorne, Xu Dong Zhang, Xiaoying Liu, Gang Liu
Frontiers in Microbiology.2023;[Epub] CrossRef
Metachronous Colorectal Adenomas Occur Close to the Index Lesion
Ria Rosser, Bernard M. Corfe, Keith S. Chapple
Journal of Clinical Gastroenterology.2023; 57(9): 937. CrossRef
Genetic heterogeneity of colorectal cancer and the microbiome
Marina A Senchukova
World Journal of Gastrointestinal Oncology.2023; 15(3): 443. CrossRef
Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment
Sasha Waldstein, Marianne Spengler, Iryna V. Pinchuk, Nelson S. Yee
Journal of Personalized Medicine.2023; 13(7): 1114. CrossRef
Fusobacterium nucleatum-Mediated Alteration in Expression of VEGF and CCL3 Genes and KRAS Mutation in Colorectal Cancer Patients
Hataw Jalal Taher, Fouad Kamel
Jundishapur Journal of Microbiology.2023;[Epub] CrossRef
Risk of developing metachronous colorectal neoplasia after the resection of proximal versus distal adenomas
Yoon Suk Jung, Nam Hee Kim, Youngwoo Kim, Dong Il Park
Digestive and Liver Disease.2022; 54(4): 537. CrossRef
Faeces from malnourished colorectal cancer patients accelerate cancer progression
Xu Chao, Zhang Lei, Liu Hongqin, Wang Ziwei, Li Dechuan, Du Weidong, Xu Lu, Chen Haitao, Zhang Bo, Ju Haixing, Yao Qinghua
Clinical Nutrition.2022; 41(3): 632. CrossRef
Clinical and molecular profile of young adults with early‐onset colorectal cancer: Experience from four Australian tertiary centers
Derrick Ho Wai Siu, Arwa Ali, Angelina Tjokrowidjaja, Madhawa De Silva, Joanna Lee, Philip R. Clingan, Morteza Aghmesheh, Daniel Brungs, Cristina Mapagu, David Goldstein, Siobhan O'Neill, Winston S. Liauw, Katrin M. Sjoquist, David Thomas, Nick Pavlakis,
Asia-Pacific Journal of Clinical Oncology.2022; 18(6): 660. CrossRef
Microbial Characteristics of Common Tongue Coatings in Patients with Precancerous Lesions of the Upper Gastrointestinal Tract
Xiaoyu Kang, Bin Lu, Pan Xiao, Zhaolai Hua, Rui Shen, Jianping Wu, Juan Wu, Zhenfeng Wu, Chun Cheng, Junfeng Zhang, Enas Abdulhay
Journal of Healthcare Engineering.2022; 2022: 1. CrossRef
Colorectal microbiota after removal of colorectal cancer
Peter Cronin, Clodagh L Murphy, Maurice Barrett, Tarini Shankar Ghosh, Paola Pellanda, Eibhlis M O’Connor, Syed Akbar Zulquernain, Shane Kileen, Morgan McCourt, Emmet Andrews, Micheal G O’Riordain, Fergus Shanahan, Paul W O’Toole
NAR Cancer.2022;[Epub] CrossRef
Pretreatment inflammatory markers predicting treatment outcomes in colorectal cancer
Sanghyun An, Hongjin Shim, Kwangmin Kim, Bora Kim, Hui-Jae Bang, Hyejin Do, Hyang-Rae Lee, Youngwan Kim
Annals of Coloproctology.2022; 38(2): 97. CrossRef
Tumor tissue-specific bacterial biomarker panel for colorectal cancer: Bacteroides massiliensis, Alistipes species, Alistipes onderdonkii, Bifidobacterium pseudocatenulatum, Corynebacterium appendicis
Rizwana Hasan, Sudeep Bose, Rahul Roy, Debarati Paul, Saumitra Rawat, Pravin Nilwe, Neeraj K. Chauhan, Sangeeta Choudhury
Archives of Microbiology.2022;[Epub] CrossRef
Association of tumor-infiltrating lymphocytes with survival depends on primary tumor sidedness in stage III colon cancers (NCCTG N0147) [Alliance]
B. Saberzadeh-Ardestani, N.R. Foster, H.E. Lee, Q. Shi, S.R. Alberts, T.C. Smyrk, F.A. Sinicrope
Annals of Oncology.2022; 33(11): 1159. CrossRef
Fecal Luminal Factors from Patients with Gastrointestinal Diseases Alter Gene Expression Profiles in Caco-2 Cells and Colonoids
Luiza Holst, Cristina Iribarren, Maria Sapnara, Otto Savolainen, Hans Törnblom, Yvonne Wettergren, Hans Strid, Magnus Simrén, Maria K. Magnusson, Lena Öhman
International Journal of Molecular Sciences.2022; 23(24): 15505. CrossRef
Phosphorylated transducer and activator of transcription-3 (pSTAT3) immunohistochemical expression in paired primary and metastatic colorectal cancer
Esmeralda C. Marginean, Joanna Gotfrit, Horia Marginean, Daniel W. Yokom, Justin J. Bateman, Manijeh Daneshmand, Shelly Sud, Allen M. Gown, Derek Jonker, Timothy Asmis, Rachel A. Goodwin
Translational Oncology.2021; 14(2): 100996. CrossRef
Construction of a long noncoding RNA-based competing endogenous RNA network and prognostic signatures of left- and right-side colon cancer
Ke-zhi Li, Yi-xin Yin, Yan-ping Tang, Long Long, Ming-zhi Xie, Ji-lin Li, Ke Ding, Bang-li Hu
Cancer Cell International.2021;[Epub] CrossRef
Gut Microbiota as Potential Biomarker and/or Therapeutic Target to Improve the Management of Cancer: Focus on Colibactin-Producing Escherichia coli in Colorectal Cancer
Julie Veziant, Romain Villéger, Nicolas Barnich, Mathilde Bonnet
Cancers.2021; 13(9): 2215. CrossRef
Association of Habitual Preoperative Dietary Fiber Intake With Complications After Colorectal Cancer Surgery
Dieuwertje E. Kok, Melissa N. N. Arron, Tess Huibregtse, Flip M. Kruyt, Dirk Jan Bac, Henk K. van Halteren, Ewout A. Kouwenhoven, Evertine Wesselink, Renate M. Winkels, Moniek van Zutphen, Fränzel J. B. van Duijnhoven, Johannes H. W. de Wilt, Ellen Kampma
JAMA Surgery.2021; 156(9): 827. CrossRef
Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies
Andreas Koulouris, Christos Tsagkaris, Ippokratis Messaritakis, Nikolaos Gouvas, Maria Sfakianaki, Maria Trypaki, Vasiliki Spyrou, Manousos Christodoulakis, Elias Athanasakis, Evangelos Xynos, Maria Tzardi, Dimitrios Mavroudis, John Souglakos
Cancers.2021; 13(14): 3522. CrossRef
Effects of Helicobacter pylori Infection on the Oral Microbiota of Reflux Esophagitis Patients
Tian Liang, Fang Liu, Lijun Liu, Zhiying Zhang, Wenxue Dong, Su Bai, Lifeng Ma, Longli Kang
Frontiers in Cellular and Infection Microbiology.2021;[Epub] CrossRef
The Association of Gut Microbiota and Complications in Gastrointestinal-Cancer Therapies
Kevin M. Tourelle, Sebastien Boutin, Markus A. Weigand, Felix C. F. Schmitt
Biomedicines.2021; 9(10): 1305. CrossRef
Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4
Naroa Serna, José Vicente Carratalá, Oscar Conchillo-Solé, Carlos Martínez-Torró, Ugutz Unzueta, Ramón Mangues, Neus Ferrer-Miralles, Xavier Daura, Esther Vázquez, Antonio Villaverde
Pharmaceutics.2021; 13(11): 1922. CrossRef
Gut Microbiota Profiles in Early- and Late-Onset Colorectal Cancer: A Potential Diagnostic Biomarker in the Future
Murdani Abdullah, Ninik Sukartini, Saskia Aziza Nursyirwan, Rabbinu Rangga Pribadi, Hasan Maulahela, Amanda Pitarini Utari, Virly Nanda Muzellina, Agustinus Wiraatmadja, Kaka Renaldi
Digestion.2021; 102(6): 823. CrossRef
The gut microbiome in epilepsy
Birol Şafak, Bengü Altunan, Birol Topçu, Aynur Eren Topkaya
Microbial Pathogenesis.2020; 139: 103853. CrossRef
Therapeutic Targeting of the Colorectal Tumor Stroma
Wolf H. Fridman, Ian Miller, Catherine Sautès-Fridman, Annette T. Byrne
Gastroenterology.2020; 158(2): 303. CrossRef
Bacterial Biofilm and its Role in the Pathogenesis of Disease
Lene K. Vestby, Torstein Grønseth, Roger Simm, Live L. Nesse
Antibiotics.2020; 9(2): 59. CrossRef
Foes or Friends? Bacteria Enriched in the Tumor Microenvironment of Colorectal Cancer
Siyang Xu, Wen Yin, Yuling Zhang, Qimei Lv, Yijun Yang, Jin He
Cancers.2020; 12(2): 372. CrossRef
Esophageal microbiome signature in patients with Barrett’s esophagus and esophageal adenocarcinoma
Loris Riccardo Lopetuso, Marco Severgnini, Silvia Pecere, Francesca Romana Ponziani, Ivo Boskoski, Alberto Larghi, Gianluca Quaranta, Luca Masucci, Gianluca Ianiro, Tania Camboni, Antonio Gasbarrini, Guido Costamagna, Clarissa Consolandi, Giovanni Cammaro
PLOS ONE.2020; 15(5): e0231789. CrossRef
Unsuspected clinical presentation of coronavirus disease 2019: acute bowel disease
Marco Lotti, Michela Giulii Capponi, Dusanka Dokic, Paolo Bertoli, Alessandro Lucianetti
ANZ Journal of Surgery.2020; 90(9): 1772. CrossRef
Does Sidedness Matter in Unresectable Colorectal Cancer?
Suneel D. Kamath, Alok A. Khorana
Annals of Surgical Oncology.2019; 26(6): 1588. CrossRef
Morphological characteristics of mucinous adenocarcinoma of the colon and its embryogenetic premises
Yu. S. Korneva, R. V. Ukrainets
Colorectal Oncology.2019; 9(2): 16. CrossRef
Primary Tumor Sidedness Predicts Bevacizumab Benefit in Metastatic Colorectal Cancer Patients
Xia-Hong You, Can Wen, Zi-Jin Xia, Fan Sun, Yao Li, Wei Wang, Zhou Fang, Qing-Gen Chen, Lei Zhang, Yu-Huang Jiang, Xiao-Zhong Wang, Hou-Qun Ying, Zhen Zong
Frontiers in Oncology.2019;[Epub] CrossRef
Endoscopic gastric mucosal atrophy as a predictor of colorectal polyps: a large scale case-control study
Yoshinari Kawahara, Masaaki Kodama, Kazuhiro Mizukami, Tomoko Saito, Yuka Hirashita, Akira Sonoda, Kensuke Fukuda, Osamu Matsunari, Kazuhisa Okamoto, Ryo Ogawa, Tadayoshi Okimoto, Kazunari Murakami
Journal of Clinical Biochemistry and Nutrition.2019; 65(2): 153. CrossRef
Gut Microbiome: A Promising Biomarker for Immunotherapy in Colorectal Cancer
Sally Temraz, Farah Nassar, Rihab Nasr, Maya Charafeddine, Deborah Mukherji, Ali Shamseddine
International Journal of Molecular Sciences.2019; 20(17): 4155. CrossRef

Cite this Article

Cite this Article: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer

Ann Coloproctol. 2018;34(6):280-285. Published online December 31, 2018

DOI: https://doi.org/10.3393/ac.2018.12.17

XML Download

Figure

Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer

Fig. 1. Molecular features of right and left colon cancers. AREG, amphiregulin; CIMP, CpG island methylator phenotype; SCNA, somatic copy number alterations; EGFR, epidermal growth factor receptor; EREG, epiregulin; MSI, microsatellite instability; VEGF-1, vascular endothelial growth factor 1.

Fig. 1.

Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer

Feature	Right	Left
Age at diagnosis	Older	Younger
Sex	More women	More men
Tumor size	Larger	Smaller
Tumor condition at diagnosis	More advanced	Less advanced
Differentiation	Poor	Well
Prognosis	Poor	Good
Biofilm	Abundant	Less abundant
Microbiome	Prevotella	Fusobacterium
	-	Escherichia/Shigella
	Selenomonas	Leptotrichia
	Peptostreptococcus	-
Bile salt	Abundant	Less abundant
Association with Western dietary pattern	Less	More

Table 1. Different clinical features and gut microbiota between right and left colon cancers