Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum

Mai Yamauchi, Teppei Morikawa, Aya Kuchiba, Yu Imamura, Zhi Rong Qian, Reiko Nishihara, Xiaoyun Liao, Levi Waldron, Yujin Hoshida, Curtis Huttenhower, Andrew T. Chan, Edward Giovannucci, Charles Fuchs, Shuji Ogino

Research output: Contribution to journalArticle

332 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)847-854
Number of pages8
JournalGut
Volume61
Issue number6
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

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Colorectal Neoplasms
Transverse Colon
Microsatellite Instability
CpG Islands
Rectum
Ascending Colon
Neoplasms
Phenotype
Mutation
Cecal Neoplasms
Descending Colon
Translational Medical Research
Microbiota
Sigmoid Colon
Mutation Rate
Rectal Neoplasms
Epigenomics
Colonic Neoplasms
Methylation
Linear Models

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. / Yamauchi, Mai; Morikawa, Teppei; Kuchiba, Aya; Imamura, Yu; Qian, Zhi Rong; Nishihara, Reiko; Liao, Xiaoyun; Waldron, Levi; Hoshida, Yujin; Huttenhower, Curtis; Chan, Andrew T.; Giovannucci, Edward; Fuchs, Charles; Ogino, Shuji.

In: Gut, Vol. 61, No. 6, 01.06.2012, p. 847-854.

Research output: Contribution to journalArticle

Yamauchi, M, Morikawa, T, Kuchiba, A, Imamura, Y, Qian, ZR, Nishihara, R, Liao, X, Waldron, L, Hoshida, Y, Huttenhower, C, Chan, AT, Giovannucci, E, Fuchs, C & Ogino, S 2012, 'Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum', Gut, vol. 61, no. 6, pp. 847-854. https://doi.org/10.1136/gutjnl-2011-300865
Yamauchi, Mai ; Morikawa, Teppei ; Kuchiba, Aya ; Imamura, Yu ; Qian, Zhi Rong ; Nishihara, Reiko ; Liao, Xiaoyun ; Waldron, Levi ; Hoshida, Yujin ; Huttenhower, Curtis ; Chan, Andrew T. ; Giovannucci, Edward ; Fuchs, Charles ; Ogino, Shuji. / Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. In: Gut. 2012 ; Vol. 61, No. 6. pp. 847-854.
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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.",
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T1 - Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum

AU - Yamauchi, Mai

AU - Morikawa, Teppei

AU - Kuchiba, Aya

AU - Imamura, Yu

AU - Qian, Zhi Rong

AU - Nishihara, Reiko

AU - Liao, Xiaoyun

AU - Waldron, Levi

AU - Hoshida, Yujin

AU - Huttenhower, Curtis

AU - Chan, Andrew T.

AU - Giovannucci, Edward

AU - Fuchs, Charles

AU - Ogino, Shuji

PY - 2012/6/1

Y1 - 2012/6/1

N2 - 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.

AB - 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.

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