Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival

Xabier Garcia-Albeniz, Hongmei Nan, Linda Valeri, Teppei Morikawa, Aya Kuchiba, Amanda I. Phipps, Carolyn M. Hutter, Ulrike Peters, Polly A. Newcomb, Charles S. Fuchs, Edward L. Giovannucci, Shuji Ogino, Andrew T. Chan

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Abstract

The minor allele (G) of rs4939827, a SMAD7 (18q21) intronic variant, is associated with a lower risk of developing colorectal cancer (CRC) and poorer survival after diagnosis. Our objective was to evaluate the associations of this variant with different tumor phenotype and intratumoral molecular characteristics. We evaluated 1509 CRC cases and 2307 age-matched controls nested within the Nurses' Health Study and the Health Professionals Follow-up Study. We used the TaqMan assay to genotype rs4939827 and logistic regression to assess the association of rs4939827 with risk of CRC according to different phenotypic and molecular characteristics. We found that the minor allele (G) in rs4939827 (SMAD7, 18q21) was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95% confidence interval (CI) 0.62-0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95% CI 0.93-1.23, P for heterogeneity = 1.2 × 10-4). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95% CI, 1.02-1.42). We can conclude that the minor allele (G) of the germline intronic SMAD7 variant rs4939827 is associated with a lower risk of CRC with earlier tumor stage and CRC without methylation of the tumor suppressor RUNX3. These findings suggest that individuals with this SMAD7 variant that develop CRC are more probably to have tumors with greater invasiveness and methylation of RUNX3, which potentially contributes to their poorer observed survival.

Original languageEnglish (US)
Pages (from-to)292-298
Number of pages7
JournalCarcinogenesis
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2013
Externally publishedYes

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Colorectal Neoplasms
Neoplasms
Alleles
Methylation
Confidence Intervals
Odds Ratio
Health
Logistic Models
Nurses
Genotype
Phenotype

ASJC Scopus subject areas

  • Cancer Research

Cite this

Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival. / Garcia-Albeniz, Xabier; Nan, Hongmei; Valeri, Linda; Morikawa, Teppei; Kuchiba, Aya; Phipps, Amanda I.; Hutter, Carolyn M.; Peters, Ulrike; Newcomb, Polly A.; Fuchs, Charles S.; Giovannucci, Edward L.; Ogino, Shuji; Chan, Andrew T.

In: Carcinogenesis, Vol. 34, No. 2, 01.02.2013, p. 292-298.

Research output: Contribution to journalArticle

Garcia-Albeniz, X, Nan, H, Valeri, L, Morikawa, T, Kuchiba, A, Phipps, AI, Hutter, CM, Peters, U, Newcomb, PA, Fuchs, CS, Giovannucci, EL, Ogino, S & Chan, AT 2013, 'Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival', Carcinogenesis, vol. 34, no. 2, pp. 292-298. https://doi.org/10.1093/carcin/bgs335
Garcia-Albeniz, Xabier ; Nan, Hongmei ; Valeri, Linda ; Morikawa, Teppei ; Kuchiba, Aya ; Phipps, Amanda I. ; Hutter, Carolyn M. ; Peters, Ulrike ; Newcomb, Polly A. ; Fuchs, Charles S. ; Giovannucci, Edward L. ; Ogino, Shuji ; Chan, Andrew T. / Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival. In: Carcinogenesis. 2013 ; Vol. 34, No. 2. pp. 292-298.
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abstract = "The minor allele (G) of rs4939827, a SMAD7 (18q21) intronic variant, is associated with a lower risk of developing colorectal cancer (CRC) and poorer survival after diagnosis. Our objective was to evaluate the associations of this variant with different tumor phenotype and intratumoral molecular characteristics. We evaluated 1509 CRC cases and 2307 age-matched controls nested within the Nurses' Health Study and the Health Professionals Follow-up Study. We used the TaqMan assay to genotype rs4939827 and logistic regression to assess the association of rs4939827 with risk of CRC according to different phenotypic and molecular characteristics. We found that the minor allele (G) in rs4939827 (SMAD7, 18q21) was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95{\%} confidence interval (CI) 0.62-0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95{\%} CI 0.93-1.23, P for heterogeneity = 1.2 × 10-4). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95{\%} CI, 1.02-1.42). We can conclude that the minor allele (G) of the germline intronic SMAD7 variant rs4939827 is associated with a lower risk of CRC with earlier tumor stage and CRC without methylation of the tumor suppressor RUNX3. These findings suggest that individuals with this SMAD7 variant that develop CRC are more probably to have tumors with greater invasiveness and methylation of RUNX3, which potentially contributes to their poorer observed survival.",
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AU - Nan, Hongmei

AU - Valeri, Linda

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AU - Kuchiba, Aya

AU - Phipps, Amanda I.

AU - Hutter, Carolyn M.

AU - Peters, Ulrike

AU - Newcomb, Polly A.

AU - Fuchs, Charles S.

AU - Giovannucci, Edward L.

AU - Ogino, Shuji

AU - Chan, Andrew T.

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