The Colorectal Cancer Risk at 18q21 is Caused by a Novel Variant Altering SMAD7 Expression

Overview

Journal Genome Res

Specialty Genetics

Date 2009 Apr 28

PMID 19395656

Citations 50

Authors

Alan M Pittman

Silvia Naranjo

Emily Webb

Peter Broderick

Esther H Lips

Tom van Wezel

Hans Morreau

Kate Sullivan

Sarah Fielding

Philip Twiss

Jayaram Vijayakrishnan

Fernando Casares

Mobshra Qureshi

Jose Luis Gomez-Skarmeta

Richard S Houlston

Affiliations

Soon will be listed here.

Abstract

Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.

Citing Articles

Identification of potential functional variants and genes at 18q21.1 associated with the carcinogenesis of colorectal cancer.

Cheng X, Zhang F, Gong J, Li Y, Zhou D, Wang J PLoS Genet. 2022; 18(2):e1010050.

PMID: 35108261 PMC: 8870576. DOI: 10.1371/journal.pgen.1010050.

Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis.

Wu M, Yuan Y, Huang B, Chen J, Li B, Fang J Signal Transduct Target Ther. 2021; 6(1):395.

PMID: 34785655 PMC: 8595887. DOI: 10.1038/s41392-021-00781-3.

Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants.

Campbell P, Lin Y, Bien S, Figueiredo J, Harrison T, Guinter M J Natl Cancer Inst. 2020; 113(1):38-47.

PMID: 32324875 PMC: 7781451. DOI: 10.1093/jnci/djaa058.

The association between SMAD7 polymorphisms and colorectal cancer susceptibility as well as clinicopathological features in the Iranian population.

Akbari Z, Safari-Alighiarloo N, Aghdaei H, Vahedi M, Montazer Haghighi M, Matani Borkheili M Gastroenterol Hepatol Bed Bench. 2020; 13(1):23-30.

PMID: 32190221 PMC: 7069530.

Contrasting effects of an Mdm2 functional polymorphism on tumor phenotypes.

Ortiz G, Li Y, Post S, Pant V, Xiong S, Larsson C Oncogene. 2017; 37(3):332-340.

PMID: 28925402 PMC: 5775049. DOI: 10.1038/onc.2017.344.

References

Houlston R, Webb E, Broderick P, Pittman A, Di Bernardo M, Lubbe S . Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet. 2008; 40(12):1426-35. PMC: 2836775. DOI: 10.1038/ng.262. View

Zanke B, Greenwood C, Rangrej J, Kustra R, Tenesa A, Farrington S . Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007; 39(8):989-94. DOI: 10.1038/ng2089. View

Tuupanen S, Niittymaki I, Nousiainen K, Vanharanta S, Mecklin J, Nuorva K . Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution. Cancer Res. 2008; 68(1):14-7. DOI: 10.1158/0008-5472.CAN-07-5766. View

De Gobbi M, Viprakasit V, Hughes J, Fisher C, Buckle V, Ayyub H . A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science. 2006; 312(5777):1215-7. DOI: 10.1126/science.1126431. View

Levy L, Hill C . Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev. 2005; 17(1-2):41-58. DOI: 10.1016/j.cytogfr.2005.09.009. View

Qin Z, Niu T, Liu J . Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet. 2002; 71(5):1242-7. PMC: 385113. DOI: 10.1086/344207. View

Dermitzakis E, Reymond A, Antonarakis S . Conserved non-genic sequences - an unexpected feature of mammalian genomes. Nat Rev Genet. 2005; 6(2):151-7. DOI: 10.1038/nrg1527. View

Paoni N, Feldman M, Gutierrez L, Ploplis V, Castellino F . Transcriptional profiling of the transition from normal intestinal epithelia to adenomas and carcinomas in the APCMin/+ mouse. Physiol Genomics. 2003; 15(3):228-35. DOI: 10.1152/physiolgenomics.00078.2003. View

Penegar S, Wood W, Lubbe S, Chandler I, Broderick P, Papaemmanuil E . National study of colorectal cancer genetics. Br J Cancer. 2007; 97(9):1305-9. PMC: 2360468. DOI: 10.1038/sj.bjc.6603997. View

10.

Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman A . A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet. 2008; 40(5):623-30. DOI: 10.1038/ng.111. View

11.

Tenesa A, Farrington S, Prendergast J, Porteous M, Walker M, Haq N . Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet. 2008; 40(5):631-7. PMC: 2778004. DOI: 10.1038/ng.133. View

12.

McCarthy M, Abecasis G, Cardon L, Goldstein D, Little J, Ioannidis J . Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008; 9(5):356-69. DOI: 10.1038/nrg2344. View

13.

Minichiello M, Durbin R . Mapping trait loci by use of inferred ancestral recombination graphs. Am J Hum Genet. 2006; 79(5):910-22. PMC: 1698562. DOI: 10.1086/508901. View

14.

Ten Dijke P, Hill C . New insights into TGF-beta-Smad signalling. Trends Biochem Sci. 2004; 29(5):265-73. DOI: 10.1016/j.tibs.2004.03.008. View

15.

Steidl U, Steidl C, Ebralidze A, Chapuy B, Han H, Will B . A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. J Clin Invest. 2007; 117(9):2611-20. PMC: 1937499. DOI: 10.1172/JCI30525. View

16.

Gomez-Skarmeta J, Lenhard B, Becker T . New technologies, new findings, and new concepts in the study of vertebrate cis-regulatory sequences. Dev Dyn. 2006; 235(4):870-85. DOI: 10.1002/dvdy.20659. View

17.

Hudson T . Wanted: regulatory SNPs. Nat Genet. 2003; 33(4):439-40. DOI: 10.1038/ng0403-439. View

18.

Lips E, de Graaf E, Tollenaar R, van Eijk R, Oosting J, Szuhai K . Single nucleotide polymorphism array analysis of chromosomal instability patterns discriminates rectal adenomas from carcinomas. J Pathol. 2007; 212(3):269-77. DOI: 10.1002/path.2180. View

19.

Ku J, Kang S, Shin Y, Kang H, Hong S, Kim I . Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene. 2004; 23(40):6736-42. DOI: 10.1038/sj.onc.1207731. View

20.

Curtin K, Lin W, George R, Katory M, Shorto J, Cannon-Albright L . Meta association of colorectal cancer confirms risk alleles at 8q24 and 18q21. Cancer Epidemiol Biomarkers Prev. 2009; 18(2):616-21. PMC: 2729170. DOI: 10.1158/1055-9965.EPI-08-0690. View