The colorectal cancer risk at 18q21 is caused by a novel variant altering <i>SMAD7</i> expression

Pittman, Alan; Naranjo, Silvia; Webb, Emily L.; Broderick, Peter; Lips, Esther H.; Wezel, Tom van; Morreau, Hans; Sullivan, Kate; Fielding, Sarah; Twiss, Philip; Vijayakrishnan, Jayaram; Casares, Fernando; Qureshi, Mobshra; Gómez-Skármeta, José Luis; Houlston, Richard S.

doi:10.1101/gr.092668.109

Cited by 87 publications

(87 citation statements)

References 27 publications

(26 reference statements)

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“…44 For the 8q24.3 locus, allelic imbalance specific for the risk allele was reported, 45 while for the loci on chromosome 8q23.3 (EIF3H) and 18q21 (SMAD7), this association with CRC was not found. 46,47 In our study, no evidence for allele specific imbalance was found for the SNPs that increase the risk of CRC.…”

Section: Cancer Geneticscontrasting

confidence: 78%

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Middeldorp

Eijk

Oosting

et al. 2011

Intl Journal of Cancer

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Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMRproficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families.

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Section: Cancer Geneticscontrasting

confidence: 78%

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Middeldorp

Eijk

Oosting

et al. 2011

Intl Journal of Cancer

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“…green fl uorecent protein (GFP) 42 . Transgenesis was performed using the I-SceI method following the protocol already described 43 .…”

Section: Methodsmentioning

confidence: 99%

An evolutionarily conserved three-dimensional structure in the vertebrate Irx clusters facilitates enhancer sharing and coregulation

et al. 2011

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Developmental gene clusters are paradigms for the study of gene regulation; however, the mechanisms that mediate phenomena such as coregulation and enhancer sharing remain largely elusive. Here we address this issue by analysing the vertebrate Irx clusters. We fi rst present a deep enhancer screen of a 2-Mbp span covering the IrxA cluster. Using chromosome conformation capture, we show that enhancer sharing is widespread within the cluster, explaining its evolutionarily conserved organization. We also identify a three-dimensional architecture, probably formed through interactions with CCCTC-binding factor, which is present within both Irx clusters of mouse, Xenopus and zebrafi sh. This architecture brings the promoters of the fi rst two genes together in the same chromatin landscape. We propose that this unique and evolutionarily conserved genomic architecture of the vertebrate Irx clusters is essential for the coregulation of the fi rst two genes and simultaneously maintains the third gene in a partially independent regulatory landscape.

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“…A possible mechanism of action is thought to be via the influence of these SNPs on distal enhancer elements that regulate the expression of critical target genes (9)(10)(11)(12). Evidence exists for regulatory activity of SNPs located in several regions, including 8q24, 8q21, and 17q24 (13,14).…”

Section: Role Of Gwas Snps In Gene Regulationmentioning

confidence: 99%

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur

Tuupanen²,

Whitington

et al. 2013

Cancer Research

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Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.

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The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression

Cited by 87 publications

References 27 publications

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

An evolutionarily conserved three-dimensional structure in the vertebrate Irx clusters facilitates enhancer sharing and coregulation

Lessons from Functional Analysis of Genome-Wide Association Studies

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