Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in lynch syndrome

Talseth‐Palmer, Bente A.; Brenne, Ingvild S; Ashton, Katie A.; Evans, Tiffany‐Jane; McPhillips, Mary; Groombridge, Claire; Suchy, Janina; Kurzawski, Grzegorz; Spigelman, Allan D.; Lubiński, Jan; Scott, Rodney J.

doi:10.1136/jmg.2010.079962

Cited by 40 publications

(36 citation statements)

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“…12 These results were partly confirmed in a cohort of Australian and Polish MMR mutation carriers, but were not replicated in a French cohort. 13,14 We selected the hTERT variant rs2075786 by somehow combining candidate gene and GWAS-based approaches. First, hTERT has an important role at very early stages of carcinogenesis, its expression has been linked to increased susceptibility to tumorigenesis, and rs2075786 has been associated with cancer risk.…”

Section: Rs2075786 and Telomere Lengthmentioning

confidence: 99%

“…11 In contrast, two genetic variants previously identified in CRC genome-wide association studies (GWAS), rs16892766 and rs3802842, might modify cancer risk in LS families. [12][13][14] Telomeres are located at the end of chromosomes and protect the chromosome ends from nucleolitic degradation, end-to-end fusions and irregular recombination, being thus critical for genome stability and integrity. Telomeres progressively shorten with each cell replication cycle.…”

Section: Introductionmentioning

confidence: 99%

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Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

et al. 2012

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Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative risk LScao45_AA ¼ 2.90; 95% confidence interval ¼ 1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.

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Section: Rs2075786 and Telomere Lengthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

et al. 2012

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“…[38][39][40] Thus, variants on 8q23.3 and 11q23.1 have been found to modify colorectal cancer risk in Lynch syndrome. 41,42 On the other hand, some polygenic diseases such as age-related macular degeneration have been attributed to several genetic variants with considerably large effect sizes (eg, the variants in CFH; odds ratio ¼ 4.6), which taken together, account for 50% of the heritability of the disease. By contrast, 32 genetic variants identified as being associated with Crohn's disease are able to explain only 20% of the heritability.…”

Section: Common Approaches To Interrogate the Genetic Basis Of Diseasementioning

confidence: 99%

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

Cooper

et al. 2012

Modern Pathology

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Recent advances in genotyping and sequencing technologies have provided powerful tools with which to explore the genetic basis of both Mendelian (monogenic) and sporadic (polygenic) diseases. Several hundred genomewide association studies have so far been performed to explore the genetics of various polygenic or complex diseases including those cancers with a genetic predisposition. Exome sequencing has also proven very successful in elucidating the etiology of a range of hitherto poorly understood Mendelian disorders caused by high-penetrance mutations. Despite such progress, the genetic etiology of several familial cancers, such as familial colorectal cancer type X, has remained elusive. Familial colorectal cancer type X and Lynch syndrome are similar in terms of their fulfilling certain clinical criteria, but the former group is not characterized by germline mutations in DNA mismatch-repair genes. On the other hand, the genetics of sporadic colorectal cancer have been investigated by genome-wide association studies, leading to the identification of multiple new susceptibility loci. In addition, there is increasing evidence to suggest that familial and sporadic cancers exhibit similarities in terms of their genetic etiologies. In this review, we have summarized our current knowledge of familial colorectal cancer type X, discussed current approaches to probing its genetic etiology through the application of new sequencing technologies and the recruitment of the results of colorectal cancer genome-wide association studies, and explore the challenges that remain to be overcome given the uncertainty of the current genetic model (ie, monogenic vs polygenic) of familial colorectal cancer type X.

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“…1,2 If these SNPs also predicted CRC risk for carriers of mismatch repair (MMR) gene mutations (which cause Lynch syndrome), there is potential to use them for a personalized risk assessment and therefore a tailored surveillance program. Two studies 3,4 have reported that MMR gene mutation carriers, who also carry either the C-allele of rs16892766 on 8q23.3 or the C-allele of rs3802842 on 11q23.1, are at increased risk of CRC compared with carriers without these alleles, especially for MLH1 mutation carriers 4 and especially for females. 3 However, another study 5 of these SNPs observed no such association.…”

mentioning

confidence: 99%

“…In a recent study, Talseth-Palmer et al 6 conducted a pooled analysis by combing the studies by Wijnen et al 3 and Talseth-Palmer et al 4 to investigate the role of seven SNPs from six independent loci on CRC risk for MMR gene mutation carriers. They reported that carriers of the C-allele of rs16892766 (8q23.3) and the C-allele of rs3802842 (11q23.1) are at increased risk of CRC for MLH1 mutation carriers.…”

mentioning

confidence: 99%

Is the reported modifying effect of 8q23.3 and 11q23.1 on colorectal cancer risk for MLH1 mutation carriers valid?

Win

Jenkins

2013

Intl Journal of Cancer

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Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in lynch syndrome

Abstract: The authors were able to replicate the association between the CRC susceptibility loci on chromosomes 8q23.3 and 11q23 and the risk of developing CRC in patients with Lynch syndrome, but the association could only be detected in MLH1 mutation carriers in this study.

Cited by 40 publications

References 24 publications

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

Is the reported modifying effect of 8q23.3 and 11q23.1 on colorectal cancer risk for MLH1 mutation carriers valid?

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