Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

Tezcan, Gülçin; Tunca, Berrin; Ak, Seçil; Çeçener, Gülşah; Egelí, Ünal

doi:10.4251/wjgo.v8.i1.83

Cited by 22 publications

(25 citation statements)

References 166 publications

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“…Early-onset CRC includes approximately 30% of hereditary and 70% of sporadic CRC cases10. The molecular mechanisms driving hereditary early-onset CRC have been well defined as germline mutations such as the MLH1, MSH2, MSH6, PMS2 , and EPCAM mutations in Lynch syndrome and APC and MUTYH mutations in FAP11, whereas sporadic early-onset CRC has not been fully clarified10.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanisms driving hereditary early-onset CRC have been well defined as germline mutations such as the MLH1, MSH2, MSH6, PMS2 , and EPCAM mutations in Lynch syndrome and APC and MUTYH mutations in FAP11, whereas sporadic early-onset CRC has not been fully clarified10. Although sporadic early-onset CRC is thought to be attributable to common genetic variants with low penetrance4, only a few SNPs, including rs10795668 at 10p14, rs3802842 at 11q23.1, and rs4779584 at 15q13.3, have been associated with an increased risk for early-onset CRC12.…”

Section: Discussionmentioning

confidence: 99%

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Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset

Song

Shin

Park

et al. 2017

Sci Rep

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Common genetic risk variants for colorectal cancer (CRC) have been identified at approximately 40 loci by genome-wide association studies (GWAS). We investigated the association of these risk variants by age at onset of CRC using case-only and case-control analysis. A total of 1,962 CRC cases and 2,668 controls from two independent case-control studies conducted by Korea’s National Cancer Center were included in this study. We genotyped 33 GWAS-identified single-nucleotide polymorphisms (SNPs) associated with CRC risk. The risk allele in SNP rs704017, located at 10q22.3 in the ZMIZ1-AS1 gene, was consistently less frequent among CRC patients aged <50 years than among CRC patients aged ≥50 years in the case-only analysis (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.66–0.92, P = 2.7 × 10−3, in an additive model), although this did not surpass the threshold for multiple testing. The direction of associations between rs704017 and CRC risk differed by age group in the combined case-control analysis (<50 years: OR = 0.77, 95% CI = 0.60–0.98, P = 0.03 and ≥50 years: OR = 1.13, 95% CI = 0.98–1.29, P = 0.09, in a dominant model); the p-values for heterogeneity (Pheterogeneity = 7.5 × 10−3) and for interaction were statistically significant (Pinteraction = 7.8 × 10−3, in the dominant model). Our results suggest that the CRC susceptibility SNP rs704017 has a hereditary effect on onset age of CRC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset

Song

Shin

Park

et al. 2017

Sci Rep

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“…Mutations in APC cause familial adenomatous polyposis, occurring in <1% of CRCs [12, 13]. While these and several other rarer germline gene mutations are known contributors to ~10% of CRCs, twin and family studies have estimated the heritability of CRC to be up to 35% [14].…”

Section: Introductionmentioning

confidence: 99%

The dynamic DNA methylation landscape of the mutL homolog 1 shore is altered by MLH1-93G>A polymorphism in normal tissues and colorectal cancer

et al. 2017

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BackgroundColorectal cancers (CRCs) undergo distinct genetic and epigenetic alterations. Expression of mutL homolog 1 (MLH1), a mismatch repair gene that corrects DNA replication errors, is lost in up to 15% of sporadic tumours due to mutation or, more commonly, due to DNA methylation of its promoter CpG island. A single nucleotide polymorphism (SNP) in the CpG island of MLH1 (MLH1-93G>A or rs1800734) is associated with CpG island hypermethylation and decreased MLH1 expression in CRC tumours. Further, in peripheral blood mononuclear cell (PBMC) DNA of both CRC cases and non-cancer controls, the variant allele of rs1800734 is associated with hypomethylation at the MLH1 shore, a region upstream of its CpG island that is less dense in CpG sites. ResultsTo determine whether this genotype-epigenotype association is present in other tissue types, including colorectal tumours, we assessed DNA methylation in matched normal colorectal tissue, tumour, and PBMC DNA from 349 population-based CRC cases recruited from the Ontario Familial Colorectal Cancer Registry. Using the semi-quantitative real-time PCR-based MethyLight assay, MLH1 shore methylation was significantly higher in tumour tissue than normal colon or PBMCs (P < 0.01). When shore methylation levels were stratified by SNP genotype, normal colorectal DNA and PBMC DNA were significantly hypomethylated in association with variant SNP genotype (P < 0.05). However, this association was lost in tumour DNA. Among distinct stages of CRC, metastatic stage IV CRC tumours incurred significant hypomethylation compared to stage I–III cases, irrespective of genotype status. Shore methylation of MLH1 was not associated with MSI status or promoter CpG island hypermethylation, regardless of genotype. To confirm these results, bisulfite sequencing was performed in matched tumour and normal colorectal specimens from six CRC cases, including two cases per genotype (wildtype, heterozygous, and homozygous variant). Bisulfite sequencing results corroborated the methylation patterns found by MethyLight, with significant hypomethylation in normal colorectal tissue of variant SNP allele carriers.ConclusionsThese results indicate that the normal tissue types tested (colorectum and PBMC) experience dynamic genotype-associated epigenetic alterations at the MLH1 shore, whereas tumour DNA incurs aberrant hypermethylation compared to normal DNA.

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“…Colorectal carcinogenesis is a complex, multistep process involving environmental, demographic, and lifestyle factors in addition to gene alterations and viral infections. The highest incidence of CRCs is observed in Western Europe, North America, Australia as well as in some Middle-Eastern countries [3,4]. It is notable also that although the rate of this disease is relatively lower in sub-Saharan African communities, South America, and Asia; however, CRCs are gradually increasing due to assimilating life style and dietary habits of Western countries [3][4][5].…”

Section: Introductionmentioning

confidence: 95%

“…The highest incidence of CRCs is observed in Western Europe, North America, Australia as well as in some Middle-Eastern countries [3,4]. It is notable also that although the rate of this disease is relatively lower in sub-Saharan African communities, South America, and Asia; however, CRCs are gradually increasing due to assimilating life style and dietary habits of Western countries [3][4][5]. Additionally, around twothirds of CRC patients will develop distant metastases during the course of their illness, which is the main cause of cancer-related death of this disease [6].…”

Section: Introductionmentioning

confidence: 99%

High-Risk Human Papillomavirus and Colorectal Carcinogenesis

Moustafa¹,

Al-Antary²,

Yasmeen³

2016

Human Papillomavirus - Research in a Global Perspective

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Colorectal, colon and rectal, cancer is the third most common malignancy in both men and women worldwide. Colorectal carcinogenesis is a complex, multistep process implicating environmental and lifestyle factors in addition to gene mutation and viral infections. On the other hand, it is well established that human papillomaviruses (HPVs) infection play a crucial role in certain types of human carcinomas including cervical and head and neck (HN); as roughly 96% and 30% of these cancers are positive for high-risk HPVs, respectively. Moreover, it has been reported that the presence of high-risk HPVs is associated with vascular invasion, lymph node metastases, and tumor size in cervical and HN cancers. Recently, several investigations pointed-out that high-risk HPVs are present in around 70% of human colorectal cancers. Likewise, our group has demonstrated that E6/E7 oncoproteins of HPV type 16 convert noninvasive and nonmetastatic human cancer cells to invasive and metastatic form. Accordingly, it is evident that high-risk HPVs are present in human colorectal cancers where they could play an important role in the development of these malignancies. In this chapter, we will discuss the presence and role of high-risk HPVs in human colorectal carcinogenesis and metastasis; particularly, the interaction between E5 and E6/E7 oncoproteins of high-risk HPVs in colorectal malignancies, which has been linked with the initiation and progression of these tumors.

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Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

Cited by 22 publications

References 166 publications

Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset

Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset

The dynamic DNA methylation landscape of the mutL homolog 1 shore is altered by MLH1-93G>A polymorphism in normal tissues and colorectal cancer

High-Risk Human Papillomavirus and Colorectal Carcinogenesis

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