DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Pardini, Barbara; Corrado, Alda; Paolicchi, Elisa; Cugliari, Giovanni; Berndt, Sonja I.; Bézieau, Stéphane; Bien, Stephanie A.; Brenner, Hermann; Caan, Bette J.; Campbell, Peter T.; Casey, Graham; Chan, Andrew T.; Chang‐Claude, Jenny; Cotterchio, Michelle; Gala, Manish; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hsu, Li; Huyghe, Jeroen R.; Jenkins, Mark A.; Marchand, Loı̈c Le; Lin, Yi; Lindor, Noralane M.; Nan, Hongmei; Newcomb, Polly A.; Ogino, Shuji; Potter, John D.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Vodičková, Ľudmila; Vymetalková, Veronika; Vodička, Pavel; Gemignani, Federica; Peters, Ulrike; Naccarati, Alessio; Landi, Stefano

doi:10.1002/ijc.32516

Cited by 21 publications

(14 citation statements)

References 51 publications

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“…The activation of PI3K/AKT signaling has been shown to promote EMT ( Liu et al, 2018 ). “Wnt/beta-catenin signaling”, “MYC target v1”, and “DNA repair” are closely related to tumorigenesis and the development of HCC ( Dolezal et al, 2017 ; Dimri and Satyanarayana, 2020 ; Pardini et al, 2020 ). Taken together, the findings clearly suggest that these genes are closely associated with the mechanisms underlying HCC cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

Song

Ding

et al. 2020

Front. Genet.

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Background Bioinformatics provides a valuable tool to explore the molecular mechanisms underlying pathogenesis of hepatocellular carcinoma (HCC). To improve prognosis of patients, identification of robust biomarkers associated with the pathogenic pathways of HCC remains an urgent research priority. Methods We employed the Robust Rank Aggregation method to integrate nine qualified HCC datasets from the Gene Expression Omnibus. A robust set of differentially expressed genes (DEGs) between tumor and normal tissue samples were screened. Weighted gene co-expression network analysis was applied to cluster DEGs and the key modules related to clinical traits identified. Based on network topology analysis, novel risk genes derived from key modules were mined and biological verification performed. The potential functions of these risk genes were further explored with the aid of miRNA–mRNA regulatory networks. Finally, the prognostic ability of these genes was assessed by constructing a clinical prediction model. Results Two key modules showed significant association with clinical traits. In combination with protein–protein interaction analysis, 29 hub genes were identified. Among these genes, 19 from one module showed a pattern of upregulation in HCC and were associated with the tumor node metastasis stage, and 10 from the other module displayed the opposite trend. Survival analyses indicated that all these genes were significantly related to patient prognosis. Based on the miRNA-mRNA regulatory network, 29 genes strongly linked to tumor activity were identified. Notably, five of the novel risk genes, ABAT, DAO, PCK2, SLC27A2, and HAO1, have rarely been reported in previous studies. Gene set enrichment analysis for each gene revealed regulatory roles in proliferation and prognosis of HCC. Least absolute shrinkage and selection operator regression analysis further validated DAO, PCK2, and HAO1 as prognostic factors in an external HCC dataset. Conclusion Analysis of multiple datasets combined with global network information presents a successful approach to uncover the complex biological mechanisms of HCC. More importantly, this novel integrated strategy facilitates identification of risk hub genes as candidate biomarkers for HCC, which could effectively guide clinical treatments.

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Section: Resultsmentioning

confidence: 99%

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

Song

Ding

et al. 2020

Front. Genet.

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“…Several association studies addressed the role of low penetrance BER gene variants in sporadic CRC with often controversial results. The recent whole genome association studies failed to identify these variants in large CRC patient cohorts [5,145]. Despite it was shown that hOGG1 326Cys SNP significantly affected BER DRC, the overall effect is rather minor, and these gene variants may rather find their relevance in interactions [146,147].…”

Section: Discussionmentioning

confidence: 99%

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

Vodička

Urbanová

Makovický

et al. 2020

IJMS

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Oxidative stress with subsequent premutagenic oxidative DNA damage has been implicated in colorectal carcinogenesis. The repair of oxidative DNA damage is initiated by lesion-specific DNA glycosylases (hOGG1, NTH1, MUTYH). The direct evidence of the role of oxidative DNA damage and its repair is proven by hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome), where germline mutations cause loss-of-function in glycosylases of base excision repair, thus enabling the accumulation of oxidative DNA damage and leading to the adenoma-colorectal cancer transition. Unrepaired oxidative DNA damage often results in G:C>T:A mutations in tumor suppressor genes and proto-oncogenes and widespread occurrence of chromosomal copy-neutral loss of heterozygosity. However, the situation is more complicated in complex and heterogeneous disease, such as sporadic colorectal cancer. Here we summarized our current knowledge of the role of oxidative DNA damage and its repair on the onset, prognosis and treatment of sporadic colorectal cancer. Molecular and histological tumor heterogeneity was considered. Our study has also suggested an additional important source of oxidative DNA damage due to intestinal dysbiosis. The roles of base excision repair glycosylases (hOGG1, MUTYH) in tumor and adjacent mucosa tissues of colorectal cancer patients, particularly in the interplay with other factors (especially microenvironment), deserve further attention. Base excision repair characteristics determined in colorectal cancer tissues reflect, rather, a disease prognosis. Finally, we discuss the role of DNA repair in the treatment of colon cancer, since acquired or inherited defects in DNA repair pathways can be effectively used in therapy.

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“…A meta-analysis further strengthened the above evidence for rs1800734 as an event in a specific CRC subtype ( p = 3.43 × 10 −12 ) [ 40 ]. Finally, a recent study based on genome-wide association studies (GWAS) data by Pardini et al comprising over 27,000 individuals showed rs1800734 to be significantly associated with the risk of colon cancer (OR = 1.13, 95% CI = 1.07–1.18, p = 3.48 × 10 −6 ) [ 55 ]. When looking at tumour site, rs1800734 was mainly associated with proximal colon tumours (OR = 1.13, 95% CI = 1.07–1.18).…”

Section: Results On Mmr Gene Variantsmentioning

confidence: 99%

DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers

Čaja

Vodičková

Král

et al. 2020

IJMS

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The phenotypic effects of single nucleotide polymorphisms (SNPs) in the development of sporadic solid cancers are still scarce. The aim of this review was to summarise and analyse published data on the associations between SNPs in mismatch repair genes and various cancers. The mismatch repair system plays a unique role in the control of the genetic integrity and it is often inactivated (germline and somatic mutations and hypermethylation) in cancer patients. Here, we focused on germline variants in mismatch repair genes and found the outcomes rather controversial: some SNPs are sometimes ascribed as protective, while other studies reported their pathological effects. Regarding the complexity of cancer as one disease, we attempted to ascertain if particular polymorphisms exert the effect in the same direction in the development and treatment of different malignancies, although it is still not straightforward to conclude whether polymorphisms always play a clear positive role or a negative one. Most recent and robust genome-wide studies suggest that risk of cancer is modulated by variants in mismatch repair genes, for example in colorectal cancer. Our study shows that rs1800734 in MLH1 or rs2303428 in MSH2 may influence the development of different malignancies. The lack of functional studies on many DNA mismatch repair SNPs as well as their interactions are not explored yet. Notably, the concerted action of more variants in one individual may be protective or harmful. Further, complex interactions of DNA mismatch repair variations with both the environment and microenvironment in the cancer pathogenesis will deserve further attention.

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DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility

Cited by 21 publications

References 51 publications

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers

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