Update on genetic predisposition to colorectal cancer and polyposis

Valle, Laura; Voer, Richarda M. de; Goldberg, Yael; Sjursen, Wenche; Försti, Asta; Ruíz-Ponte, Clara; Caldés, Trinidad; Garré, Pilar; Olsen, Maren Fridtjofsen; Nordling, Margareta; Castellví–Bel, Sergi; Hemminki, Kari

doi:10.1016/j.mam.2019.03.001

Cited by 126 publications

(132 citation statements)

References 177 publications

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“…The twist transcription factor, encoded by the TWIST1 gene (TWIST1; OMIM* 601622) is a member of the basic helix loop helix transcription factor family and has an ORIGINAL ARTICLE HEREDITARY CRC IN MACEDONIANS pathogenic variants [22,23]. In 12/25 (48%) patients we did not detect any pathogenic variant, further supporting the notion that the molecular basis of this condition is highly heterogenous and probably involves defect(s) in other gene(s) not tested in our assay [24].…”

Section: P R O O F Introductionsupporting

confidence: 77%

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

Staninova-Stojovska

Matevska-Geskovska

Panovski

et al. 2019

Balkan Journal of Medical Genetics

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Hereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.

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Section: P R O O F Introductionsupporting

confidence: 77%

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

Staninova-Stojovska

Matevska-Geskovska

Panovski

et al. 2019

Balkan Journal of Medical Genetics

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“…On the other hand, the risk of developing CRC is influenced by both environmental and genetic factors. Part of this germline CRC predisposition is already known including both rare, high-penetrance and common, low-penetrance genetic variants 4. Genome-wide association studies (GWAS) have been conducted since 2007 and have identified ~130 common, low-penetrance genetic variants associated with CRC risk 5…”

Section: Introductionmentioning

confidence: 99%

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

et al. 2020

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BackgroundSerrated polyposis syndrome (SPS) is a clinical entity characterised by large and/ormultiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored.ObjectiveThe aim of this study was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility.MethodsA case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed.ResultsStatistically significant associations with SPS were found for seven genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). The GREM1 risk allele was remarkably over-represented in SPS cases compared with controls (OR=1.573, 1.21–2.04, p value=0.0006). A fourfold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥65) with those in the first decile (≤50).ConclusionsGenetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3H and rs3217810-CCND2.

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“…CRC is the third most common malignancy, and the fourth most common cause of cancer-associated mortality globally (2). Despite substantial advances in modern medicine, including the development of novel treatment methods, the mortality of patients with CRC remains high, which may be due to the lack of specific biomarkers and effective treatments for the disease (23,24). Therefore the identification of novel prognostic markers and therapeutic targets for use in CRC treatment is urgently required.…”

Section: Discussionmentioning

confidence: 99%

GGCT promotes colorectal cancer migration and invasion via epithelial‑mesenchymal transition

Huang

Zhou

et al. 2020

Oncol Lett

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Colorectal cancer (CRC) is one of the most common malignancies, and the fourth most common cause of cancer-associated mortality globally. The epithelial to mesenchymal transition (EMT) serves an important function in metastatic dissemination and determines the aggressiveness of CRC. However, the regulatory mechanism of EMT in CRC has not yet been elucidated. γ-glutamylcyclotransferase (GGCT) is an important enzyme in glutathione metabolism and highly expressed in numerous forms of cancer, making it a promising therapeutic target. In the present study, GGCT was demonstrated to be highly expressed in CRC tissues, and patients with CRC with a higher expression of GGCT exhibited a worse prognosis compared with patients exhibiting a lower expression of GGCT. This result suggests that GGCT may serve as a novel prognostic marker for CRC. Furthermore, GGCT was indicated to promote CRC cell migration and invasion through regulating EMT-associated genes, including N-cadherin, Vimentin, snail family transcriptional repressor 2 and snail family transcriptional repressor 1. In conclusion, the present study provides novel insights into the mechanism governing CRC migration and invasion, and identified GGCT as a promising therapeutic target that may be used in the treatment of CRC.

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Update on genetic predisposition to colorectal cancer and polyposis

Cited by 126 publications

References 177 publications

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility

GGCT promotes colorectal cancer migration and invasion via epithelial‑mesenchymal transition

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