New genes emerging for colorectal cancer predisposition

Esteban-Jurado, Clara; Garré, Pilar; Vila, Maria del Mar; Lozano, Juan José; Přistoupilová, Anna; Beltrán, Sergi; Abulí, Anna; Muñoz, Jenifer; Balaguer, Francesc; Ocaña, Teresa; Castells, Antoni; Piqué, Josep M.; Carracedo, Ángel; Ruíz-Ponte, Clara; Bessa, Xavier; Andreu, Montserrat; Bujanda, Luís; Caldés, Trinidad; Castellví–Bel, Sergi

doi:10.3748/wjg.v20.i8.1961

Cited by 32 publications

(27 citation statements)

References 59 publications

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“…Recent discovery of germline mutations in the proofreading domains of two DNA polymerases (POLE and POLD1) now implicate a new highly penetrant hereditary syndrome referred to as ‘polymerase proofreading-associated polyposis’ (PAPP) leading to a large number of somatically acquired mutations (hypermutant tumors). [30–33] These discoveries reinforce the importance of mechanisms related to correct DNA replication, and show that reduced fidelity can result in a mutator phenotype increasing cancer susceptibility.…”

Section: Genetic Mutations Predisposing To Hereditary Syndromesmentioning

confidence: 83%

Genetic architecture of colorectal cancer

Peters

Bien

Zubair

2015

Gut

161

140

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Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3–5%) of cases arises from hereditary syndromes predisposing to early onset CRC as a result of mutations in over a dozen well-defined genes. In contrast, CRC is predominantly a late-onset “sporadic” disease, developing in individuals with no obvious hereditary syndrome. In recent years genome-wide association studies have discovered over 40 genetic regions to be associated with weak effects on sporadic CRC and it has been estimated that increasingly large genome-wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies, and development of higher-throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarizing the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention, and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease.

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Section: Genetic Mutations Predisposing To Hereditary Syndromesmentioning

confidence: 83%

Genetic architecture of colorectal cancer

Peters

Bien

Zubair

2015

Gut

161

140

View full text Add to dashboard Cite

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“…In addition, findings from genome-wide association studies (GWAS) support a polygenic model of CRC in which several common low penetrance susceptibility genes such genetic variants in vitamin D [19], cyclin D1, and Smad7 [20] contribute to increased risk of adenoma and CRC [21, 22]. Family history and age are also considered to be important CRC predictors as they have been associated with higher risk of adenomas and CRC.…”

Section: Risk Factors For Colorectal Adenomas and Crcmentioning

confidence: 99%

“…Family history and age are also considered to be important CRC predictors as they have been associated with higher risk of adenomas and CRC. Studies suggest that genetic predisposition and somatic alterations in combination with environmental factors are responsible for CRC as a complex disease [20]. …”

Section: Risk Factors For Colorectal Adenomas and Crcmentioning

confidence: 99%

Gut Microbiome and Colorectal Adenomas

Dulal¹,

Keku²

2014

The Cancer Journal

103

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The trillions of bacteria that naturally reside in the human gut collectively constitute the complex system known the gut microbiome, a vital player for the host’s homeostasis and health. However, there is mounting evidence that dysbiosis, a state of pathological imbalance in the gut microbiome is present in many disease states. In this review, we present recent insights concerning the gut microbiome’s contribution to the development of colorectal adenomas and the subsequent progression to colorectal cancer (CRC). In the United States alone, CRC is the second leading cause of cancer deaths. As a result, there is a high interest in identifying risk factors for adenomas, which are intermediate precursors to CRC. Recent research on CRC and the microbiome suggest that modulation of the gut bacterial composition and structure may be useful in preventing adenomas and CRC. We highlight the known risk factors for colorectal adenomas and the potential mechanisms by which microbial dysbiosis may contribute to the etiology of CRC. We also underscore novel findings from recent studies on the gut microbiota and colorectal adenomas along with current knowledge gaps. Understanding the microbiome may provide promising new directions towards novel diagnostic tools, biomarkers, and therapeutic interventions for CRC.

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“…Mutations in NTHL1 affect base‐excision repair and are associated with a non‐hypermutated state . Testing for POLE , POLD‐1 and NTHL1 has been proposed for patients with unexplained personal or familial history of multiple adenomas and/or early onset CRC with identified carriers for the mutations having early, frequent and regular colonoscopy surveillance .…”

Section: Discussionmentioning

confidence: 99%

Translating colorectal cancer genetics into clinically useful biomarkers

et al. 2016

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Colorectal cancer (CRC) is a major health problem worldwide accounting for over a million deaths annually. While many patients with Stage II and III CRC can be cured with combinations of surgery, radiotherapy and chemotherapy, this is morbid costly treatment and a significant proportion will suffer recurrence and eventually die of CRC. Increased understanding of the molecular pathogenesis of CRC has the potential to identify high risk patients and target therapy more appropriately. Despite increased understanding of the molecular events underlying CRC development, established molecular techniques have only produced a limited number of biomarkers suitable for use in routine clinical practice to predict risk, prognosis and response to treatment. Recent rapid technological developments, however, have made genomic sequencing of CRC more economical and efficient, creating potential for the discovery of genetic biomarkers that have greater diagnostic, prognostic and therapeutic capabilities for the management of CRC. This paper reviews the current understanding of the molecular pathogenesis of CRC, and summarizes molecular biomarkers that surgeons will encounter in current clinical use as well as those under development in clinical and preclinical trials. New molecular technologies are reviewed together with their potential impact on the understanding of the molecular pathogenesis of CRC and their potential clinical utility in classification, diagnosis, prognosis and targeting of therapy.

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New genes emerging for colorectal cancer predisposition

Cited by 32 publications

References 59 publications

Genetic architecture of colorectal cancer

Genetic architecture of colorectal cancer

Gut Microbiome and Colorectal Adenomas

Translating colorectal cancer genetics into clinically useful biomarkers

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