Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Win, Aung Ko; Jenkins, Mark A.; Dowty, James G.; Antoniou, Antonis C.; Lee, Andrew; Giles, Graham G.; Buchanan, Daniel D.; Clendenning, Mark; Rosty, Christophe; Ahnen, Dennis J.; Thibodeau, Stephen N.; Casey, Graham; Gallinger, Steven; Marchand, L Le; Haile, Robert W.; Potter, John D.; Zheng, Yingye; Lindor, Noralane M.; Newcomb, Polly A.; Hopper, John L.; MacInnis, Robert J.

doi:10.1158/1055-9965.epi-16-0693

Cited by 377 publications

(301 citation statements)

References 55 publications

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“…A recent study of a large number of DNA samples from colorectal cancer patients found that one in 45 individuals are MUTYH mutation carriers [136]; these estimates were similar to those from previous studies [137]. Notably, only 12 well-characterized MUTYH variants (such as Y165C, G382D, and several truncating mutations) were tested for, and this prompts concern that such studies may underestimate the prevalence of MUTYH mutations.…”

Section: Mutyh-associated Polyposissupporting

confidence: 54%

Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

Banda

Nuñez

Burnside

et al. 2017

Free Radical Biology and Medicine

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Reactive oxygen and nitrogen species (RONS) may infringe on the passing of pristine genetic information by inducing DNA inter- and intra-strand crosslinks, protein-DNA crosslinks, and chemical alterations to the sugar or base moieties of DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most prevalent DNA lesions formed by RONS and is repaired through the base excision repair (BER) pathway involving the DNA repair glycosylases OGG1 and MUTYH in eukaryotes. MUTYH removes adenine (A) from 8-oxoG:A mispairs, thus mitigating the potential of G:C to T:A transversion mutations from occurring in the genome. The paramount role of MUTYH in guarding the genome is well established in the etiology of a colorectal cancer predisposition syndrome involving variants of MUTYH, referred to as MUTYH-associated polyposis. In this review, we highlight recent advances in understanding how MUTYH structure and related function participate in the manifestation of human disease such as MAP. Here we focus on the importance of MUTYH’s metal cofactor sites, including a recently discovered “Zinc linchpin” motif, as well as updates to the catalytic mechanism. Finally, we touch on the insight gleaned from studies with MAP-associated MUTYH variants and recent advances in understanding the multifaceted roles of MUTYH in the cell, both in the prevention of mutagenesis and tumorigenesis.

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Section: Mutyh-associated Polyposissupporting

confidence: 54%

Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

Banda

Nuñez

Burnside

et al. 2017

Free Radical Biology and Medicine

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“…Taking, in contrast to previous lower estimations, all four genes into account, the most recent empiric estimation, based on a large North American/Australian registry, calculated carrier frequencies of 1 in 1946 for MLH1 , 1 in 2841 for MSH2 , 1 in 758 for MSH6 and 1 in 714 for PMS2 mutations 36. Based on these frequencies, CMMRD incidence was calculated to be about 1:1 000 000 children of unrelated parents (figure 1).…”

Section: Estimated Frequency Of Cmmrd As a Differential Diagnosis Of Nf1mentioning

confidence: 97%

“…According to Win et al ,36 in the general population one in 279 children tested will be heterozygous for an MMR gene mutation. Particularly in the case of a clearly pathogenic MLH1 or MSH2 mutation, this results is the unintentional diagnosis of Lynch syndrome in a minor.…”

Section: Potential Benefits and Harm Of Cmmrd Counselling And Testingmentioning

confidence: 99%

“…The situation is more complex for MSH6 and even more so for PMS2 . Heterozygous mutations in these genes have a 2–4 times higher prevalence,36 but a substantially lower penetrance than MLH1 and MSH2 mutations 19 51 52. Hence, in an individual lacking a personal or family history of Lynch syndrome-associated cancer, it is uncertain whether the mutation-associated cancer risk is sufficient to diagnose an individual with a cancer predisposition syndrome that warrants intensive cancer surveillance.…”

Section: Potential Benefits and Harm Of Cmmrd Counselling And Testingmentioning

confidence: 99%

“…The risk of having CMMRD based on the allele frequencies of MMR gene mutations36 in for example a child of first cousins is ~1/8849 (using the equation [p i f I +p i 2 (1−f I )]+[p j f I +p j 2 (1−f I )]+[p k f I +p k 2 (1−f I )]+[p l f I +p l 2 (1−f I )], where p i , p j , p k and p l are the allele frequencies of MLH1 , MSH2 , MSH6 and PMS2 mutations, respectively, and the consanguinity coefficient f I for first cousins=1/16),59 which is about 110 times higher than for a child with unrelated parents.…”

Section: Limiting Potential Harm Associated With Cmmrd Counselling Anmentioning

confidence: 99%

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Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

et al. 2018

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Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

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Diagnosis and Treatment of Metastatic Colorectal Cancer

Biller

Schrag

2021

JAMA

1,379

851

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ImportanceColorectal cancer (CRC) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850 000 deaths annually. Of new colorectal cancer diagnoses, 20% of patients have metastatic disease at presentation and another 25% who present with localized disease will later develop metastases.ObservationsColorectal cancer is the third most common cause of cancer mortality for men and women in the United States, with 53 200 deaths projected in 2020. Among people diagnosed with metastatic colorectal cancer, approximately 70% to 75% of patients survive beyond 1 year, 30% to 35% beyond 3 years, and fewer than 20% beyond 5 years from diagnosis. The primary treatment for unresectable metastatic CRC is systemic therapy (cytotoxic chemotherapy, biologic therapy such as antibodies to cellular growth factors, immunotherapy, and their combinations.) Clinical trials completed in the past 5 years have demonstrated that tailoring treatment to the molecular and pathologic features of the tumor improves overall survival. Genomic profiling to detect somatic variants is important because it identifies the treatments that may be effective. For the 50% of patients with metastatic CRC with KRAS/NRAS/BRAF wild-type tumors, cetuximab and panitumumab (monoclonal antibodies to the epithelial growth factor receptor [EGFR]), in combination with chemotherapy, can extend median survival by 2 to 4 months compared with chemotherapy alone. However, for the 35% to 40% of patients with KRAS or NRAS sequence variations (formerly termed mutations), effective targeted therapies are not yet available. For the 5% to 10% with BRAF V600E sequence variations, targeted combination therapy with BRAF and EGFR inhibitors extended overall survival to 9.3 months, compared to 5.9 months for those receiving standard chemotherapy. For the 5% with microsatellite instability (the presence of numerous insertions or deletions at repetitive DNA units) or mismatch repair deficiency, immunotherapy may be used in the first or subsequent line and has improved treatment outcomes with a median overall survival of 31.4 months in previously treated patients.Conclusions and RelevanceAdvances in molecular profiling of metastatic CRC facilitate the ability to direct treatments to the biologic features of the tumor for specific patient subsets. Although cures remain uncommon, more patients can anticipate extended survival. Genomic profiling allows treatment selection so that more patients derive benefit and fewer are exposed to toxicity from ineffective therapies.

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Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Cited by 377 publications

References 55 publications

Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

Diagnosis and Treatment of Metastatic Colorectal Cancer

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