Cancer Risks For Mismatch Repair Gene Mutation Carriers: A Population-Based Early Onset Case-Family Study

Jenkins, Mark A.; Baglietto, Laura; Dowty, James G.; Vliet, Christine van; Smith, Letitia; Mead, Leeanne J.; Macrae, Finlay; John, David; Jass, Jeremy R.; Giles, Graham G.; Hopper, John L.; Southey, Melissa C.

doi:10.1016/j.cgh.2006.01.002

Cited by 150 publications

(140 citation statements)

References 32 publications

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“…There have been numerous other studies estimating penetrance for LS-associated cancers for MLH1 and MSH2 mutation carriers to be even higher, however the majority were based on families that were ascertained because they had striking clinical histories and as penetrance estimates were not conditioned on this ascertainment, the previous estimates were upwardly biased. 9,44,45 If the risks of cancer for PMS2 mutation carriers are lower than that for carriers of mutations in other mismatch repair genes, which is consistent with the observed data, the molecular explanation for this is unclear. It has been hypothesized that MLH1 can form a heterodimer with MLH3 or PMS1 in the absence of functional PMS2, which may compensate for the MutLα heterodimer in the mismatch repair process.…”

Section: Discussionmentioning

confidence: 63%

“…7 In Australian families ascertained from a population-based series of CRC diagnosed before age 45, the corresponding risks were 75% and 86%. 9 In a series of Scottish families ascertained from a population-based series of CRC diagnosed before age 35 the risks for CRC and endometrial cancers alone were 70% for males and 72% for females. 6 However, due to the substantial size of the 95% confidence intervals of our estimates, we cannot definitively conclude that the penetrance for PMS2 mutations is lower than for mutations in other mismatch repair genes.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Most recent valid estimates of cancer risks to age 70 suggest that individuals with LS have an increased risk of colorectal cancer (22-74%), endometrial cancer (32-42%), and a number of other cancers (such as those of the stomach, ovary, small intestine, biliary tract, and urinary tract). [6][7][8][9] However, previous studies did not often include PMS2 analysis and therefore little is known about the cancer risks for PMS2 monoallelic mutation carriers. This is primarily due to the limited number of carriers described to date, which can be attributed to the historic difficulty in the identification of PMS2 mutations given the presence of a large family of pseudogenes located on the same chromosome.…”

Section: Introductionmentioning

confidence: 99%

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The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

et al. 2008

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Background and Aims-Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

et al. 2008

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“…2005; Jenkins et al. 2006). Therefore, according to the InSiGHT 5‐tiered classification system this variant should be classified as class 5.…”

Section: Discussionmentioning

confidence: 99%

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Sjursen

McPhillips²,

Scott

et al. 2016

Molec Gen & Gen Med

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BackgroundLynch syndrome, the most frequent hereditary colorectal cancer syndrome, is caused by defects in mismatch repair genes. Genetic testing is important in order to identify mutation carriers who can benefit from intensive surveillance programs. One of the challenges with genetic testing is the interpretation of pathogenicity of detected DNA variants. The aim of this study was to investigate all putative pathogenic variants tested for at the Division of Molecular Medicine, Pathology North, in Newcastle, Australia, to establish whether previous variant classification is in accordance with that recently performed in the InSiGHT collaboration.MethodsPrediction programs and available literature were used to classify new variants or variants without classification.ResultsWe identified 333 mutation positive families, in which 211 different putative pathogenic mismatch repair mutations were found. Most variants with an InSiGHT classification (141 out of 146) were in accordance with our classification. Five variants were discordant, of which one can definitively be reclassified according to the InSiGHT scheme as class 5. Sixty‐four variants had not been classified by InSiGHT, of whom 55 have not been previously reported.ConclusionIn conclusion, we found that our classifications were mostly in accordance with the InSiGHT scheme. In addition to already known MMR mutations, we have also presented 55 novel pathogenic or putative pathogenic mutations.

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“…This risk is even higher if more than one relative is affected or if a relative was diagnosed under age 50 (Cremin et al 2009;Leddin et al 2004). Those with Lynch syndrome have a lifetime risk of CRC ranging between 30 and 74 % (Dunlop et al 1997;Hampel et al 2005;Jenkins et al 2006) with average age at diagnosis between 44 and 61 years (Cremin et al 2009;Hampel et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of an educational intervention on family physicians’ risk assessment and management of colorectal cancer

et al. 2014

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We developed a point-of-care tool indicating risk categories for colorectal cancer (CRC) based on family history (FH) and management recommendations tailored to risk. The study objective was to determine if this CRC Risk Triage/ Management Too would enable family physicians (FPs) to appropriately triage and make screening and genetics referral recommendations for patients with CRC FH. Baseline questionnaires were mailed to a random sample of FPs in Ontario and Newfoundland, Canada. Participants were asked to use the tool for 3 months and then complete a follow-up questionnaire. The primary outcomes were correct responses to questions regarding CRC risk category, screening method, starting age, frequency, and decision to refer to genetics, for eight clinical vignettes. The study was completed by 75/121 (62 %) participating FPs. Most (77 %) agreed they routinely recommended fecal occult blood testing for average risk patients age ≥50. This did not change significantly following the intervention. There was a significant increase in confidence in CRC risk assessment (52 % pre; 88 % post; p<0.001), correct management recommendations for patients with CRC FH (51 % pre; 84 % post; p<0.001), and improvement in total mean scores on outcome measures for all vignettes. Most demonstrates the value of point-of-care tools and illustrates a process for development, evaluation, and dissemination of tools needed by FPs if potential impacts of genomic advances are to be achieved.

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Cancer Risks For Mismatch Repair Gene Mutation Carriers: A Population-Based Early Onset Case-Family Study

Cited by 150 publications

References 32 publications

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Efficacy of an educational intervention on family physicians’ risk assessment and management of colorectal cancer

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