Incidence of Hereditary Nonpolyposis Colorectal Cancer and the Feasibility of Molecular Screening for the Disease

Aaltonen, Lauri A.; Salovaara, Reijo; Kristo, Paula; Canzian, Federico; Hemminki, Akseli; Peltomäki, Païvi; Chadwick, Robert B.; Kääriäinen, Helena; Eskelinen, Matti; Järvinen, Heikki; Mecklin∥, Jukka–Pekka; Chapelle, Albert de la

doi:10.1056/nejm199805213382101

Cited by 995 publications

(719 citation statements)

References 27 publications

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“…MSI is found in ~ 10 -15 % of sporadic CRC and results from defective DNA mismatch repair (dMMR) ( 3 ). Th is phenotype can be assayed using either polymerase chain reaction polymerase chain reaction-based methods or immunohistochemistry for loss of MLH1 mismatch repair protein expression.…”

Section: Introductionmentioning

confidence: 99%

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Mouradov

Domingo

Gibbs

et al. 2013

American Journal of Gastroenterology

123

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Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC).Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of " doublenegative " (MSI − / CIN − ) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specifi c molecular changes, such as mutations in KRAS and BRAF , that have been associated with prognosis. It is not known which of MSI, CIN, and the specifi c gene mutations are primary predictors of survival. METHODS:We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS , NRAS , BRAF , PIK3CA , FBXW7 , and TP53 , and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II / III CRC. We followed up promising associations in an Australian community-based cohort ( N = 375). RESULTS:In the VICTOR patients, no specifi c mutation was associated with DFS, but individually MSI and CIN showed signifi cant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR) = 0.58, 95 % confi dence interval (CI) 0.36 -0.93, and P = 0.021; for CIN, HR = 1.54, 95 % CI 1.14 -2.08, and P = 0.005), and joint CIN / MSI testing signifi cantly improved the prognostic prediction of MSI alone ( P = 0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN + / − variable . All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

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Section: Introductionmentioning

confidence: 99%

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Mouradov

Domingo

Gibbs

et al. 2013

American Journal of Gastroenterology

123

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“…7,8 Most tumours exhibiting the MSI phenotype are in older patients, very few of whom carry germline MMR gene mutations. 9,10 The principal mechanism responsible for MSI in these age groups is epigenetic gene inactivation by hypermethylation of the hMLH1 promoter. [11][12][13][14] Hypermethylation of this promoter is associated with increasing age and proximal tumour location.…”

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confidence: 99%

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Farrington

McKinley

Carothers

et al. 2002

Intl Journal of Cancer

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It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n ‫؍‬ 118; non-age-selected, n ‫؍‬ 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p ϳ 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression.

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“…Deficiency in MMR machinery creates genomic instability that can be observed as frequently mutated microsatellite sequences (microsatellite instability (MSI)) in tumor cells of the HNPCC patients (Aaltonen et al, 1993). High frequency of MSI can also be seen in 12-20% of unselected colorectal cancers (Ionov et al, 1993;Thibodeau et al, 1993;Aaltonen et al, 1998;Salovaara et al, 2000).…”

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confidence: 99%

“…We have previously collected a population-based series of 1044 fresh-frozen colorectal cancers and respective normal tissue specimens, and analysed these for MSI and MSH2 and MLH1 mutations (Aaltonen et al, 1998;Salovaara et al, 2000). Twenty-five of 29 cases with pathogenic mutation were available for this study, whereas in four cases, either normal or tumor DNA had been exhausted.…”

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confidence: 99%

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No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

et al. 2006

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Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P ¼ 0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.

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Incidence of Hereditary Nonpolyposis Colorectal Cancer and the Feasibility of Molecular Screening for the Disease

Cited by 995 publications

References 27 publications

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

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