Mutations Predisposing to Hereditary Nonpolyposis Colorectal Cancer

Peltomäki, Païvi; A, de la Chapelle

doi:10.1016/s0065-230x(08)60097-4

Cited by 156 publications

(79 citation statements)

References 93 publications

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“…An alternative pathway of tumor development is characterized by microsatellite instability resulting from defects in DNA MMR pathways (30). Defects in DNA MMR are responsible for the familial syndrome HNPCC, an autosomal dominant disease which accounts for up to 5% of colorectal cancer cases (31).…”

Section: Discussionmentioning

confidence: 99%

Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer

Smith

Carey

Beattie

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

426

318

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Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.

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Section: Discussionmentioning

confidence: 99%

Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer

Smith

Carey

Beattie

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

426

318

View full text Add to dashboard Cite

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“…Although pre-symptomatic testing for Huntington's disease has been available for over a decade, its uptake has in most countries been only 10-15% [8,9]. Predictive testing for some forms of cancer, including hereditary nonpolyposis colorectal cancer (HNPCC), has been available since 1995 [10,11]. HNPCC mutation carriers are estimated to have an 80% lifetime risk of colorectal cancer and an additional risk of extra-colonic malignancies, especially endometrial cancer [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer

et al. 2005

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“…Most patients with HNPCC harbor germline mutations in one of several genes involved in DNA MMR, and tumors from HNPCC patients frequently show DNA microsatellite instability (Marra and Boland, 1995). Germline mutations in hMLH1 and hMSH2 are the most prominent of the diseasepredisposing mutations and account for approximately 60% of the HNPCC kindreds (Peltomaki and de la Chapelle, 1997).…”

Section: Introductionmentioning

confidence: 99%

Tumor-associated Apc mutations in Mlh1−/−Apc1638N mice reveal a mutational signature of Mlh1 deficiency

et al. 2000

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Apc 1638N mice, which are heterozygous for a germline mutation in Apc, typically develop three to ®ve spontaneous intestinal tumors per animal. In most cases this is associated with allelic loss of wildtype Apc. We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc 1638N with an Mlh1-de®cient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC). The increased tumor multiplicity in these mice was associated with somatic mutations in the Apc tumor suppressor gene. Here, we have examined the nature and distribution of 91 Apc mutations implicated in the development of intestinal tumors in Mlh1 7/7 Apc 1638N animals. Protein truncation mutations were detected in a majority of tumor samples, indicating that the prevailing mechanism of Apc mutation in tumors is altered from allelic loss to intragenic mutation as a result of Mlh1 de®ciency. The observed mutations were a mixture of base substitutions (27%) and frameshifts (73%). Most frameshifts were detected within dinucleotide repeats and there were prominent mutational hotspots within sequences of this sort at codons 927 ± 929, 1209 ± 1211 and 1461 ± 1464. The observed Apc mutations caused protein truncation upstream of the third 20 amino acid b-catenin binding domain and the ®rst Axin-binding SAMP repeat, yielding Apc proteins that are predicted to be de®cient in destabilizing b-catenin. Our results reveal a characteristic mutational signature in Apc that is attributable to Mlh1 de®ciency. This demonstrates a direct e ect of Mlh1 de®ciency in the mutation of Apc in these tumors, and provides data that clarify the role of Mlh1 in mammalian DNA mismatch repair.

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Mutations Predisposing to Hereditary Nonpolyposis Colorectal Cancer

Cited by 156 publications

References 93 publications

Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer

Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer

Tumor-associated Apc mutations in Mlh1−/−Apc1638N mice reveal a mutational signature of Mlh1 deficiency

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