Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma

Furukawa, Taiji; Konishi, Fumio; Shitoh, Kazuhisa; Kojima, Masayasu; Nagai, Hideo; Tsukamoto, Tatsuro

doi:10.1002/cncr.10332

Cited by 37 publications

(14 citation statements)

References 38 publications

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“…38,39 The overall prevalence of patients with pathogenic mutations was 20.6% in our cohort, which, however, might be subject to verification bias since mutation analysis has largely not been performed according to the study protocol if no abnormal result in IHC and MSA was present. Thus, although the analysis of 49 patients in this group did not reveal any pathogenic mutation, the existence of such cannot be excluded.…”

Section: Discussionmentioning

confidence: 91%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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Clinical criteria, microsatellite analysis (MSA) and immunohistochemistry (IHC) are important diagnostic tools for identification of hereditary nonpolyposis colorectal cancer (HNPCC) patients who are likely to carry pathogenic germline mutations in mismatch repair genes. Based on MSA and IHC results and subsequent mutation analyses of 1,119 unrelated index patients meeting the Amsterdam II criteria or the classical Bethesda guidelines, we analyzed the value of these tools to predict MLH1 and MSH2 mutations with the aim of establishing optimal strategies for their most efficient sequential use. The overall prevalence of pathogenic germline mutations in our cohort was 20.6% (95% CI 5 18.3-23.0%) and 61.8% (95% CI 5 56.8-66.6%), respectively, after MSA/IHC-based preselection. IHC was highly predictive (99.1%) and specific (99.6%) with regard to MSA. However, 14 out of 230 mutations (6%) escaped detection by IHC. Thus, IHC cannot be recommended to substitute MSA fully. Nonetheless, IHC is important to indicate the gene that is likely to be affected. To combine both methods efficiently, we propose a novel screening strategy that provides 2 alternative ways of sequential IHC and MSA application, either using IHC or MSA in the first place. A logistic regression model based on the age of the index patient at first tumor diagnosis and the number of fulfilled HNPCC criteria is used to allocate individual patients to that alternative pathway that is expected to be least expensive. A cost analysis reveals that about 25% of the costs can be saved using this strategy. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 91%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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“…The Msh2 D506Y variant was found in a Korean individual with early onset rectal cancer; however, no other information about the cancer phenotype was reported (13). The Msh2 A600V variant, originally identified in a 35-y-old Japanese male with rectal cancer (14), was also found in his mother, who suffered endometrial, ovarian, and colon cancer (15). Tumors from both individuals displayed significant microsatellite instability, and Msh2 was not detectable by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 93%

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

Arlow

Scott

Wagenseller

et al. 2012

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

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MSH2 is required for DNA mismatch repair recognition in eukaryotes. Deleterious mutations in human MSH2 account for approximately half of the alleles associated with a common hereditary cancer syndrome. Previously, we characterized clinically identified MSH2 missense mutations, using yeast as a model system, and found that the most common cause of defective DNA mismatch repair was low levels of the variant Msh2 proteins. Here, we show that increased protein turnover is responsible for the reduced cellular levels. Increasing gene dosage of more than half of the missense alleles fully restored function. A titration experiment revealed that raising the expression level of one variant to less than wildtype levels restored mismatch repair, suggesting that overexpression is not always required to regain function. We found that the ubiquitin-mediated proteasome degradation pathway is the major mechanism for increased turnover of the Msh2 variants and identified the primary ubiquitin ligase as San1. Deletion of San1 restored protein levels for all but one variant, but did not elevate wild-type Msh2 levels. The unstable variants interacted with San1, whereas wild-type Msh2 did not. Additionally, san1Δ suppressed the mismatch repair defect of unstable variants. Of medical significance, the clinically approved drug Bortezomib partially restored protein levels and mismatch repair function for low-level variants and reversed the resistance to cisplatin, a common chemotherapeutic. Our results provide the foundation for an innovative therapeutic regime for certain mismatch-repair-defective cancers that are refractory to conventional chemotherapies.Lynch syndrome | MutS | mutator | hereditary nonpolyposis clorectal cancer L ynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a leading cause of inherited cancer mortality in the United States (1). Approximately 2-7% of colorectal cancer cases are the consequence of Lynch syndrome, a dominant and highly penetrant disease afflicting individuals at an early age (1). Although colorectal is the most common form of cancer found in Lynch syndrome families, endometrial, ovarian, stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate cancers are all associated with the syndrome.Lynch syndrome cancers, as well as many sporadic tumors, are a consequence of defects in mismatch repair; for example, ∼17% of all colorectal cancers originate from defects in mismatch repair (2). DNA mismatch repair is a conserved mechanism that significantly contributes to the accurate preservation of genetic material (3). Mismatch recognition is accomplished in eukaryotes by MutS heterodimers in which Msh2 is the invariant partner (4). Mismatch binding initiates subsequent events, including cleavage and excision of the error-containing strand followed by new synthesis and ligation (5). Without mismatch repair, DNA displays microsatellite instability and acquires numerous mutations, some of which are deleterious. Included among the types of harmfu...

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“…An intronic variant, c.1668-1 G > A, found in a heterozygous individual in 2KJPN, may cause exon skipping and is considered to be pathogenic [40]. Another missense variant, p.Arg687Trp, found in a heterozygous individual, was previously reported in two Japanese families with LS [41]. Other RP variants are considered to be not pathogenic or of unknown significance in other databases.…”

Section: Lynch Syndrome Genesmentioning

confidence: 99%

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

et al. 2017

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

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Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma

Cited by 37 publications

References 38 publications

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Proteasome inhibition rescues clinically significant unstable variants of the mismatch repair protein Msh2

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

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