A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting Highlights and Bethesda Guidelines

Rodrı́guez-Bigas, Miguel A.; Boland, C. Richard; Hamilton, Stanley R.; Henson, Donald E.; Jass, Jeremy R.; Khan, P. Meera; Lynch, Henry T.; Perucho, Manuel; Smyrk, Thomas C.; Sobin, Leslie H.; Srivastava, Sudhir

doi:10.1093/jnci/89.23.1758

Cited by 999 publications

(621 citation statements)

References 18 publications

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“…The clinical utility of such an assay is well recognized for screening of suspicious tumors to initiate the process of identifying HNPCC families. 20,22 The assay may also be useful as a prognostic marker 18,19 or potentially in the elucidation of the pharmacogenetic properties of a tumor (SR Hamilton, submitted).…”

Section: Discussionmentioning

confidence: 99%

“…18,19 Thus, it may become important clinically to identify tumors with MSI not only to implicate germline MMR defects (HNPCC families), but also for prognostic stratification. While clinical (Bethesda guidelines 20 ) and histopathological features 21 may raise the suspicion that a colorectal tumor is microsatellite-unstable and perhaps has arisen in an HNPCC family, clinicopathological features are insufficient to diagnose the presence of MSI; thus, direct molecular testing has importance in documenting the MSI status of a clinically suspicious tumor. 22 Many different microsatellite markers or loci have been used by different investigators to identify MSI in tumors.…”

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confidence: 99%

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Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

Berg

Glaser

Thompson

et al. 2000

The Journal of Molecular Diagnostics

139

121

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We have created a clinical molecular diagnostic assay to test for microsatellite instability (MSI) at multiple loci simultaneously in paraffin-embedded surgical pathology colon resection specimens. This fluorescent multiplex polymerase chain reaction (PCR) assay analyzes the five primary microsatellite loci recommended at the 1997 National Cancer Institute-sponsored conference on MSI for the identification of MSI or replication errors in colorectal cancer: Bat-25, Bat-26, D2S123, D5S346, and D17S250. Amplicon detection is accomplished by capillary electrophoresis using the ABI 310 Genetic Analyzer. Assay validation compared 18 specimens previously assessed by radioactive PCR and polyacrylamide gel electrophoresis detection to results generated by the reported assay. Germline and tumor DNA samples were amplified in separate multiplex PCR reactions, sized in separate capillary electrophoresis runs, and compared directly to identify novel length alleles in tumor tissue. A concordance of 100% between the two modalities was achieved. The multiplex assay routinely detected a subpopulation of 10% tumor alleles in the presence of 90% normal alleles. A novel statistical model was generated that corroborates the validity of using results generated by analysis of five independent microsatellites to achieve a single overall MSI diagnosis. The assay presented is superior to standard radioactive monoplex PCR, polyacrylamide gel electrophoretic analysis, primarily due to the multiplex PCR format. (J Mol Diag 2000, 2:20 -28)Microsatellite instability (MSI), or replication error, is a manifestation of genomic instability arising in a variety of human neoplasms where tumor cells have a decreased overall ability to faithfully replicate DNA. This phenomenon has been shown to be a frequent, if not obligatory, surrogate marker of underlying functional inactivation of one of the human DNA mismatch repair (MMR) genes. [1][2][3][4][5][6]

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

Berg

Glaser

Thompson

et al. 2000

The Journal of Molecular Diagnostics

139

121

View full text Add to dashboard Cite

show abstract

“…The specific guideline(s) that the participant met was captured. An individual was categorized as “Bethesda 1” if diagnosed under 50 and “Bethesda 2” if they had an additional Lynch syndrome-associated cancer diagnoses 25, 26 . Individuals with one or more first-degree relatives with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed under age 50 years, was categorized as “Bethesda 4.” Participants with two or more first- or second-degree relatives with Lynch syndrome-associated tumors, regardless of age of diagnosis, were categorized as “Bethesda 5.” The Bethesda guideline 3 pertaining to MSI-histology (tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucin/signet ring cell differentiation, medullary growth pattern) was not included in this study, as pathology reports did not uniformly capture these features.…”

Section: Methodsmentioning

confidence: 99%

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Ricker

Hanna

Peng

et al. 2017

Cancer

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Background The landscape of hereditary syndromes and clinicopathologic characteristics among U.S. Latinos/Hispanics with colorectal cancer (CRC) remains poorly understood. Methods A total of 265 CRC patients enrolled in the Hispanic Colorectal Cancer Study were included in this study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data was abstracted from clinical charts. Tumor studies and germline genetic testing results were collected from medical records or performed using standard molecular methods. Results The mean age at diagnosis was 53.7 years (SD=10.3), and 48.3% were female. Overall, 21.2% reported a first- or second-degree relative with CRC; 3.4% met Amsterdam I/II criteria. With respect to Bethesda guidelines, 38.5% met at least one criterion. Of the 161 individuals who had immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing performed, 21 (13.0%) had mismatch repair (MMR) deficient tumors. dMMR tumors were associated with female sex (61.9%), earlier age of diagnosis (50.4 ± 12.4 years), proximal location (61.9%), and first (23.8%) or second (9.5%) degree family history of CRC. Among individuals with dMMR tumors, 13 (61.9%) had a germline MMR mutation (MLH1=6, MSH2=4, MHS6=2, and PMS2=1). We identified two additional MLH1 mutation carriers by genetic testing who had not received IHC/MSI testing. In total, 5.7% of the entire cohort were confirmed cases of Lynch syndrome. Additionally, six individuals (2.3%) had a polyposis phenotype. Conclusions The proportion of dMMR tumors in Latinos (13%) is similar to estimates in non-Hispanic Whites. The majority of individuals with dMMR tumors were confirmed to have Lynch syndrome.

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“…Germline mutations in MMR genes can lead to a variety of clinical presentations, including sporadic early-onset colorectal cancer and familial endometrial cancer (Farrington et al, 1998;Wijnen et al, 1999). Therefore, additional clinical criteria were developed which may indicate an MMR gene defect, in particular the Bethesda and Amsterdam II criteria (Rodriguez-Bigas et al, 1997;Vasen et al, 1999). Identification of a germline defect in colorectal cancer patients is crucial to establish the etiology of the disease and to direct clinical decision making for patients and family members.…”

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confidence: 99%

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

et al. 2002

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Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatchrepair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

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A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting Highlights and Bethesda Guidelines

Cited by 999 publications

References 18 publications

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

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