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Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

ABSTRACT: Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model.We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes.We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset.Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.

SUBMITTER: Chen J

PROVIDER: S-EPMC3917505 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

Chen Jinyun J Etzel Carol J CJ Amos Christopher I CI Zhang Qing Q Viscofsky Nancy N Lindor Noralane M NM Lynch Patrick M PM Frazier Marsha L ML

Cancer causes & control : CCC 20090819 9

<h4>Purpose</h4>Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model.<h4>Experimental design</h4>We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 ...[more]

PMID: 19690970

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Project description:IntroductionSeveral studies evaluated the prevalence of Lynch Syndrome (LS) in young onset colorectal cancer (CRC) patients and the results were extremely variable (5%-20%). Immunohistochemistry (IHC) for MMR proteins and/or MSI analysis are screening tests that are done, either by themselves or in conjunction, on colon cancer tissue to identify individuals at risk for LS. The primary aim of our study was to evaluate the prevalence of LS in a large series of early-onset CRC without family history compared with those with family history. The secondary aim was to assess the diagnostic accuracy of IHC and MSI analysis as pre-screening tools for LS.MethodsEarly-onset CRC patients (≤ 50 years) were prospectively recruited in the study. IHC and MSI analysis were performed in all the patients. Germ-line mutation analysis (GMA) was carried out in all MMR deficient tumors. A logistic regression model was performed to identify clinical features predictive of MSI-H.Results117 early onset CRC cases were categorized in three groups (A, B, C) according with family history of CRC. IHC and MSI analysis showed MMR deficiency in 6/70 patients (8.6%) of group A, 24/40 patients (60%) of group B and none of group C. GMA showed a deleterious mutation in 19 (47.5%) patients of group B. MSI analysis had a diagnostic accuracy of 95.7% (CI 92.1-99.4) and IHC of 83.8% (CI 77.1-90.4). The logistic regression model revealed that by using a combination of the two features "No Amsterdam Criteria" and "left sided CRC" to exclude MSI-H, accuracy was 89.7% (84.2-95.2).ConclusionsEarly-onset CRC patients, with left sided CRC and without family history are "at very low risk" for Lynch syndrome. The two simple criteria of family history and CRC site could be used as a pre-screening tool to evaluate whether or not patients should undergo tissue molecular screening. In the few cases of suspected LS (right sided CRC and/or Amsterdam Criteria), a reasonable approach could be to perform MSI analysis first and IHC afterwards only in MSI-H patients.

Project description:ObjectiveAlthough widely recommended, Lynch syndrome (LS) testing with tumor microsatellite instability (MSI) and/or immunohistochemistry (IHC) is infrequently performed in early-onset colorectal cancer (CRC), and CRC generally. Reasons are poorly understood. Hence, we conducted a national survey focusing on gastroenterologists, as they are frequently first to diagnose CRC, assessing testing barriers and which specialist is felt responsible for ordering MSI/IHC. Additionally, we assessed factors influencing timing of MSI/IHC ordering; testing on colonoscopy biopsy, opposed to post-operative surgical specimens, assists decisions on preoperative germline genetic testing and extent of colonic resection (ECR).MethodsA 21-question web-based survey was distributed through an American College of Gastroenterology email listing.ResultsIn total 509 completed the survey. 442 confirmed gastroenterologists were analyzed. Only 33.4% felt gastroenterologists were responsible for MSI/IHC ordering; pathologists were believed most responsible (38.6%). Cost, unfamiliarity interpreting results and unavailable genetic counseling most commonly prevented routine ordering (33.3%, 29.2%, 24.9%, respectively). In multivariable analysis, non-academic and rural settings were associated with cost and genetic counseling barriers. Only 46.1% felt MSI/IHC should always be performed on colonoscopy biopsy. Guideline familiarity predicted whether respondents felt surgical resection should be delayed until results returned given potential effect on ECR decisions.ConclusionInconsistencies in who is felt should order MSI/IHC may lead to diffusion of responsibility, preventing consistent testing, including preoperatively. Assuring institutional universal testing protocols are in place, with focus on timing of testing, can optimize care. Strategies addressing cost barriers and genomic service availability in rural and non-academic settings can enhance testing. Greater emphasis on guideline familiarity is required.

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Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

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Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome.

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