Fay Kastrinos

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

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Publications (31)263.4 Total impact

  • Elena M. Stoffel, Fay Kastrinos
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    ABSTRACT: Although 30% of individuals diagnosed with colorectal cancer (CRC) report a family history of the disease, only 5% to 6% carry germline mutations in genes associated with known hereditary cancer syndromes. The evaluation and management of families affected with CRC can be complicated by variability in disease phenotypes and limited sensitivity of genetic tests. In this review, we examine what is currently known about familial CRC and what we have yet to learn, and explore how novel genomic approaches might be used to identify additional genetic and epigenetic factors implicated in heritable risk for cancer.
    Clinical Gastroenterology and Hepatology. 01/2014; 12(7):1059–1068.
  • Elena M Stoffel, Fay Kastrinos
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    ABSTRACT: Although 30% of individuals diagnosed with CRC report a family history of the disease, only 5-6% carry germline mutations in genes associated with known hereditary cancer syndromes. The evaluation and management of families affected with CRC can be complicated by variability in disease phenotypes and limited sensitivity of genetic tests. In this review we examine what is currently known about familial CRC and what we have yet to learn, and explore how novel genomic approaches might be used to identify additional genetic and epigenetic factors implicated in heritable risk for cancer.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 08/2013; · 5.64 Impact Factor
  • Fay Kastrinos, Elena M Stoffel
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    ABSTRACT: Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the third cause of cancer death in men and women in the United States. The majority of CRC cases diagnosed annually are due to sporadic events but up to 6% are attributed to known monogenic disorders that confer a markedly increased risk for the development of CRC and multiple extracolonic malignancies. Lynch syndrome is the most common inherited CRC syndrome and is associated with mutations in DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2, but also MSH6, PMS2, and EPCAM. While the risk of CRC and endometrial cancer may approach near 75% and 50% respectively in gene mutation carriers, the identification of these individuals and at-risk family members through predictive genetic testing provides opportunities for cancer prevention including specialized cancer screening, intensified surveillance, and/or prophylactic surgeries. This article will provide a review of the major advances in risk assessment, molecular genetics, DNA mutational analyses, and cancer prevention and management made since Lynch Syndrome was first described 100 years ago.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 07/2013; · 5.64 Impact Factor
  • Fay Kastrinos, Judith Balmaña, Sapna Syngal
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    ABSTRACT: Prediction models for the identification of Lynch syndrome have been developed to quantify an individual's risk of carrying a mismatch repair gene mutation and help clinicians decide for whom further risk assessment and genetic testing is necessary. There are diverse clinical settings in which a healthcare provider has the opportunity to assess an individual for Lynch syndrome. Prediction models offer a potentially feasible and useful strategy to systematically identify at-risk individuals, whether they are affected with colorectal cancer or not, and to help with management of the implications of molecular and germline test results. Given the complexity of diagnostic information currently available to clinicians involved in identifying and caring for patients with Lynch syndrome, prediction models provide a useful and complementary aid in medical decision-making. Systematic implementation of prediction models estimates should be considered in routine clinical care and at various stages of cancer risk assessment and prevention. In this manuscript, we review the main prediction models developed for Lynch syndrome, focus on their specific features and performance assessed in several validation studies, compare the models with other clinical and molecular strategies for the diagnosis of Lynch syndrome, and discuss their potential uses in clinical practice.
    Familial Cancer 04/2013; · 1.94 Impact Factor
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    ABSTRACT: PURPOSEProstate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous studies quantifying prostate cancer risk in LS have provided conflicting results. METHODS We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population.ResultsNinety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03). CONCLUSION The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.
    Journal of Clinical Oncology 03/2013; · 18.04 Impact Factor
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    ABSTRACT: Introduction Declining rates in the incidence of colorectal can-cer (CRC) in the past decade have been attrib-uted to the upsurge in CRC screening, particularly with the use of colonoscopy [Edwards et al. 2010]. Nationally, 64.7% of Americans in 2010 reported
    Therapeutic Advances in Gastroenterology 01/2013; 6:5-14.
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    ABSTRACT: Rates of suboptimal bowel preparation up to 30% have been reported. Liberalized precolonoscopy diet, split dose purgative, and the use of MiraLAX-based bowel preparation (MBBP) prior to colonoscopy are recently developed measures to improve bowel preparation quality but little is known about the utilization prevalence of these measures. We examined the patterns of utilization of these newer approaches to improve precolonoscopy bowel preparation quality among American gastroenterologists. Surveys were distributed to a random sample of members of the American College of Gastroenterologists. Participants were queried regarding demographics, practice characteristics, and bowel preparation recommendations including recommendations for liberal dietary restrictions, split dose purgative, and the use of MBBP. Approaches were evaluated individually and in combination. Of the 999 eligible participants, 288 responded; 15.2% recommended a liberal diet, 60.0% split dose purgative, and 37.4% MBBP. Diet recommendations varied geographically with gastroenterologists in the West more likely to recommend a restrictive diet (odds ratio [OR] 2.98, 95% confidence interval [CI] 1.16-7.67) and physicians in the Northeast more likely to recommend a liberal diet more likely. Older physicians more often recommended split dosing (OR 1.04, 95% CI 1.04-2.97). Use of MBBP was more common in suburban settings (OR 2.14, 95% CI 1.23-3.73). Evidence suggests that physicians in private practice were more likely to prescribe split dosing (p = 0.03) and less often recommended MBBP (p = 0.02). Likelihood of prescribing MBBP increased as weekly volume of colonoscopy increased (p = 0.03). To enhance bowel preparation quality American gastroenterologists commonly use purgative split dosing. The use of MBBP is becoming more prevalent while a liberalized diet is infrequently recommended. Utilization of these newer approaches to improve bowel preparation quality varies by physician and practice characteristics. Further evaluation of the patterns of usage of these measures is indicated.
    Therapeutic Advances in Gastroenterology 01/2013; 6(1):5-14.
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    ABSTRACT: PURPOSE: Suboptimal bowel preparation can result in decreased neoplasia detection, shortened surveillance intervals, and increased costs. We assessed bowel preparation recommendations and the relationship to self-reported proportion of suboptimal bowel preparations in practice; and evaluated the impact of suboptimal bowel preparation on colonoscopy surveillance practices. A random sample of a national organization of gastroenterologists in the U.S. was surveyed. METHODS: Demographic and practice characteristics, bowel preparation regimens, and proportion of suboptimal bowel preparations in practice were ascertained. Recommended follow-up colonoscopy intervals were evaluated for optimal and suboptimal bowel preparation and select clinical scenarios. RESULTS: We identified 6,777 physicians, of which 1,354 were randomly selected; 999 were eligible, and 288 completed the survey. Higher proportion of suboptimal bowel preparations/week (≥10 %) was associated with hospital/university practice, teaching hospital affiliation, >25 % Medicaid insured patients, recommendation of PEG alone and sulfate-free. Those reporting >25 % Medicare and privately insured patients, split dose recommendation, and use of MoviPrep® were associated with a <10 % suboptimal bowel preparations/week. Shorter surveillance intervals for three clinical scenarios were reported for suboptimal preparations and were shortest among participants in the Northeast who more often recommended early follow-up for normal findings and small adenomas. Those who recommended 4-l PEG alone more often advised <1 year surveillance interval for a large adenoma. CONCLUSIONS: Our study demonstrates significantly shortened surveillance interval recommendations for suboptimal bowel preparation and that these interval recommendations vary regionally in the United States. Findings suggest an interrelationship between dietary restriction, purgative type, and practice and patient characteristics that warrant additional research.
    International Journal of Colorectal Disease 08/2012; · 2.24 Impact Factor
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    ABSTRACT: Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. Prevalence of pathogenic mutations in APC and MUTYH genes. Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.
    JAMA The Journal of the American Medical Association 08/2012; 308(5):485-92. · 29.98 Impact Factor
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    B Lebwohl, K Capiak, A I Neugut, F Kastrinos
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    ABSTRACT: Racial and ethnic differences in the risk of premalignant colorectal neoplasia have not been extensively studied. To measure adenoma prevalence among asymptomatic white, black and Hispanic patients undergoing screening colonoscopy. In this cross sectional cohort study, data from individuals ≥50 years undergoing first-time colonoscopy since 2006 at a single tertiary-care medical centre were obtained from the electronic medical record. Adenoma prevalence among whites, blacks and Hispanics was calculated; multivariate Poisson and logistic regression were used to identify factors independently associated with adenoma rates and the presence of advanced adenomas. We identified 5075 eligible subjects: 3542 (70%) whites, 942 (18%) Hispanics and 591 (12%) blacks. The mean age was 62.2 years with 58% women. At least one adenoma was detected in 19%, 22% and 26% of whites, Hispanics and blacks respectively (Hispanics vs. whites P = 0.09; blacks vs. whites P = 0.0001). Isolated proximal adenomas were present in 9% of whites, 11% of Hispanics (P = 0.03) and 11% of blacks (P = 0.03). In multivariate analyses, a higher rate of adenomas was present in Hispanics (RR: 1.37, 95% CI: 1.20-1.57) and blacks (RR: 1.76, 95% CI: 1.52-2.04) than whites. Hispanics and blacks also had an increased risk of advanced adenomas compared to whites (OR(Hispanics) : 2.25, 95% CI: 1.62-3.11; OR(blacks) : 1.91, 95% CI: 1.27-2.86). Adenoma prevalence was higher in blacks and Hispanics than in whites. Both groups were at greater risk of having proximal adenomas in the absence of any distal pathology than whites, where these lesions would have only been detected by colonoscopy. Efforts to promote screening are necessary among diverse, under-represented populations.
    Alimentary Pharmacology & Therapeutics 04/2012; 35(12):1467-73. · 4.55 Impact Factor
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    ABSTRACT: Poor quality bowel preparation has been reported in almost one third of all colonoscopies. To better understand factors associated with poor bowel preparation, we explored perceived patient barriers to optimal pre-colonoscopy bowel preparation from the perspective of the gastroenterologist. A random sample of physician members of the American College of Gastroenterology was surveyed via the internet and postal mailing. Demographic and practice characteristics and practice-related and perceived patient barriers to optimal bowel preparation were assessed among 288 respondents. Lack of time, no patient education reimbursement, and volume of information were not associated with physician level of suboptimal bowel preparation. Those reporting ≥10 % suboptimal bowel preparations were more likely to believe patients lack understanding of the importance of following instructions, have problems with diet, and experience trouble tolerating the purgative. Bowel preparation instruction communication and unmet patient educational needs contribute to suboptimal bowel preparation. Educational interventions should address both practice and patient-related factors.
    Journal of Cancer Education 04/2012; 27(3):526-32. · 0.88 Impact Factor
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    ABSTRACT: Knowledge of quality measures in endoscopy among trainees is unknown. To assess knowledge of endoscopy-related quality indicators among U.S. trainees and determine whether it improves with a Web-based intervention. Randomized, controlled study. Multicenter. This study involved trainees identified from the American Society for Gastrointestinal Endoscopy membership database. Participants were invited to complete an 18-question online test. Respondents were randomized to receive a Web-based tutorial (intervention) or not. The test was readministered 6 weeks after randomization to determine the intervention's impact. Baseline knowledge of endoscopy-related quality indicators and impact of the tutorial. A total of 347 of 1220 trainees (28%) completed the test; the mean percentage of correct responses was 55%. For screening colonoscopy, 44% knew the adenoma detection rate benchmark, 42% identified the cecal intubation rate goal, and 74% knew the recommended minimum withdrawal time. A total of 208 of 347 trainees (59%) completed the second test; baseline scores were similar for the tutorial (n = 106) and no tutorial (n = 102) groups (56.4% vs 56.9%, respectively). Scores improved after intervention for the tutorial group (65%, P = .003) but remained unchanged in the no tutorial group. On multivariate analysis, each additional year in training (odds ratio [OR] 2.3; 95% confidence interval [CI], 1.5-3.4), training at an academic institution (OR 2.6; 95% CI, 1.1-6.3), and receiving the tutorial (OR 3.2; 95% CI, 1.7-5.9) were associated with scores in the upper tertile. Low response rate. Knowledge of endoscopy-related quality performance measures is low among trainees but can improve with a Web-based tutorial. Gastroenterology training programs may need to incorporate a formal didactic curriculum to supplement practice-based learning of quality standards in endoscopy.
    Gastrointestinal endoscopy 03/2012; 76(1):100-6.e1-4. · 6.71 Impact Factor
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    ABSTRACT: Purpose:Lynch syndrome accounts for 2-5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases.Methods:Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM(1,2,6), MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases.Results:A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM(1,2,6), MMRpredict, and MMRpro were able to distinguish mutation carriers from noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM(1,2,6), 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases.Conclusion:Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients.Genet Med advance online publication 8 March 2012.
    Genetics in medicine: official journal of the American College of Medical Genetics 03/2012; 14(7):670-80. · 3.92 Impact Factor
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    Fay Kastrinos, Sapna Syngal
    Journal of Clinical Oncology 02/2012; 30(10):1024-7. · 18.04 Impact Factor
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    ABSTRACT: BACKGROUND: Lynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM(1,2,6) model predicts the likelihood of a MMR gene mutation based on personal and family cancer history. OBJECTIVE: To compare strategies using PREMM(1,2,6) and tumour testing (microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining) to identify mutation carriers. DESIGN: Data from population-based or clinic-based patients with colorectal cancers enrolled through the Colon Cancer Family Registry were analysed. Evaluation included MSI, IHC and germline mutation analysis for MLH1, MSH2, MSH6 and PMS2. Personal and family cancer histories were used to calculate PREMM(1,2,6) predictions. Discriminative ability to identify carriers from non-carriers using the area under the receiver operating characteristic curve (AUC) was assessed. Predictions were based on logistic regression models for (1) cancer assessment using PREMM(1,2,6), (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM(1,2,6)+MSI, (6) PREMM(1,2,6)+IHC, (7) PREMM(1,2,6)+IHC+MSI. RESULTS: Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM(1,2,6) discriminated well with AUC 0.90 (95% CI 0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each had lower AUCs: 0.77, 0.82 and 0.82, respectively. The added value of IHC+PREMM(1,2,6) was slightly greater than PREMM(1,2,6)+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM(1,2,6)+IHC did not improve discrimination. CONCLUSION: PREMM(1,2,6) and IHC showed excellent performance in distinguishing mutation carriers from non-carriers and performed best when combined. MSI may have a greater role in distinguishing Lynch syndrome from other familial colorectal cancer subtypes among cases with high PREMM(1,2,6) scores where genetic evaluation does not disclose a MMR mutation.
    Gut 02/2012; · 10.73 Impact Factor
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    Fay Kastrinos, Sapna Syngal
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    ABSTRACT: Colorectal cancer is the most common gastrointestinal malignancy and the second leading cause of cancer death in both men and women in the United States. Most colorectal cancer cases diagnosed annually are due to sporadic events, but up to 5% are attributed to known monogenic disorders including Lynch syndrome, familial adenomatous polyposis, MYH-associated polyposis, and the rare hamartomatous polyposis syndromes. These inherited colorectal cancer syndromes confer a markedly increased risk for the development of multiple cancers, and predictive genetic testing is available to identify mutation carriers and at-risk family members. Through personalized strategies for diagnosis and management, a substantial reduction in morbidity and mortality has been appreciated among patients at highest risk for the development of colorectal cancer.
    The Cancer Journal 11/2011; 17(6):405-15. · 3.66 Impact Factor
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    ABSTRACT: There are no guidelines for the recommended interval to the next examination after colonoscopy with suboptimal bowel preparation. To identify factors associated with early repeat colonoscopy after initial examinations with suboptimal preparations and to measure adenoma miss rates in this context. Retrospective study. Hospital-based endoscopy unit. Bowel preparation quality was recorded in 12,787 patients. Of 12,787 colonoscopies, preparation quality was suboptimal (poor or fair) in 3047 patients (24%). Among these 3047 patients, repeat examination was performed in <3 years in 505 (17%). Factors associated with early repeat colonoscopy included lack of cecal intubation (odds ratio [OR] 3.62, 95% confidence interval [CI], 2.50-5.24) and finding a polyp (OR 1.55, 95% CI, 1.17-2.07). Among 216 repeat colonoscopies with optimal preparation, 198 adenomas were identified, of which 83 were seen only on the second examination, an adenoma miss rate of 42% (95% CI, 35-49). The advanced adenoma miss rate was 27% (95% CI, 17-41). For colonoscopies repeated in <1 year, the adenoma and advanced adenoma miss rates were 35% and 36%, respectively. Single-center, retrospective study. Although a minority of patients undergo early repeat examination after colonoscopies done with suboptimal bowel preparation, the miss rates for colonoscopies done with suboptimal bowel preparation were high, suggesting that suboptimal bowel preparation substantially decreases colonoscopy effectiveness and may mandate an early follow-up examination.
    Gastrointestinal endoscopy 06/2011; 73(6):1207-14. · 6.71 Impact Factor
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    ABSTRACT: We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer. Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92). We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.
    Gastroenterology 01/2011; 140(1):73-81. · 12.82 Impact Factor
  • Gastroenterology 01/2011; 140(5). · 12.82 Impact Factor
  • Gastrointestinal Endoscopy - GASTROINTEST ENDOSCOP. 01/2011; 73(4).

Publication Stats

362 Citations
263.40 Total Impact Points

Institutions

  • 2013
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2011–2013
    • Columbia University
      • • Department of Epidemiology
      • • Medical Center
      • • Division of Digestive and Liver Disease
      New York City, NY, United States
  • 2012
    • Dana-Farber Cancer Institute
      • Division of Population Sciences
      Boston, MA, United States
  • 2007–2012
    • Brigham and Women's Hospital
      • • Center for Brain Mind Medicine
      • • Division of General Internal Medicine and Primary Care
      Boston, MA, United States