Grant Number:	5R01CA132829-11 Interpret this number
Primary Investigator:	Syngal, Sapna
Organization:	Dana-Farber Cancer Inst
Project Title:	Development and Validation of Clinical Prediction Models for the Use and Interpretation of Multigene Hereditary Cancer Risk Assessment
Fiscal Year:	2020

Project Summary Over the past two decades, risk assessment for inherited cancers has been driven by syndrome specific models for the identification of high risk individuals who should undergo genetic testing. Genetic testing results allow the clinician to ensure strategies for surveillance and/or intervention to prevent cancer in susceptible individuals. This motivated our previous work in development of the PREMM models, the most recent of which predicts risk of mutation in 5 genes that cause Lynch syndrome. The PREMM models have been incorporated into national guidelines for the identification of Lynch syndrome. Parallel syndrome specific models have been developed for hereditary breast and ovarian cancer (HBOC) based on the prediction of two genes (BRCA1,2). While these models are well accepted in clinical practice, many individuals with hereditary cancer syndromes remain unidentified as current models predict risk of a limited number of gene mutations. Evidence from the use of multigene panel tests has provided an opportunity for the evolution of hereditary risk assessment models that can lead to increased identification of high risk individuals. These tests have found that an additional 15+ genes are implicated in both Lynch syndrome and HBOC, and that there is overlap in genetic profiles across syndromes i.e. BRCA1/2 detected in Lynch patients and mismatch repair gene mutations detected in HBOC patients. To address these unmet needs and as an extension of our prior work, we propose to develop a multigene model that will predict risk of mutation in 20+ genes including the genes in current models for HBOC and Lynch syndromes as well as an additional 15+ cancer susceptibility genes. We will develop the multigene model in a study of more than 260,000 individuals both affected and unaffected with cancer, compare its performance to current syndrome specific models, and perform validation in separate populations. To this end, we propose the following specific aims: 1. To develop a genetic risk assessment tool that will identify individuals who should undergo multigene panel testing for germline mutations associated with inherited cancer susceptibility genes, 2. To compare the performance of the multigene risk assessment model with syndrome specific models, including PREMM1,2,6, MMRpro, and BRCAPRO in a cohort of 2000 ethnically and racially diverse patients, and 3. To externally validate the multigene risk-assessment model in (A) a clinic- based population of patients without a personal history of cancer referred for hereditary cancer risk assessment due to a family history of cancer and (B) unselected clinic-based populations of patients with colorectal, breast, and pancreatic cancer. This work will lead to streamlined and comprehensive genetic risk assessment of personal and family cancer histories and the first prediction model that can be used by clinicians to determine who should undergo multigene panel genetic testing. Systematic application of this model in clinical practice will lead to increased identification of individuals who carry mutations in cancer susceptibility genes while reducing the number of low-risk individuals undergoing genetic testing.  




PREMM5 distinguishes sporadic from Lynch syndrome-associated MMR-deficient/MSI-high colorectal cancer.
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Source: Familial Cancer, 2023-08-12 00:00:00.0; , .
EPub date: 2023-08-12 00:00:00.0.
PMID: 37572151
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Clinical factors associated with skin neoplasms in individuals with Lynch syndrome in a longitudinal observational cohort.
Authors: Zhong C.S. , Horiguchi M. , Uno H. , Ukaegbu C. , Chittenden A. , LeBoeuf N.R. , Syngal S. , Nambudiri V.E. , Yurgelun M.B. .
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EPub date: 2023-02-09 00:00:00.0.
PMID: 36773823
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Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment.
Authors: Yurgelun M.B. , Uno H. , Furniss C.S. , Ukaegbu C. , Horiguchi M. , Yussuf A. , LaDuca H. , Chittenden A. , Garber J.E. , Syngal S. .
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PMID: 35960913
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A validation of models for prediction of pathogenic variants in mismatch repair genes.
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Literacy-adapted, electronic family history assessment for genetics referral in primary care: patient user insights from qualitative interviews.
Authors: Mittendorf K.F. , Lewis H.S. , Duenas D.M. , Eubanks D.J. , Gilmore M.J. , Goddard K.A.B. , Joseph G. , Kauffman T.L. , Kraft S.A. , Lindberg N.M. , et al. .
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Laboratory-related outcomes from integrating an accessible delivery model for hereditary cancer risk assessment and genetic testing in populations with barriers to access.
Authors: Amendola L.M. , Shuster E. , Leo M.C. , Dorschner M.O. , Rolf B.A. , Shirts B.H. , Gilmore M.J. , Okuyama S. , Zepp J.M. , Kauffman T.L. , et al. .
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Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene.
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A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO.
Authors: Blackford A.L. , Childs E.J. , Porter N. , Petersen G.M. , Rabe K.G. , Gallinger S. , Borgida A. , Syngal S. , Cote M.L. , Schwartz A.G. , et al. .
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Familial Burden and Other Clinical Factors Associated With Various Types of Cancer in Individuals With Lynch Syndrome.
Authors: Biller L.H. , Horiguchi M. , Uno H. , Ukaegbu C. , Syngal S. , Yurgelun M.B. .
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PMID: 33794268
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Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.
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Source: The Lancet. Oncology, 2021 07; 22(7), p. 1014-1022.
EPub date: 2021-06-07 00:00:00.0.
PMID: 34111421
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Adaptation and early implementation of the PREdiction model for gene mutations (PREMM₅™) for lynch syndrome risk assessment in a diverse population.
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Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm₅ Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing.
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PMID: 32997573
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Characterizing germline APC and MUTYH variants in Ashkenazi Jews compared to other individuals.
Authors: Ukaegbu C. , Levi Z. , Fehlmann T.D. , Uno H. , Chittenden A. , Inra J.A. , Grover S. , Kastrinos F. , Syngal S. , Yurgelun M.B. .
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PMID: 32743790
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Recent advances in Lynch syndrome: response to Møller et al.
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PMID: 32743791
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A Multi-Institutional Cohort of Therapy-Associated Polyposis in Childhood and Young Adulthood Cancer Survivors.
Authors: Biller L.H. , Ukaegbu C. , Dhingra T.G. , Burke C.A. , Chertock Y. , Chittenden A. , Church J.M. , Koeppe E.S. , Leach B.H. , Levinson E. , et al. .
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PMID: 32051178
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Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome.
Authors: Wischhusen J.W. , Ukaegbu C. , Dhingra T.G. , Uno H. , Kastrinos F. , Syngal S. , Yurgelun M.B. .
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Clinical Factors Associated With Gastric Cancer in Individuals With Lynch Syndrome.
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Surgical Outcomes After Pancreatic Resection of Screening-Detected Lesions in Individuals at High Risk for Developing Pancreatic Cancer.
Authors: Canto M.I. , Kerdsirichairat T. , Yeo C.J. , Hruban R.H. , Shin E.J. , Almario J.A. , Blackford A. , Ford M. , Klein A.P. , Javed A.A. , et al. .
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Recent advances in Lynch syndrome.
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Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting.
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Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.
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Recommended care and care adherence following a diagnosis of Lynch syndrome: a mixed-methods study.
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Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance.
Authors: Canto M.I. , Almario J.A. , Schulick R.D. , Yeo C.J. , Klein A. , Blackford A. , Shin E.J. , Sanyal A. , Yenokyan G. , Lennon A.M. , et al. .
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are associated with pancreatic cancer.
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Reply to M.S. Daniels et al.
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Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome.
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Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.
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Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.
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Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.
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Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
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Family matters in lynch syndrome.
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Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm.
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Comparison of the clinical prediction model PREMM(1,2,6) and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer.
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Performance of PREMM(1,2,6), MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases.
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The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.
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