Grant Number:	5R01CA132829-12 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:	2021

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.  




Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm₅ Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing.
Authors: Mannucci A. , Furniss C.S. , Ukaegbu C. , Horiguchi M. , Fehlmann T. , Uno H. , Yurgelun M.B. , Syngal S. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2020-12-01; 38(34), p. 4086-4094.
EPub date: 2020-09-30.
PMID: 32997573
Related Citations

Recent advances in Lynch syndrome: response to Møller et al.
Authors: Biller L.H. , Syngal S. , Yurgelun M.B. .
Source: Familial cancer, 2020-08-03; , .
EPub date: 2020-08-03.
PMID: 32743791
Related Citations

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. .
Source: Familial cancer, 2020-08-03; , .
EPub date: 2020-08-03.
PMID: 32743790
Related Citations

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. .
Source: Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract, 2020 05; 24(5), p. 1101-1110.
EPub date: 2019-06-13.
PMID: 31197699
Related Citations

Clinical Factors Associated With Gastric Cancer in Individuals With Lynch Syndrome.
Authors: Kim J. , Braun D. , Ukaegbu C. , Dhingra T.G. , Kastrinos F. , Parmigiani G. , Syngal S. , Yurgelun M.B. .
Source: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2020 04; 18(4), p. 830-837.e1.
EPub date: 2019-07-15.
PMID: 31319185
Related Citations

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. .
Source: Cancer prevention research (Philadelphia, Pa.), 2020 03; 13(3), p. 291-298.
EPub date: 2020-02-12.
PMID: 32051178
Related Citations

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. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 01; 29(1), p. 193-199.
EPub date: 2019-10-15.
PMID: 31615790
Related Citations

Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting.
Authors: Clarke E.V. , Muessig K.R. , Zepp J. , Hunter J.E. , Syngal S. , Acheson L.S. , Wiesner G.L. , Peterson S.K. , Bergen K.M. , Shuster E. , et al. .
Source: Familial cancer, 2019 07; 18(3), p. 317-325.
PMID: 30729418
Related Citations

Recent advances in Lynch syndrome.
Authors: Biller L.H. , Syngal S. , Yurgelun M.B. .
Source: Familial cancer, 2019 04; 18(2), p. 211-219.
PMID: 30627969
Related Citations

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.
Authors: Yurgelun M.B. , Chittenden A.B. , Morales-Oyarvide V. , Rubinson D.A. , Dunne R.F. , Kozak M.M. , Qian Z.R. , Welch M.W. , Brais L.K. , Da Silva A. , et al. .
Source: Genetics in medicine : official journal of the American College of Medical Genetics, 2019 01; 21(1), p. 213-223.
EPub date: 2018-07-02.
PMID: 29961768
Related Citations

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. .
Source: Gastroenterology, 2018 09; 155(3), p. 740-751.e2.
EPub date: 2018-05-24.
PMID: 29803839
Related Citations

Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer.
Authors: Tamura K. , Yu J. , Hata T. , Suenaga M. , Shindo K. , Abe T. , MacGregor-Das A. , Borges M. , Wolfgang C.L. , Weiss M.J. , et al. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2018-05-01; 115(18), p. 4767-4772.
EPub date: 2018-04-18.
PMID: 29669919
Related Citations

Community Practice Implementation of a Self-administered Version of PREMM_1,2,6 to Assess Risk for Lynch Syndrome.
Authors: Luba D.G. , DiSario J.A. , Rock C. , Saraiya D. , Moyes K. , Brown K. , Rushton K. , Ogara M.M. , Raphael M. , Zimmerman D. , et al. .
Source: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2018 Jan; 16(1), p. 49-58.
EPub date: 2017-06-28.
PMID: 28668538
Related Citations

Reply to M.S. Daniels et al.
Authors: Yurgelun M.B. , Syngal S. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017-08-01; 35(22), p. 2588-2589.
EPub date: 2017-05-16.
PMID: 28510494
Related Citations

Development and Validation of the PREMM₅ Model for Comprehensive Risk Assessment of Lynch Syndrome.
Authors: Kastrinos F. , Uno H. , Ukaegbu C. , Alvero C. , McFarland A. , Yurgelun M.B. , Kulke M.H. , Schrag D. , Meyerhardt J.A. , Fuchs C.S. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017-07-01; 35(19), p. 2165-2172.
EPub date: 2017-05-10.
PMID: 28489507
Related Citations

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.
Authors: Yurgelun M.B. , Kulke M.H. , Fuchs C.S. , Allen B.A. , Uno H. , Hornick J.L. , Ukaegbu C.I. , Brais L.K. , McNamara P.G. , Mayer R.J. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017-04-01; 35(10), p. 1086-1095.
EPub date: 2017-01-30.
PMID: 28135145
Related Citations

Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.
Authors: Kastrinos F. , Ojha R.P. , Leenen C. , Alvero C. , Mercado R.C. , Balmaña J. , Valenzuela I. , Balaguer F. , Green R. , Lindor N.M. , et al. .
Source: Journal of the National Cancer Institute, 2016 Feb; 108(2), .
EPub date: 2015-11-18.
PMID: 26582061
Related Citations

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.
Authors: Inra J.A. , Steyerberg E.W. , Grover S. , McFarland A. , Syngal S. , Kastrinos F. .
Source: Genetics in medicine : official journal of the American College of Medical Genetics, 2015 Oct; 17(10), p. 815-21.
EPub date: 2015-01-15.
PMID: 25590978
Related Citations

Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
Authors: Yurgelun M.B. , Allen B. , Kaldate R.R. , Bowles K.R. , Judkins T. , Kaushik P. , Roa B.B. , Wenstrup R.J. , Hartman A.R. , Syngal S. .
Source: Gastroenterology, 2015 Sep; 149(3), p. 604-13.e20.
EPub date: 2015-05-14.
PMID: 25980754
Related Citations

Family matters in lynch syndrome.
Authors: Kastrinos F. , Steyerberg E.W. .
Source: Journal of the National Cancer Institute, 2015 Apr; 107(4), .
EPub date: 2015-03-20.
PMID: 25794515
Related Citations

Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm.
Authors: Everett J.N. , Raymond V.M. , Dandapani M. , Marvin M. , Kohlmann W. , Chittenden A. , Koeppe E. , Gustafson S.L. , Else T. , Fullen D.R. , et al. .
Source: JAMA dermatology, 2014 Dec; 150(12), p. 1315-21.
PMID: 25006859
Related Citations

Prediction models in Lynch syndrome.
Authors: Kastrinos F. , Balmaña J. , Syngal S. .
Source: Familial cancer, 2013 Jun; 12(2), p. 217-28.
PMID: 23553450
Related Citations

Comparison of the clinical prediction model PREMM(1,2,6) and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer.
Authors: Kastrinos F. , Steyerberg E.W. , Balmaña J. , Mercado R. , Gallinger S. , Haile R. , Casey G. , Hopper J.L. , LeMarchand L. , Lindor N.M. , et al. .
Source: Gut, 2013 Feb; 62(2), p. 272-9.
EPub date: 2012-02-16.
PMID: 22345660
Related Citations

Performance of PREMM(1,2,6), MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases.
Authors: Mercado R.C. , Hampel H. , Kastrinos F. , Steyerberg E. , Balmana J. , Stoffel E. , Cohn D.E. , Backes F.J. , Hopper J.L. , Jenkins M.A. , et al. .
Source: Genetics in medicine : official journal of the American College of Medical Genetics, 2012 Jul; 14(7), p. 670-80.
EPub date: 2012-03-08.
PMID: 22402756
Related Citations

The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.
Authors: Kastrinos F. , Steyerberg E.W. , Mercado R. , Balmaña J. , Holter S. , Gallinger S. , Siegmund K.D. , Church J.M. , Jenkins M.A. , Lindor N.M. , et al. .
Source: Gastroenterology, 2011 Jan; 140(1), p. 73-81.
EPub date: 2010-08-19.
PMID: 20727894
Related Citations