Grant Number:	4R01CA132829-08 Interpret this number
Primary Investigator:	Syngal, Sapna
Organization:	Dana-Farber Cancer Inst
Project Title:	Validation and Extension of the Premm Model for Inherited Colorectal Cancer
Fiscal Year:	2016

DESCRIPTION (provided by applicant): We have recently developed the PREMM1,2,6 model, a clinical prediction rule designed to be used by healthcare providers to estimate the probability that an individual carries a mutation in the MLH1, MSH2 and MSH6 mismatch repair (MMR) genes (Balmana et al. JAMA 2006, Kastrinos et. al Gastroenterology 2011). PREMM1,2,6 was developed and subsequently validated in thousands of patients who were undergoing genetic evaluation for Lynch Syndrome, the most common form of hereditary colon cancer. Since the development of the model, two additional genes, PMS2 and EPCAM, have been implicated in the condition. In addition to the PREMM1,2,6 model, we have developed a Polyposis model (Grover et al., JAMA 2012) which predicts the likelihood of an individual carrying a germline mutation in the APC and MYH genes, related to Familial Adenomatous Polyposis and MYH-Associated Polyposis. This model was developed from over 9000 individuals who had undergone genetic testing for these two genes but requires independent, external validation that necessitates a large, multicenter collaborative effort. Finally, although the PREMM1,2,6 model, (available on the Dana-Farber Cancer Institute website at www.dfci.org/premm) is widely used by providers around the world who are familiar with the syndrome, our work and that of others have consistently shown that many patients who are at risk for a familial cancer syndrome are not identified or referred for genetic testing. Systematic approaches of risk assessment are necessary to identify and correctly manage patients with inherited forms of cancer, an issue that will be increasingly important as the number of cancer susceptibility genes to be considered expands and complexity of test interpretation increases. In consideration of these issues, and as an expansion of our prior work, the aims of this R01 renewal application are (1) To expand and validate PREMM1,2,6 to include PMS2 and EPCAM gene mutation prediction using an unpublished cohort of 12,000 patients for model development, and data from an international consortium of family registries for model validation~ (2) To validate the performance of the clinical prediction model for the inherited polyposis syndromes, Familial Adenomatous and MYH-associated Polyposis, in subjects enrolled through an international consortium of collaborators~ and (3) (i) To adapt the Lynch Syndrome and Polyposis models into a single risk assessment tool that can be completed by patients electronically on a mobile device and subsequently used by physicians to generate individualized prediction risk scores of the patient's likelihood of carrying MMR, APC or MYH gene mutations for shared decision making, and (ii) to validate the patient application by comparing its predictions to those made when the model estimates were derived by genetic counselors and healthcare providers.




PREMM5 distinguishes sporadic from Lynch syndrome-associated MMR-deficient/MSI-high colorectal cancer.
Authors: Sandoval R.L. , Horiguchi M. , Ukaegbu C. , Furniss C.S. , Uno H. , Syngal S. , Yurgelun M.B. .
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. .
Source: Journal Of The American Academy Of Dermatology, 2023 Jun; 88(6), p. 1282-1290.
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. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2022-12-10 00:00:00.0; 40(35), p. 4083-4094.
EPub date: 2022-08-12 00:00:00.0.
PMID: 35960913
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A validation of models for prediction of pathogenic variants in mismatch repair genes.
Authors: Shyr C. , Blackford A.L. , Huang T. , Ke J. , Ouardaoui N. , Trippa L. , Syngal S. , Ukaegbu C. , Uno H. , Nafa K. , et al. .
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PMID: 35997715
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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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PMID: 35689290
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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. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2022 06; 24(6), p. 1196-1205.
EPub date: 2022-03-16 00:00:00.0.
PMID: 35305866
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Risk of Pancreatic Cancer Among Individuals With Pathogenic Variants in the ATM Gene.
Authors: Hsu F.C. , Roberts N.J. , Childs E. , Porter N. , Rabe K.G. , Borgida A. , Ukaegbu C. , Goggins M.G. , Hruban R.H. , Zogopoulos G. , et al. .
Source: Jama Oncology, 2021-11-01 00:00:00.0; 7(11), p. 1664-1668.
PMID: 34529012
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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. .
Source: British Journal Of Cancer, 2021-10-26 00:00:00.0; , .
EPub date: 2021-10-26 00:00:00.0.
PMID: 34703010
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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. .
Source: Gastroenterology, 2021 07; 161(1), p. 143-150.e4.
EPub date: 2021-03-29 00:00:00.0.
PMID: 33794268
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Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.
Authors: International Mismatch Repair Consortium .
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.
Authors: Mittendorf K.F. , Ukaegbu C. , Gilmore M.J. , Lindberg N.M. , Kauffman T.L. , Eubanks D.J. , Shuster E. , Allen J. , McMullen C. , Feigelson H.S. , et al. .
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EPub date: 2021-03-23 00:00:00.0.
PMID: 33754278
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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.
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 00:00:00.0; 38(34), p. 4086-4094.
EPub date: 2020-09-30 00:00:00.0.
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. .
Source: Familial Cancer, 2020-08-03 00:00:00.0; , .
EPub date: 2020-08-03 00:00:00.0.
PMID: 32743790
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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 00:00:00.0; , .
EPub date: 2020-08-03 00:00:00.0.
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. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2020 Mar; 13(3), p. 291-298.
EPub date: 2020-02-12 00:00:00.0.
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. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2020 Jan; 29(1), p. 193-199.
EPub date: 2019-10-15 00:00:00.0.
PMID: 31615790
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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. .
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EPub date: 2019-07-15 00:00:00.0.
PMID: 31319185
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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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EPub date: 2019-06-13 00:00:00.0.
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Recent advances in Lynch syndrome.
Authors: Biller L.H. , Syngal S. , Yurgelun M.B. .
Source: Familial Cancer, 2019 04; 18(2), p. 211-219.
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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. .
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PMID: 30729418
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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 00:00:00.0.
PMID: 29961768
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Recommended care and care adherence following a diagnosis of Lynch syndrome: a mixed-methods study.
Authors: Mittendorf K.F. , Hunter J.E. , Schneider J.L. , Shuster E. , Rope A.F. , Zepp J. , Gilmore M.J. , Muessig K.R. , Davis J.V. , Kauffman T.L. , et al. .
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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.
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. .
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PMID: 29669919
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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 00:00:00.0; 35(22), p. 2588-2589.
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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. .
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Community Practice Implementation of a Self-administered Version of PREMM1,2,6 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. .
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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. .
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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. .
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PMID: 26582061
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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. .
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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. .
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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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Prediction models in Lynch syndrome.
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PMID: 23553450
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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.
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. .
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PMID: 22345660
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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. .
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PMID: 22402756
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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.
PMID: 20727894
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