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application are (1) To expand and validate PREMM1,2,6 to include PMS2 and EPCAM gene mutation prediction using an unpublished cohort of 12,000 patients for model development, and data from an international consortium of family registries for model validation~ (2) To validate the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.

Public Health Relevance

The results of this effort will achieve several goals of PA-10-025. It will support work in development, application, and evaluation of new and existing cancer risk and prognostic prediction models for use by researchers, clinicians, and the general public. It also addresses several major challenges in model development described in the Program Announcement: integrating diverse types of data, ensuring adequate validation of prediction models, and evaluating their utility in research and clinical settings. The ultimate goal of the application is to develop an extensively validated tool that is easy to use by patients and physicians, and improves identification of patients who are at increased risk for having an inherited colorectal cancer syndrome.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Shelburne, Nonniekaye F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
Tamura, Koji; Yu, Jun; Hata, Tatsuo et al. (2018) Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci U S A 115:4767-4772
Canto, Marcia Irene; Almario, Jose Alejandro; Schulick, Richard D et al. (2018) Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance. Gastroenterology 155:740-751.e2
Luba, Daniel G; DiSario, James A; Rock, Colleen et al. (2018) Community Practice Implementation of a Self-administered Version of PREMM1,2,6 to Assess Risk for Lynch Syndrome. Clin Gastroenterol Hepatol 16:49-58
Kastrinos, Fay; Uno, Hajime; Ukaegbu, Chinedu et al. (2017) Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome. J Clin Oncol 35:2165-2172
Yurgelun, Matthew B; Kulke, Matthew H; Fuchs, Charles S et al. (2017) Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol 35:1086-1095
Kastrinos, Fay; Ojha, Rohit P; Leenen, Celine et al. (2016) Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer. J Natl Cancer Inst 108:
Inra, Jennifer A; Steyerberg, Ewout W; Grover, Shilpa et al. (2015) Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing. Genet Med 17:815-21
Yurgelun, Matthew B; Allen, Brian; Kaldate, Rajesh R et al. (2015) Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology 149:604-13.e20
Kastrinos, Fay; Steyerberg, Ewout W (2015) Family matters in lynch syndrome. J Natl Cancer Inst 107:
Everett, Jessica N; Raymond, Victoria M; Dandapani, Monica et al. (2014) Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm. JAMA Dermatol 150:1315-21

Showing the most recent 10 out of 14 publications