Colon Cancer Family Registry Cohort (CCFRC)
Principal Investigators (PIs):
- Robert W. Haile, Dr.P.H.
Stanford Cancer Institute
- Mark A. Jenkins, Ph.D.
University of Melbourne
- Noralane M. Lindor, M.D.
Established in 1997, the Colorectal Cancer Family Registry (CCFR) was developed by a multidisciplinary team of international investigators interested in conducting population- and clinic-based studies of the genetic and molecular epidemiology of colorectal cancer (CRC). Six field centers participate in the CCFR: Fred Hutchinson Cancer Research Center (FHCRC), Lunenfeld-Tanenbaum Research Institute (LTRI), Mayo Clinic, University of Hawaii (UHI), University of Melbourne (Australasia), and University of Southern California Consortium (USC). Stanford Cancer Institute serves as the administrative center. All six field centers utilized population-based ascertainment techniques; four also recruited participants through clinic-based sources (USC, Australasia, Mayo Clinic and LTRI).
The CCFR recruited participants (probands, family members, and spouse and population-based controls) starting in 1997 and ending in 2012 using a family-based ascertainment scheme from both population-based cancer registries and high-risk clinics. At enrollment, subjects completed a detailed baseline questionnaire. Blood or buccal samples and tumor tissue were collected and consent to access medical records and for future contact for follow-up was obtained. Subjects were re-contacted every 5 years to complete a follow-up questionnaire. Linkages to local cancer registries and national death indices were performed annually. As of December 2012, nearly 15,000 families comprised of 41,989 subjects had been enrolled.
Beginning in 2013, the Colon CFR received funding through PAR-10-283: Core Infrastructure and Methodological Research for Cancer Epidemiology Cohorts (CEC) and was restructured to a cohort study design. CCFR cohort subjects (with the exception of population-based controls) are re-contacted every 5 years to complete a follow-up questionnaire. Of the overall cohort, 8,865 population-based case probands had a verified CRC. Blood has been collected from 7,358 of these participants and tumor blocks from 6,400. Since completing the baseline survey, 2,271 enrolled cohort subjects have been diagnosed with an incident cancer. A pre-diagnosis blood sample was collected from 1,904. Of these, 560 are incident colorectal cancer cases.
A distinguishing feature of this cohort of prevalent and incident cancers is the extensive genetic and molecular characterization that has been completed to date. CRC-affected probands have had testing for evidence of known genetic susceptibilities to cancer. All available colorectal cancer tumors have been tested for evidence of mismatch repair deficiency by testing for microsatellite instability (Phase I samples only) and/or by testing for absence of mismatch repair (MMR) protein expression using immunohistochemistry (IHC) for all four MMR proteins (MLH1, MSH2, MSH6 and PMS2). Proband tumors with MSI data were analyzed for CpG Island Methylator Phenotype (CIMP) and KRAS somatic mutations. Triaged by IHC, Phase I cases were analyzed for point mutations and small insertion/deletion mutations in MSH2 and MLH1. Further, MMR testing was conducted for participants showing loss of MSH6 only by IHC. All samples tested for specific genes were also tested for the presence of large deletions and/or insertions with the use of MLPA. For Phase II and III cases, cohort participants with CRC tumors exhibiting mismatch repair deficiency by IHC had their lymphocytic DNA tested directly for mutations in the genes indicated by the IHC testing results. All proband CRC tumors exhibiting deficiency of MLH1 by IHC were analyzed for hypermethylation of the MLH1 gene. All CRC tumors were tested for BRAF mutations and all probands had their lymphocytic DNA analyzed for the presence of a mutation in the MutYH gene. Finally, Genome-wide Association Study (GWAS) testing will soon be complete on all population-based, non-Hispanic Caucasian probands.
The CCFRC has served as an international resource for studies of the genetic epidemiology of CRC. The CCFRC is the largest single family-based resource in the world for the study of CRC (and other cancers, such as endometrial cancer, that occur in these families). It has supported and enabled over 200 scientific projects, many including collaborations with other top CRC groups in the world, that range from etiological to behavioral to clinical studies and has generated over 270 publications to date.