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1 Fred Hutchinson Cancer Research Center, Seattle, Washington; 2 Dartmouth Medical School, Lebanon, New Hampshire; 3 Cancer Care Ontario, Toronto, Ontario, Canada; 4 University of Hawaii, Honolulu, Hawaii; 5 University of Southern California, Los Angeles, California; 6 Research Triangle Institute, Research Triangle Park, North Carolina; 7 University of Melbourne, Carlton, Victoria, Australia; 8 McGill University, Montreal, Quebec, Canada; 9 Mayo Clinic, Rochester, Minnesota; and 10 National Cancer Institute, Bethesda, Maryland
Requests for reprints: Polly Newcomb, Cancer Prevention Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, P.O. Box 10924, M4-B402, Seattle, WA 98109-1024. Phone: 206-667-3476; Fax: 206-667-7850. E-mail: pnewcomb{at}fhcrc.org
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Abstract |
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Materials and Methods: The Colorectal Cancer Family Registry (Colon CFR) is an international consortium of six centers in North America and Australia formed as a resource to support studies on the etiology, prevention, and clinical management of colorectal cancer. Differences in design and sampling schemes ensures a resource that covers the continuum of disease risk. Two separate recruitment strategies identified colorectal cancer cases: population-based (incident case probands identified by cancer registries; all six centers) and clinic-based (families with multiple cases of colorectal cancer presenting at cancer family clinics; three centers). At this time, the Colon CFR is in year 10 with the second phase of enrollment nearly complete. In phase I recruitment (1998-2002), population-based sampling ranged from all incident cases of colorectal cancer to a subsample based on age at diagnosis and/or family cancer history. During phase II (2002-2007), population-based recruitment targeted cases diagnosed before the age of 50 years are more likely attributable to genetic factors. Standardized protocols were used to collect information regarding family cancer history and colorectal cancer risk factors, and biospecimens were obtained to assess microsatellite instability (MSI) status, expression of mismatch repair proteins, and other molecular and genetic processes.
Results: Of the 8,369 case probands enrolled to date, 2,602 reported having one or more colorectal cancer–affected relatives and 799 met the Amsterdam I criteria for Lynch syndrome. A large number of affected (1,324) and unaffected (19,816) relatives were enrolled, as were population-based (4,108) and spouse (983) controls. To date, 91% of case probands provided blood (or, for a few, buccal cell) samples and 75% provided tumor tissue. For a selected sample of high-risk subjects, lymphocytes have been immortalized. Nearly 600 case probands had more than two affected colorectal cancer relatives, and 800 meeting the Amsterdam I criteria and 128, the Amsterdam II criteria. MSI testing for 10 markers was attempted on all obtained tumors. Of the 4,011 tumors collected in phase I that were successfully tested, 16% were MSI-high, 12% were MSI-low, and 72% were microsatellite stable. Tumor tissues from clinic-based cases were twice as likely as population-based cases to be MSI-high (34% versus 17%). Seventeen percent of phase I proband tumors and 24% of phase II proband tumors had some loss of mismatch repair protein, with the prevalence depending on sampling. Active follow-up to update personal and family histories, new neoplasms, and deaths in probands and relatives is nearly complete.
Conclusions: The Colon CFR supports an evolving research program that is broad and interdisciplinary. The greater scientific community has access to this large and well-characterized resource for studies of colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2331–43)
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Introduction |
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The Colon CFR was developed by a multidisciplinary team of international investigators as a consortium of six field centers and an informatics support center (ISC). The participating centers are Cancer Care Ontario (CCO), Fred Hutchinson Cancer Research Center (FHCRC), Mayo Clinic, University of Hawaii (UHI), University of Southern California (USC), University of Melbourne (Australasia). The ISC developed a central database with limited data sets from all the participating centers. By the end of the second grant cycle of the Colon CFR in 2007, data and biospecimens would have been collected from nearly 10,000 probands and nearly 27,000 selected affected and unaffected relatives and controls. To facilitate the use of this resource by the scientific community, we describe the design and methods of the Colon CFR and the baseline data on colorectal cancer cases, their families, and controls, and provide a brief overview of the research and plans to date.
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Materials and Methods |
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Structure
The participating centers are supported by the National Cancer Institute through the Cooperative Agreement grant mechanism. The investigators of the Colon CFR comprise a multidisciplinary team of epidemiologists, molecular biologists, medical and surgical clinicians, geneticists, pathologists, biostatisticians, and behavioral scientists. A steering committee is responsible for developing and applying Colon CFR–wide policies and procedures, setting research agendas, monitoring study progress, reviewing research proposals, addressing operational problems, and resolving intraconsortium issues. Voting members of the Steering Committee are defined as the principal investigator and one coinvestigator from each of the six research institutions and the ISC, one community representative, one elected nonaffiliated research scientist with expertise in multidisciplinary and translational colorectal cancer research, and the National Cancer Institute project officer. The Steering Committee has established several working groups that coordinate the work of the Colon CFR. These working groups include Epidemiology and Analysis; Biospecimens and Microsatellite Instability (MSI); Molecular Characterization and Pathology; Access and Tracking; Diet; Prevention Trials; Treatment and Outcomes; Behavioral and Education; and Technical. These groups have produced the protocols and procedures used at each site and collaborate closely with the ISC to assure the timely and accurate transmission of data. The Advisory Committee provides external oversight of the research agenda and reviews specific applications to use consortium resources. Additionally, the ISC manages the storage, archiving, and dissemination of deidentified data from each of the Colon CFR centers. In collaboration with the Colon CFR investigators and working groups, the ISC has developed and implemented a comprehensive system for processing, storing, and retrieving core data. Using secure FTP for transfers, the centers upload the data files according to regular schedules. The ISC has worked closely with the Colon CFR investigators and working groups to define quality control procedures. The ISC runs extensive computer edits on transmitted data and posts any resulting edit discrepancies to a secure Web site. The ISC has developed additional core software systems and assembles data sets for approved investigator requests (Fig. 1
).
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Phase I Population-Based Recruitment (1997-2002). All six Colon CFR centers enrolled families with incident colorectal cancer identified through population-based cancer registries in defined geographic areas. Sampling probabilities differed according to age at diagnosis, race, and/or family history of colorectal cancer, depending on center. Sampling schemes ranged from inviting all eligible cases to participate (FHCRC) to a single-stage design in which all early-onset and a fraction of older-onset cases were recruited, irrespective of family history, sex, or any other factor (Australasia), to a two-stage stratified sampling design in which race/ethnicity and/or age at diagnosis were used to select case probands to approach for family history data collection and the resulting family history information to select probands for enrollment (UHI, Mayo Clinic, CCO, USC). Table 1 describes recruitment for population-based centers. At all centers except Australasia, all case probands reporting a first-degree family history of colorectal cancer were eligible and recruited. In Australasia, sampling fractions were based on age at diagnosis, not family history. After enrollment of the case proband, his/her permission and assistance was sought to contact eligible and available relatives. The selection of family members for recruitment was center-specific, ranging from first-degree only to the inclusion of second- and third-degree relatives.
Because of these differing sampling schemes, for some analyses it may be necessary to use proband weights. These weights are defined as the inverse of the probability that a case proband was selected for recruitment. For example, for the two-stage designs, the overall sampling probability is the product of the stage 1 and stage 2 sampling probabilities. For FHCRC, where all case probands of eligible age were eligible, all case probands receive a sampling probability of 1. The UHI contributed only family history–positive cases, thus proband weights by family history are not definable and data from this center are most suitable for analyses limited to familial forms of colorectal cancer. Proband weights have been calculated for all population-based families in the Colon CFR and have been transmitted to the ISC. Weights are available to users through the ISC.
During Phase I, controls were either randomly sampled from the general population living in the relevant recruitment area using Medicare and Driver's License files (FHCRC), telephone subscribers lists (CCO), or electoral rolls (Australasia), or were ascertained through the case proband, either as the spouse (UHI, Australasia, and Mayo Clinic) or as an unaffected family member (USC).
Phase I Clinic-Based Recruitment. Three centers also recruited families with multiple or early-onset cases of colorectal cancer through clinical settings: Mayo Clinic, USC (Cleveland Clinic subcenter), and Australasia (seven family cancer clinics across Australia and New Zealand). Clinic-based probands, defined as the first family member enrolled in the Colon CFR registry, may or may not have had a personal history of colorectal cancer. Instead, eligibility was based on one or more of the following criteria: two or more relatives with a personal history of colorectal cancer or Lynch syndrome cancer, a proband diagnosed with colorectal cancer at a young age, or a proband presenting at a clinic with Lynch syndrome or Lynch-like syndrome. After proband enrollment, permission and assistance were sought to contact eligible and available relatives. Control participants were also ascertained through the proband: spouse (Mayo Clinic, Australasia) or unaffected family member (USC). Table 2 provides an overview of the sampling strategies for the clinic-based families.
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Protocols and Procedures
The Colon CFR centers all use standardized core protocols and instruments for personal and family history data, biospecimens collection, laboratory analysis, and data transmission and summaries. These materals were developed by the relevant working groups; questionnaires and protocols are described in detail at http://epi.grants.cancer.gov/CFR/index.html.
Core Questionnaire. Family history and personal exposures (except diet; see below) have been consistently collected at all sites to facilitate joint analyses. Each selected proband, population-based and spouse controls, completed the family history questionnaire either in person (USC), by telephone (FHCRC, USC, Australasia), or by mail (UHI, CCO, Mayo Clinic). The questionnaire acquired information on the number, sex, and birthdates of first-degree relatives (parents, siblings, and children), their cancer history, vital status, and, if deceased, date of death. All cancers, except for nonmelanoma skin cancers, were recorded with dates of diagnoses. Pedigrees were expanded to second- and third-degree relatives in several centers, depending on center-specific protocols and the reported family history.
Depending on the sampling schema, subjects also completed the epidemiologic questionnaire that captures information on established and suspected risk factors for colorectal cancer, including medical history and medication use, reproductive history (for female participants), physical activity, demographics, alcohol and tobacco use, race and ethnicity, and limited dietary data. The questionnaire was given to selected Colon CFR participants, including cases, controls, and affected and unaffected relatives, and defines a participant as an enrollee. Australasia and the UHI also used a short proxy version to collect limited information on selected individuals who were deceased, unavailable, or unwilling to participate. Centers customized questions for local usage, in particular for different language conventions and brand names, and were allowed to add additional questions of local interest. Detailed question-by-question manuals for administration were developed for further standardization.
Dietary Questionnaire. Diet is important in the genesis of colorectal cancer. Four Colon CFR centers collected dietary information using a self-administered diet history questionnaire from enrollees (cases, controls, and family members). The diet history questionnaire developed at UHI for use by the Multiethnic Cohort study in Hawaii and California was used at UHI, CCO, and USC (16). Australasian centers used a locally validated dietary questionnaire developed for a cohort study of >40,000 Greek, Italian, and Australian-born citizens of Melbourne (17). Both instruments collected information on the frequency of food consumption and portion size.
Biospecimens. For hypothesis-driven research to be based on this resource, extensive characterization of the families in the resource and of their cancers was required. Biospecimens (blood and paraffin-embedded tumor tissue) were obtained from cases and selected relatives and controls according to established Colon CFR protocols. Initial processing included blood sample separation and aliquoting (or tissue sectioning) and storage.
Blood or Buccal Cell Collection. A standardized protocol was used to collect and process blood samples. In general, blood was collected in EDTA and/or ACD (or heparin) vacutainer tubes. From these blood samples, whole blood spots were prepared on Schleicher and Schuel specimen collection paper ("Guthrie cards"), dried, and stored at room temperature; plasma and buffy coat (or other WBC component) were isolated, aliquoted, and stored; viable lymphocyte cells were separated by Ficoll separation procedure, aliquoted, slow-frozen, and stored in liquid nitrogen for eventual EBV-transformation to a lymphoblastoid cell line.
For subjects who did not consent to a blood draw, some centers sought a buccal cell sample. To ensure the highest possible DNA yield and quality, we used the specimen collection and processing protocol based on the mouthwash protocol of Lum and Le Marchand (18). The mailed kit contained an informed consent document, detailed instructions, and all materials needed for producing the sample and returning it to the study center. In general, the acceptability of this protocol and the quality of DNA has been high (19).
To facilitate collaborative research on colorectal cancer, a supplementary award was obtained that enabled all centers to extract germline DNA from blood or mouthwash samples for all phase I samples. Colon CFR–wide quality control studies on a sample of DNA specimens, including checking DNA concentration, absorbance ratio (260/280), DNA fragment size, and PCR amplification at six microsatellite loci were done by Coriell Institute for Medical Research.
EBV Transformation. To provide an unlimited supply of this valuable DNA, as well as RNA, supplementary funds were obtained to transform and maintain lymphoblastoid cell lines using EBV (20) on selected phase I participants. Using standard protocols, immortalization and subsequent DNA extractions were done at four laboratories: Coriell Institute for Medical Research, Mayo Clinic, University of Queensland, and Hospital for Sick Children in Toronto. The selection of samples for transformation was based on the proband's risk status: probands from families with two or more cases of colorectal cancer and probands diagnosed with colorectal cancer under the age of 50 years had the highest priority. To date, 
4,100 specimens have been EBV-transformed.
Pathology Materials. Paraffin-embedded colorectal tumors and diagnostic pathology reports from colorectal cancer–affected probands and relatives were obtained from treating institutions, following informed consent. A standardized protocol to select and section representative blocks was developed by the Pathology working group. In general, sections were cut from each tumor and normal tissue block and stained with H&E. Stained sections were reviewed by center pathologist(s) who selected a colorectal cancer tumor block when possible, consisting of 70% to 80% tumor cells, and a block consisting of normal tissue for further sectioning. For planned immunohistochemistry and future protein-based studies, ten 4-µm or 5-µm paraffin sections from the tumor block were prepared and mounted unbaked on Probe-On Plus slides. For MSI testing and other future tumor DNA-based studies, ten 5-µm tumor sections were prepared and either mounted on glass slides or stored in microfuge tubes. When available, ten 5-µm normal tissue sections were similarly prepared and stored for DNA-based studies. DNA extractions from tumor and normal tissue for phase I recruitment was completed as part of the registry-wide MSI project, with remaining DNA stored at the local Colon CFR centers.
Confirmation of Colorectal Cancer Diagnoses. Confirmation of cancer diagnoses was sought for all reported colorectal cancers and, at some centers, for other reported invasive cancers. The level of confidence regarding a cancer diagnosis was classified into one of six categories (in decreasing order): (a) pathologist review of slides, (b) review of the pathology report; (c) cancer registry report or medical record(s) indicating treatment for the specific type of cancer; (d) report on a death certificate; (e) self-report; and (f) report by a relative. Pathology reports for all probands' qualifying colorectal cancers were reviewed, and data, including site, stage, histology, grade, distant spread, nodular involvement, etc., were abstracted onto a standardized review form developed by the Pathology Working Group. All pathology reviews are entered into a database and submitted to the ISC.
Characterization of Colorectal Cancer Tumors. One of two distinct molecular pathways leading to colorectal carcinogenesis involves the MMR pathway (21). Because it became evident that research of nearly any type on colorectal cancer would require characterizing participants' tumors according to DNA MMR competency, a competitive supplement was obtained to fund the Colon CFR–wide collection of tumors and characterization by tumor MSI, the phenotypic indicator of MMR competence (21). MSI testing was done on all available phase I Colon CFR tumors using 10 markers: four mononucleotide markers (BAT25, BAT26, BAT40, BAT34C4), four dinucleotide markers (D5S346, D17S250, D18S55, D10197), and two complex markers (ACTC and MycL; ref. 22). In general, tumors were classified as microsatellite stable (0% of unstable loci), MSI-low (>0% to <30% of unstable loci), or MSI-high (
30% of unstable loci); unequivocal results for at least four markers were required to establish and report MSI status. MSI was completed on all affected phase I probands and affected family members with tumors meeting testing criteria and, similarly, on a selected sample of phase II affected participants (clinic-based and minority participants).
Immunohistochemical staining, a simpler and less expensive test than MSI analysis, has proved to be a valid alternative approach to identify tumors with MMR (23). Thus, in addition to the MSI testing, we did immunohistochemistry on all obtained clinic-based probands and affected relative tumors and, at a minimum, microsatellite instable population-based tumors to establish the presence or absence of protein expression for MLH1, MSH2, and MSH6 (and, at some centers, PMS2), primary protein constituents of the MMR machinery. Staining was done on 4-µm to 5-µm thick formalin-fixed, paraffin-embedded tissue sections and was conducted at three centers: Mayo Clinic, University of Queensland, and Mount Sinai Hospital. Commercially available monoclonal antibodies were used with control sections in each staining run, and assessment was standardized with protocols used for that laboratory. Although, we did not use standardized antibodies in all sites, site-specific antibodies and technical details are reported by Lindor et al. (23).
Molecular characterization testing of selected phase I colorectal cancer enrollees was completed during phase II (Fig. 2 ). Briefly, mutation testing for MLH1, MSH2, and MSH6 via dHPLC was conducted at three Colon CFR Centers: CCO, Australasia, and USC. Furthermore, the detection of large genomic rearrangements by MLPA was conducted under the direction of Dr. Stephen Thibodeau at the Mayo Clinic and the evaluation of methylation status of hMLH1 gene promoter was completed under the direction of Dr. Peter Laird at USC.
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Results |
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MSI Analysis. The prevalence of MSI in the Colon CFR is based on the evaluation of over 4,000 phases I and II affected probands with tumors adequate for testing (Table 4). Of these participants who had their MSI evaluated, 72% were stable (microsatellite stable), 11% showed low instability (>0% to <30% unstable markers), and 17% showed high instability (30% unstable markers). MSI status varied by ascertainment source: clinic-based probands were twice as likely to be MSI-high as population-based probands (34% versus 17%).
Immunohistochemistry Analysis. Immunohistochemistry was used to test for the absence of protein expression for hMSH2, hMLH1, and hMSH6 (and PMS2 at Mayo Clinic, Australasia, CCO, and FHCRC). Of the 4,588 phases I and II tumors tested, 19% showed loss of expression for one or more proteins. Specifically, 499 (11%) showed loss of expression of either MLH1 or MLH1 and PMS2, 169 (4%) showed loss of expression of either MSH2 or MSH2 and MSH6, 89 (2%) showed loss of expression of MSH6 only, and 84 (2%) showed loss of expression of PMS-2 (not all centers included PMS2 testing in their immunohistochemistry protocol). Protein loss depended on sampling frame, with clinic-based proband lesions having the highest proportion of MMR protein loss.
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Discussion |
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The Colon CFR has many strengths, including the extensive enrollment of affected cases, relatives, and controls which will permit a wide variety of classic and novel designs. Furthermore, the high quality biological data and existing characterization of all tumors for MSI and germline MMR gene mutations will enable the conduct of additional molecular studies. There are some limitations to the current registry design. First, differences in sampling frames and probabilities across Colon CFR centers (25) make summarizing registry data a whole challenge; varying sampling probabilities may be addressed analytically by incorporating individual proband weights (26). However, differences in population sampling (i.e., between clinic-based and population-based) may yield disparate estimates of penetrance (e.g., for major cancer susceptibility genes; ref. 27), and therefore, stratified analyses will be essential. Conversely, concordance of results will greatly strengthen inferences. Second, study centers vary with respect to control populations. The use of siblings, spouses, or unaffected population controls may yield different strengths of association with respect to genes, phenotypes, or other common exposures. These issues may be addressed by, first, comparing stratum-specific estimates based on similar control types, and second, in the absence of heterogeneity, summarizing across centers using all control types. Third, some of the study participants eligible for this study did not participate. Indeed, there is a great range of response proportions depending on the population and design. If participation depends on the presence of a gene (or genes) or phenotype, such as MSI, the prevalence of the gene in the population may have been under- or overestimated (28); furthermore, if participation depended jointly on exposure and disease status, our estimation of any association may be biased (29). It has been shown, however, that the assessment of gene-environment interactions in case-control studies is not subject to selection bias under the assumption that genotype does not influence participation conditional upon exposure and disease status (30). Fourth, not all subjects provided blood samples for genetic studies or tissue for MSI and other future studies. Because illness and family history may be factors in this loss, we may, again, have a study group that represents different genetic and phenotypic profiles than the true source population. Nevertheless, overall, the disparate designs and multiple study centers of the Colon CFR have yielded a range of risks that will support many research opportunities.
The resources collected and developed by the Colon CFR are available for use by the international scientific community. Investigators interested in pursuing collaborative research projects that use these resources are invited to submit applications for access to available data and biological materials. The first step in the application process is the submission of a "concept description," a short form describing the proposed project and the types of resources being requested. After submitting a concept description, applicants develop a full application with the support of a scientific liaison assigned to their proposed project. The scientific liaison is an internal CFR investigator familiar with the available resources and the application process. Full applications are evaluated by the reviewing committees with careful consideration given to their scientific merit, overlap with ongoing CFR studies, and the effect of the proposed study on the inventory of biological materials. The Advisory Committee is responsible for the final approval or disapproval of applications for CFR resources. New concept descriptions are accepted through an on-line submission form hosted by the ISC. A detailed description of the application process and a link to the online submission form can be found at http://epi.grants.cancer.gov/CFR/research.html. After approval, study support is available through the ISC, as well as individual study sites, if required. Study reports should include Colon CFR authors as appropriate, based on qualifying contributions (31).
In summary, the Colon CFR is now the largest resource for multidisciplinary investigators to study colorectal cancer (Fig. 3 ). The worldwide nature and unique designs ensure that investigators will be able to study colorectal cancer as it occurs in many different populations. The Colon CFR resource is now of even greater research potential, with follow-up data on the original Colon CFR families, a sizable number of identified mutation carriers, new enrollment of minority populations, and easy access to quality biospecimens and molecular, epidemiologic, and pathology data from all centers. Colon CFR investigators have already participated in numerous projects with external researchers from throughout the world and have initiated Colon CFR projects that include new collaborators, including young investigators. This rich resource will be available to the international community of scientists interested in studying colorectal cancer for many years to come.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 7/17/07; revised 8/29/07; accepted 9/ 6/07.
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