Risk of Colorectal Cancer and Adenomas in the Families of Patients With Adenomas

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1 Risk of Colorectal Cancer and Adenomas in the Families of Patients With Adenomas A Population-Based Study in Utah Therèse M.F. Tuohy, PhD 1 ; Kerry G. Rowe, MS 2 ; Geraldine P. Mineau, PhD 1,3 ; Richard Pimentel, MS 1 ; Randall W. Burt, MD 1,4 ; and N. Jewel Samadder, MD, MSc 1,4 BACKGROUND: Guidelines recommend that individuals with a first-degree relative (FDR) diagnosed with colorectal cancer (CRC) or advanced adenoma before age 60 years should undergo colonoscopy starting at age 40 years. The authors quantified the risk of adenomas and CRC in FDRs, second-degree relatives (SDRs), and third-degree relatives (TDRs) of patients diagnosed with adenomas and advanced adenomas. METHODS: A population-based, retrospective, case-control study was performed of residents of the state of Utah aged 50 years to 80 years who underwent colonoscopy between 1995 and 2009 at Intermountain Healthcare or the University of Utah. Controls were selected from the population of colonoscopy patients who were free of adenomas or CRC and matched to each case based on sex and birth year. Colonoscopy results were linked with cancer and pedigree information from the Utah Population Database to investigate the familial aggregation of adenomas and CRC using Cox regression analysis. The unit of analysis was the relatives of cases and controls. RESULTS: Of 126,936 patients who underwent colonoscopy, 43,189 had adenomas and 5563 had advanced adenomas and defined the case population. An elevated risk of CRC was found in FDRs (relative risk [RR], 1.35; 95% confidence interval [95% CI], ), SDRs (RR, 1.15; 95% CI, ) of adenoma cases, and in FDRs of advanced adenoma cases (RR, 1.68; 95% CI, ) compared with controls. Approximately 10% of CRCs diagnosed in relatives would have been missed if the current screening guidelines were strictly adhered to. CONCLUSIONS: Relatives of colonoscopy patients with adenomas and advanced adenomas appear to have a significantly elevated risk of developing colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and their families. Cancer 2014;120: VC 2013 American Cancer Society. KEYWORDS: colorectal cancer, adenomatous polyps, familial, colonoscopy. INTRODUCTION Colorectalcancer(CRC)isthethirdmostcommoncancerin the United States and the second most common cause of cancer-related mortality. 1 The discovery of several high-penetrance susceptibility genes (APC, MLH1, MSH2, MSH6, and PMS2) has lead to a greater awareness of the role of hereditary risk factors for CRC. Familial clustering of CRC is common even when the cases are not part of a defined genetic syndrome. 2 Adenomatous polyps are accepted as the precursor lesion for most cases of CRC. Screening for CRC is widely believed to provide an opportunity to detect patients at risk for developing CRC, remove precursor lesions, or detect patients at an earlier stage of cancer. Adenomas have a higher potential for malignancy both at the time of diagnosis and on follow-up when they measure > 10 mm in diameter and/or present with severe dysplasia and/or a villous component, at which point they are then defined as advanced adenomas (AAs). 3 Screening interventions such as colonoscopy are offered earlier to individuals with such a family history. Specifically, current guidelines recommend that patients with a first-degree relative (FDR) diagnosed with CRC or AA before age 60 years should undergo screening colonoscopy starting at age 40 years or 10 years before the index patient and undergo repeat surveillance every 5 years. 3-6 The current recommendations are primarily based on a prospective study by Fuchs et al that found that FDRs of patients with CRC had a risk of CRC at age 40 years that was similar to the risk of CRC in average-risk patients at the age of 50 years (relative risk [RR], 1.72; 95% confidence interval [95% CI], ). 7 Corresponding author: N. Jewel Samadder, MD, MSc, FRCPC, Hereditary Gastrointestinal Cancer Registry, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112; Fax: (801) ; jewel.samadder@hsc.utah.edu 1 Hereditary Gastrointestinal Cancer Registry, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; 2 Department of Oncology, Intermountain Healthcare, Salt Lake City, Utah; 3 Department of Oncological Sciences, University of Utah, Salt Lake City, Utah; 4 Division of Gastroenterology, Department of Medicine, University of Utah, Salt Lake City, Utah See editorial on pages 4-6, this issue. DOI: /cncr.28227, Received: October 17, 2012; Revised: February 5, 2013; Accepted: February 26, 2013, Published online October 21, 2013 in Wiley Online Library (wileyonlinelibrary.com) Cancer January 1,

2 Because the lifetime risk of CRC is approximately 6%, millions of Americans will be counseled to undergo colonoscopy at age 40 years, based on a positive family history of CRC or AA. Therefore, it is important to validate the elevated risk of CRC in the relatives of patients with adenomas or AAs in a population-based study, and to examine that risk in immediate and more distant relatives, as well as by age groups. In this retrospective, population-based, case-control study, we quantified the risk of CRC and adenomas in the FDRs, second-degree relatives (SDRs), or third-degree relatives (TDRs; first cousins) of individuals with an adenoma or advanced adenoma, stratified by age at diagnosis. To the best of our knowledge, the current study is the first population-based assessment of the risk of colorectal neoplasia in distant relatives of individuals with an adenomatous polyp and also examines this risk based on the age of the patient at the time of the adenoma diagnosis. Comprehensive family histories were available through extensive Utah genealogies linked to a statewide cancer registry and medical records that do not rely on self-report. The design of the current study is feasible because of these unique linked resources. MATERIALS AND METHODS Design This study was approved by the Institutional Review Boards of the University of Utah and Intermountain Healthcare (IHC) and by the Utah Resource for Genetic and Epidemiologic Research ( rge/), an administrative oversight board charged by the University of Utah to govern access to the Utah Population Database (UPDB). We performed a population-based, retrospective, case-control study of residents in the state of Utah aged 50 years to 80 years who underwent colonoscopy from February 15, 1995 to January 31, 2009 at IHC and the University of Utah Health Sciences (UUHSC) clinical facilities. Deidentified medical information regarding patients undergoing colonoscopy at IHC and UUHSC was merged with family structure in the UPDB genealogies, which include cancer histories from the Utah Cancer Registry (UCR), a Surveillance, Epidemiology, and End Results (SEER) registry, to investigate the familial aggregation of CRC and colon adenomas. Description of Databases The current investigation takes advantage of unique Utah databases. The study required patient-level data integration between IHC, the UUHSC, and the UPDB. The UPDB combines genealogies often dating back to the early 1800s with data from statewide resources, including the UCR, statewide inpatient discharge and ambulatory surgery records, and driver license data, as well as birth and death certificates. This resource also has been linked to the demographic records from the UUHSC 8 and IHC. 9 In combination, the UUHSC and IHC together provide cancer-related care to > 80% of the Utah population. Previous demographic and genetic analyses have shown that the population recorded in the UPDB is genetically representative of US white and northern European populations, with a low level of inbreeding. 10 Of particular interest for the current study is the inclusion of the UCR records as part of the UPDB. The UCR is a statewide cancer registry that was established in 1966, and since 1973 it has been part of the SEER network of the National Cancer Institute registries. Given an ongoing and accurate assessment of a family history of cancer that does not depend on self-report, the UPDB provides a valuable resource for a thorough analysis of the familial nature of colorectal neoplasia. Linkage of Electronic Medical Record Data to the UPDB These linked resources have been used to assess colonoscopy screening rates in high-risk individuals 11 as well as recent studies on preeclampsia, 12 spontaneous preterm delivery, 13 cancer in twins, 14 heritability of inflammatory bowel disease, 15 and effects of family conditions on laterlife mortality. 16 Study Definition Colonoscopy was extracted from the institutional records using Current Procedural Terminology codes 45378, 45391, or Case subjects were defined as having adenomas detected during their colonoscopy as outlined in Figure 1. Adenomas were identified through pathology reports. For the purposes of the current study, AAs were defined as those that had any component of villous histology, also identified through pathology reports. We could not identify the other criteria associated with a definition of AA (measuring > 10 mm or high-grade dysplasia). The analysis evaluated the RR of CRC and colorectal neoplasia diagnosed in the FDRs, SDRs, and TDRs of cases compared with relatives of controls. Control Selection For each case patient, 1 randomly selected, age- and sexmatched control was used. These controls were sampled without replacement and were selected from the population of colonoscopy patients who did not have 36 Cancer January 1, 2014

3 Familial Risk of Colorectal Neoplasia/Tuohy et al Figure 1. Study flow diagram is shown. IHC indicates Intermountain Healthcare; UUHSC, University of Utah Health Sciences; CRC, colorectal cancer; UPDB, Utah Population Database; FDR, first-degree relative (parent, child, sibling); SDR, second-degree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). adenomatous polyps removed at the time of any colonoscopy performed between 1995 and 2009, but they could have had other findings. Controls had to have follow-up in the UPDB that was at least as long as their respective matched case. Follow-up was based on the most recent date an individual had an event recorded in Utah from vital records (deaths, births, adoptions, marriages, and divorces; Utah driver s license registrations and renewals; voter registrations; and statewide inpatient and ambulatory surgeries). Records are linked at least annually. Statistical Analysis Using software developed specifically for UPDB kinship analysis, 17 the magnitude of familial risk was estimated by Cox regression analysis to assess the RR of CRC and adenoma for FDRs, SDRs, and TDRs of colonoscopy patients who themselves were diagnosed with adenomas. 18 Because observations within families are nonindependent, a robust variance estimator for clustered data similar to the generalized estimating equation approach was incorporated. 19 This analysis corrects for the issue of families being analyzed multiple times because of multiple cases of CRC. The percentage of FDRs diagnosed with CRC based on age groups was also computed. RESULTS The current study analyzed the RRs of colorectal neoplasia from 27,646 colonoscopy patients at UUHSC and 103,680 colonoscopy patients from IHC. When combined and accounting for patients who had procedures performed in both hospital systems, there were 126,936 unique individuals who had received a colonoscopy. A total of 43,189 patients had an adenomatous polyp removed at their index or first colonoscopy and defined the case population. For cases of AA, we used 5563 Cancer January 1,

4 patients who had an adenoma with villous features removed at the index or first colonoscopy. Table 1 shows the descriptive features of cases (colonoscopy patients with a finding of an adenomatous polyp) and controls in the current study. The mean age at the time the procedure was performed for both cases and controls was similar at 61 years and 60 years, respectively. For cases and controls, the mean number of relatives with colonoscopies was similar, thereby reducing the likelihood of detection bias. Colonoscopy use among FDRs was approximately 30%, which is similar to statewide use of CRC screening in Utah. Tables 2 and 3 show the distribution of CRC among relatives of cases with adenoma and AA and controls based on the degree of relation. An elevated risk of CRC was found in FDRs of cases with adenomas (RR, 1.35; 95% CI, ) and advanced adenomas (RR, 1.68; 95% CI, ) compared with relatives of controls. TABLE 1. Descriptive Characteristics of Colonoscopy Patients With Adenomas (Cases) and Matched Controls Cases a Controls b Characteristic Sex Male Female Male Female No. 24,969 18,220 23,138 18,003 % Mean age at procedure, y Mean no. of FDRs with colonoscopy Mean no. of SDRs with colonoscopy Mean no. of TDRs with colonoscopy Abbreviations: FDR, first-degree relative (parent, child, sibling); SDR, second-degree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). a Cases diagnosed with adenomas at time of colonoscopy between 1995 and b Controls selected from colonoscopy cohort, without findings of adenomas or colorectal cancer. Matched by sex and birth year and had follow-up at least as long as the date of the case diagnosis. Although the SDRs of cases who had an adenoma removed had an elevated risk of CRC (RR, 1.15; 95% CI, ), the SDRs of cases with AAs did not. The TDRs of cases with adenomas were found to have a slightly elevated risk of CRC (RR, 1.06; 95% CI, ). Using the adenoma and advanced adenoma cases and controls cited above, we also examined their relatives risk of developing similar polyps (Tables 4 and 5). The RR of an adenoma detected in a FDR of a patient affected by a similar polyp was 1.33 (95% CI, ). This association demonstrated a familial trend, dependent on the degree of relationship, and decreasing as the level of the relationship became more distant. The RRs for an adenoma in a SDR was 1.15 (95% CI, ), and was 1.09 (95% CI, ) in a TDR. Similarly, the RR of an advanced adenoma in a FDR affected by a similar advanced polyp was 1.65 (95% CI, ), and was 1.06 (95% CI, ) in an SDR and 1.96 (95% CI, ) in a TDR. When stratified by age at the time of the diagnosis of colorectal neoplasia in cases, the FDRs and SDRs of those diagnosed with an adenoma at age < 60 years had a greater risk of CRC compared with relatives of controls (RR, 1.41; 95% CI, ). However, even for cases diagnosed with an adenoma at age 60 years, FDRs had a moderately elevated risk of CRC (RR, 1.23; 95% CI, ) (Table 6). A similar elevated risk of CRC was observed in the FDRs of cases with advanced adenoma regardless of their age at the time of polyp diagnosis (Table 7). Tables 8 and 9 show the breakdown by age group of FDRs of cases diagnosed with adenoma and advanced adenoma stratified by age and demonstrate that 10% of CRCs would have been missed using the current guidelines, which do not advise screening at a younger age for FDRs of individuals diagnosed with an adenoma at age < 60 years. TABLE 2. Relative Risk of CRC in Relatives of Cases With Adenomas CRC in Relatives of Probands Diagnosed With Adenomas Cases Controls Relationship Affected Unaffected Affected Unaffected RR 95% CI P FDR , ,962, <.001 SDR , , <.001 TDR a , , Abbreviations: 95% CI, 95% confidence interval; CRC, colorectal cancer; FDR, first-degree relative (parent, child, sibling); RR, relative risk; SDR, seconddegree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). 38 Cancer January 1, 2014

5 Familial Risk of Colorectal Neoplasia/Tuohy et al TABLE 3. Relative Risk of CRC in Relatives of Cases With Advanced Adenomas CRC in Relatives of Probands Diagnosed With AAs Cases Controls Relationship Affected Unaffected Affected Unaffected RR 95% CI P FDR , , <.001 SDR 83 39, , TDR a , , Abbreviations: 95% CI, 95% confidence interval; AA, advanced adenoma; CRC, colorectal cancer; FDR, first-degree relative (parent, child, sibling); RR, relative risk; SDR, second-degree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). TABLE 4. Relative Risk of Adenomas in Relatives of Cases With Adenomas Adenomas in Relatives of Probands Diagnosed With Adenomas Cases Controls Relationship Affected Unaffected Affected Unaffected RR 95% CI P FDR <.001 SDR <.001 TDR a 12,740 20,827 12,402 22, <.001 Abbreviations: 95% CI, 95% confidence interval; FDR, first-degree relative (parent, child, sibling); RR, relative risk; SDR, second-degree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). TABLE 5. Relative Risk of Advanced Adenomas in Relatives of Cases With Advanced Villous Adenomas AAs in Relatives of Probands Diagnosed With AAs Cases Controls Relationship Affected Unaffected Affected Unaffected RR 95% CI P FDR <.001 SDR TDR a Abbreviations: 95% CI, 95% confidence interval; AA, advanced adenoma; FDR, first-degree relative (parent, child, sibling); RR, relative risk; SDR, seconddegree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). DISCUSSION In the current study, we report that FDRs, SDRs, and TDRs of patients with adenomas and advanced adenomas have an increased risk of developing adenomas or CRC themselves. Whereas FDRs of patients with adenomas were found to have only a moderately increased risk of colorectal neoplasia of 35%, the FDRs of patients with advanced adenomas had a nearly 70% elevated risk of developing colorectal neoplasia. This supports current guidelines for increased CRC surveillance in the relatives of patients with advanced adenomas. Although this observation in FDRs could be related in part to a shared environment, this is unlikely to be true for SDRs and TDRs. The results of the current study add substantially to the available literature in view of its number of inherent strengths. First, it defines precise risk levels for both CRC and adenomatous polyps not only in FDRs but also in the SDRs and TDRs of patients with adenoma and AAs. Second, it is population-based, which avoids many of the recruitment biases inherent to referral-based and registrybased studies. Third, patient recall biases, which occur frequently in many family studies, are avoided by using primary medical records that are linked to cancer registry and genealogical records. Fourth, cases are defined as those who have undergone a colonoscopy, which reflects those patients seen by gastroenterologists in clinical practice. Finally, the numbers of cases and controls are Cancer January 1,

6 TABLE 6. Relative Risk of CRC in Relatives of Cases With Adenomas, Stratified by Age at Diagnosis Adenoma Cases Aged <60 Years Adenoma Cases Aged 60 Years Relationship RR 95% CI P RR 95% CI P FDR < SDR TDR a Abbreviations: 95% CI, 95% confidence interval; CRC, colorectal cancer; FDR, first-degree relative (parent, child, sibling); RR, relative risk; SDR, second-degree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, great-grandparent). TABLE 7. Relative Risk of CRC in Relatives of Cases With Advanced Adenomas, Stratified by Age at Diagnosis AA Cases Aged <60 Years AA Cases Aged 60 Years Relationship RR 95% CI P RR 95% CI P FDR SDR TDR a Abbreviations: 95% CI, 95% confidence interval; AA, advanced adenoma; CRC, colorectal cancer; FDR, first-degree relative (parent, child, sibling); RR, relative risk; SDR, second-degree relative (aunt/uncle, niece/nephew, grandparent/grandchild); TDR, third-degree relative (first cousin, greatgrandparent). TABLE 8. Percentage of FDRs Diagnosed With CRC Based on Age Groups, Stratified by Age of Case With Adenoma Adenoma Case Adenoma Case Age Group, Age <60 Years Aged 60 Years Relationship Years No. (%) No. (%) FDR with CRC <40 24 (2.8) 0 40 to <50 63 (7.2) (90.0) 430 (100) Abbreviations: CRC, colorectal cancer; FDR, first-degree relative (parent, child, sibling). sufficiently large to make precise cancer and adenoma risk estimates in various relatives by age group. Two case-control design studies from France found an elevated risk of developing adenomas or CRC in the FDRs of patients with large adenomas. 20,21 This was also supported by a smaller US study that demonstrated only a modest and nonsignificant increase in the risk of CRC in the relatives of patients with small tubular adenomas (odds ratio [OR], 1.26; 95% CI, ) TABLE 9. Percentage of FDRs Diagnosed With CRC Based on Age Groups, Stratified by Age of Case With Advanced Adenoma AA Case Aged AA Case Aged Age Group, <60 Years 60 Years Relationship Years No. (%) No. (%) FDR with CRC <40 1 (1.4) 0 40 to <50 4 (5.8) (92.8) 68 (100) Abbreviations: AA, advanced adenoma; CRC, colorectal cancer; FDR, firstdegree relative (parent, child, sibling). and a significant increase in the relatives of patients with AAs (those measuring > 10 mm in size and/or with a villous component or high-grade dysplasia), with an OR of 1.62 (95% CI, ). 22 This is similar to the current study findings of a moderate 35% increased risk of CRC in the FDRs of patients with adenoma (OR, 1.35; 95% CI, ) and a nearly 70% elevated risk of CRC in the FDRs of patients with villous adenomas (OR, 1.68; 95% CI, ). Similarly, in a 2001 systematic review, 8 of 9 studies found an increased risk of CRC associated with adenomas in a FDR, with a pooled OR of 1.99 (95% CI, ). 23 Despite variations in the study designs and populations examined, these studies support the findings of the current study that FDRs of patients with adenomas have a moderately increased risk of developing colorectal neoplasia whereas relatives of those with AAs (villous histology or large size) are at a higher risk of developing colorectal neoplasia. The results of the current study add considerable support to these other studies by examining risk in a population data set, but also extend the findings robustly to older relatives and more distant relatives. The most recent of these systematic reviews of familial CRC studies concluded that studies published to date have had several design problems that affect their validity and generalizability. 24 Of 12 identified studies, 10 did not answer the primary question of whether having a FDR with an adenoma increased a patient s risk of developing CRC. The remaining 2 studies suffered from a lack of generalizability due to racial homogeneity and a lack of validation of family history and colonoscopy records. The authors advocated for a cohort or cross-sectional design study that could identify all relatives and have access to medical records to establish a diagnosis of CRC, thereby reducing the effect of patient recall bias. 24 The design and data sets of the current study mitigate some of the weakness identified in this systematic 40 Cancer January 1, 2014

7 Familial Risk of Colorectal Neoplasia/Tuohy et al review. To the best of our knowledge, the current study is the largest to date of familial colorectal neoplasia, thus giving it power to examine risk in SDRs and TDRs as well as FDRs. Recall bias, as mentioned above, is avoided by having primary clinical records as well as validated genealogical records for familial relationships. Detection bias, in which relatives of cases may be more likely to undergo colonoscopy and have adenomas found than controls, is also a common issue. Although detection bias may be present in the current study, we were able to demonstrate that a similar number of relatives of cases and controls had undergone colonoscopy examinations. The current study is population-based, reflecting standard-of-care clinical practice in both a large academic medical center and a managed care organization that together provide care to approximately 85% of the population of the state of Utah. This size and inclusiveness also reduces referral bias. The population of Utah is also representative of US/European white populations, with a low level of inbreeding. Therefore, the results are applicable to similar populations in the United States. 10 To the best of our knowledge, only a few studies to date have examined the risk of CRC in relatives of patients with adenoma stratified by the age of the index case. The results of the current study are similar to the findings of studies from France 20 and New York State, 25,26 in which the risk of CRC among family members was found to increase with decreasing age at the time of diagnosis of adenoma in the index case. Familial risk for older-age probands is an important point, because increased familial risk when the index case (proband) is aged > 60 years is often not appreciated. In the current study, we were also able to examine patient age when CRC occurred in FDRs, both when index cases were age < 60 years and 60 years at the time of diagnosis of adenoma or advanced adenoma (Table 6). With this analysis, we found approximately 10% and 1.5%, respectively, of FDRs of cases of adenoma and villous adenoma developed CRC at ages younger than those currently recommended 4 to start colonoscopy screening (based on familial risk), and therefore would have been missed. There are certain limitations of the current study that also deserve mention. Patients with known hereditary cancer syndromes, in particular familial adenomatous polyposis and Lynch syndrome, could not specifically be excluded. However, because both of these conditions are rare, and account for less than approximately 3% of all colon cancers, they are unlikely to modify the statistical associations demonstrated herein. Another issue is that the extraction of data from electronic medical records has limitations with regard to the information that can be gathered. The indication for colonoscopy was not specifically ascertained and therefore might introduce bias. Many screening procedures are also coded for a diagnosis found at colonoscopy or other unrelated symptoms and thus it would be nearly impossible to establish a study population of only screening colonoscopies. However, the ascertainment of the current study reflects gastroenterologists usual clinical practice of colonoscopy, with patients referred for screening as well as other indications. We also did not have information available regarding the documented completeness of the colonoscopic examination or the quality of the bowel preparation, although these issues are likely to be similarly reflected in both the case and control groups. We conducted a retrospective, population-based, case-control study in Utah, demonstrating that FDRs, SDRs, and TDRs of patients with adenomas and AAs who are undergoing colonoscopy are at an elevated risk of developing colorectal neoplasia (CRC, adenomas, and AAs). An increased risk was observed in relatives regardless of the age of the index patient at the time of adenoma diagnosis, although the risk was greater for index cases at a younger age. The results of the current study confirm and expand the evidence for a common familial risk for colorectal neoplasia and should become part of the data considered when screening strategies are synthesized. The data from the current study support the current screening guidelines for individuals with a family history of advanced adenomas and raise the issue of whether more aggressive screening should be considered for the FDRs of patients with adenomas diagnosed at age 60 years. Future studies to examine the risk of CRC in the relatives of patients diagnosed with AAs based on other components of the definition (large size or high-grade dysplasia) are required to validate the current CRC screening guidelines. The results of the current study further support inherited factors as a part of the etiology of colorectal neoplasia. Clinician awareness of the familial risks demonstrated in the current study will be of considerable assistance when working with individuals and families with colorectal neoplasia. FUNDING SUPPORT Supported by National Cancer Institute grants P01-CA073992and R01-CA (both to Dr. Burt). Partial support for the Utah Population Database is provided by the Huntsman Cancer Institute (HCI) and the HCI Cancer Center support grant P30CA042014, from the National Cancer Institute. The Utah Cancer Registry is Cancer January 1,

8 funded by contract HHSN C from the National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) program, with additional support from the Utah State Department of Health and the University of Utah. CONFLICT OF INTEREST DISCLOSURES Dr. Burt is a consultant for and has received payment for lectures including as a member of the Speakers Bureau from Myriad Genetics. Dr. Samadder has received speaking fees from Cook Medical Inc. REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin. 2009;59: Burt RW, DiSario JA, Cannon-Albright L. Genetics of colon cancer: impact of inheritance on colon cancer risk. Annu Rev Med. 1995;46: Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology. 2006;130: Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009;104: Burt RW, Barthel JS, Dunn KB, et al; NCCN. NCCN clinical practice guidelines in oncology. Colorectal cancer screening. J Natl Compr Canc Netw. 2010;8: Levin B, Lieberman DA, McFarland B, et al; American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008;134: Fuchs CS, Giovannucci EL, Colditz GA, et al. A prospective study of family history and the risk of colorectal cancer. N Engl J Med. 1994;331: DuVall SL, Kerber RA, Thomas A. Extending the Fellegi-Sunter probabilistic record linkage method for approximate field comparators. J Biomed Inform. 2010;43: DuVall SL, Fraser AM, Rowe K, Thomas A, Mineau GP.et al. Evaluation of record linkage between a large healthcare provider and the Utah Population Database. J Am Med Inform Assoc. 2012;19:e54- e Jorde LB. Inbreeding in the Utah Mormons: an evaluation of estimates based on pedigrees, isonymy, and migration matrices. Ann Hum Genet. 1989;53: Taylor DP, Cannon-Albright LA, Sweeney C, et al. Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk. Genet Med. 2011;13: Aagaard-Tillery KM, Stoddard GJ, Holmgren C, et al. Preeclampsia and subsequent risk of cancer in Utah. Am J Obstet Gynecol. 2006; 195: Esplin MS, O Brien E, Fraser A, et al. Estimating recurrence of spontaneous preterm delivery. Obstet Gynecol. 2008;112: Neale RE, Mineau G, Whiteman DC, et al. Childhood and adult cancer in twins: evidence from the Utah genealogy. Cancer Epidemiol Biomarkers Prev. 2005;14: Guthery SL, Mineau G, Pimentel R, et al. Inflammatory bowel disease aggregation in Utah kindreds. Inflamm Bowel Dis. 2011;17: Smith KR, Mineau GP, Garibotti G, Kerber R. Effects of childhood and middle-adulthood family conditions on later-life mortality: evidence from the Utah Population Database, Soc Sci Med. 2009;68: Kerber RA, O Brien E. A cohort study of cancer risk in relation to family histories of cancer in the Utah population database. Cancer. 2005;103: Kerber RA. Method for calculating risk associated with family history of a disease. Genet Epidemiol. 1995;12: Williams RL. A note on robust variance estimation for clustercorrelated data. Biometrics. 2000;56: Cottet V, Pariente A, Nalet B, et al. Colonoscopic screening of firstdegree relatives of patients with large adenomas: increased risk of colorectal tumors. Gastroenterology. 2007;133: Pariente A, Milan C, Lafon J, Faivre J. Colonoscopic screening in first-degree relatives of patients with sporadicç colorectal cancer: a case-control study. The Association Nationale des Gastroenterologues des Hopitaux and Registre Bourguignon des Cancers Digestifs (INSERM CRI 9505). Gastroenterology. 1998;115: Lynch KL, Ahnen DJ, Byers T, et al. First-degree relatives of patients with advanced colorectal adenomas have an increased prevalence of colorectal cancer. Clin Gastroenterol Hepatol. 2003;1: Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001;96: Imperiale TF, Ransohoff DF. Risk for colorectal cancer in persons with a family history of adenomatous polyps: a systematic review. Ann Intern Med. 2012;156: Ahsan H, Neugut AI, Garbowski GC, et al. Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Ann Intern Med. 1998;128: Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med. 1996;334: Cancer January 1, 2014