Cancer Prevention and Susceptibility

CHEK2 1100delC Is a Susceptibility Allele for HNPCC-Related Colorectal Cancer Marijke Wasielewski,1HansVasen,3 Juul Wijnen,4 Maartje Hooning,1Dennis Dooijes,2 CarliTops,4 Jan G.M. Klijn,1Hanne Meijers-Heijboer,1, 2 and Mieke Schutte1

Abstract Purpose: The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 110 0 d e l C a l s o confers a colorectal cancer risk independent of its breast cancer risk. Experimental Design: CHEK2 1100delC was genotyped in the index cases of 369 Dutch colorectal cancer families that had been excluded for familial breast cancer. The cohort included 132 cases with familial adenomatous polyposis (FAP) and FAP-related disease, and 237 cases with hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-related disease. Results: None of the FAP/FAP-related cases carried the CHEK2 1100delC variant. In contrast, CHEK2 1100delC was present in 10 of 237 (4.2%) HNPCC/HNPCC-related cases that was significantly more prevalent than the 1.0% Dutch population frequency (odds ratio, 4.3; 95% confidence interval, 1.7-10.7; P =0.002).Nineofthe10CHEK2 1100delC colorectal cancer cases met the revised Amsterdam and/or Bethesda criteria. The 10 CHEK2 1100delC colorectal cancer families had a high-risk cancer inheritance pattern, including 35 colorectal cancer cases, 9 cases with polyps, and 21cases with other tumor types. Conclusion: Our analysis provides strong evidence that the1100delC variant of CHEK2 confers a colorectal cancer risk in HNPCC/HNPCC-related families, supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene.

In 2002, we and others identified CHEK2 1100delC (MIM more severely affected with breast cancer. Together, these 604373) as a breast cancer susceptibility allele (1–4). The apparent discrepancies have suggested a polygenic breast cancer CHEK2 1100delC variant was present in 5% of non-BRCA1/ susceptibility model for the CHEK2 1100delC variant, in which BRCA2 breast cancer families compared with only 1% in the CHEK2 1100delC acts in concert with another as-yet-unknown general population. Although variants with a population breast cancer susceptibility allele or alleles (1–5). frequency of 1% or more are often considered polymorphisms, We had noted that near half of Dutch CHEK2 1100delC the estimated 2-fold increased breast cancer risk for female breast cancer families also included colorectal cancer cases CHEK2 1100delC carriers had classified CHEK2 1100delC as a (11 of 25 families, together with 21 cases; refs. 1, 6). Indeed, pathogenic moderate-risk mutation. Strikingly, the prevalence when we applied stringent clinical criteria to define a new of CHEK2 1100delC increased with increasing numbers of subtype of breast cancer families with a ‘‘hereditary breast and breast cancer cases in the families, suggesting a rather high-risk colorectal cancer’’ (HBCC) phenotype, the CHEK2 1100delC breast cancer inheritance pattern for the variant. Also, the frequency was almost five times higher among the HBCC CHEK2 1100delC genotype only partially segregated with the families compared with breast cancer families not fulfilling the breast cancer phenotype, particularly so in families that were HBCC criteria (18% versus 4%; ref. 6). These results thus suggested that CHEK2 1100delC carriers may also be predis- posed to develop colorectal cancer. To evaluate the colorectal Authors’ Affiliations: Departments of 1Medical Oncology and 2Clinical Genetics, cancer risk conferred by CHEK2 1100delC independent of its Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, the breast cancer risk, we here have genotyped CHEK2 1100delC in 3 4 Netherlands; Department of Gastroentrology and Center for Human and Clinical 369 Dutch familial colorectal cancer cases. Genetics, Leiden University Medical Center, Leiden, the Netherlands Received 2/14/08; revised 3/31/08; accepted 4/2/08. Grant support: Dutch Cancer Society grant DDHK 2003-2862. The costs of publication of this article were defrayed in part by the payment of page Materials and Methods charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Colorectal cancer families. The selected familial colorectal cancer Requests for reprints: Mieke Schutte, Department of Medical Oncology, n Josephine Nefkens Institute Room Be414, Erasmus University Medical Center, PO cohort ( = 385) included all colorectal cancer families registered by the Box 2040, 3000 CA Rotterdam, the Netherlands. Phone: 31-10-7038039; Fax: 31- Dutch Foundation for Detection of Hereditary Tumors and those that 10-7044377; E-mail: [email protected]. were registered by the Rotterdam Family Cancer Clinic at Erasmus F 2008 American Association for Cancer Research. Medical Center. Sixteen hereditary nonpolyposis colorectal cancer doi:10.1158/1078-0432.CCR-08-0389 (HNPCC)-related families had been excluded because they met our

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Table 1. Cancer incidences among MMR mutation–negative HNPCC/HNPCC-related families

No of families No of cases with cancer

CRC >1960* CRC V1960* Polyps BRC Other cancers Families with colorectal cancer 1544 88 53 200 52 279 One case with CRC 11 11 43 421 Two cases with CRC 54108 12 50 19 85 Three cases with CRC 39 117 12 48 9 52 Four cases with CRC 28 112 15 53 13 62 Five or more cases with CRC 22 140 10 46 7 59

NOTE: Data include all cancer cases of families negative for mutations in the MMR genes MLH1, MSH2, and MSH6. Families were classified according to the number of colorectal cancer cases diagnosed after 1960, showing that the majority of families have at least three colorectal cancer cases. The 11 single colorectal cancer cases were all diagnosed before age 50 y and after 1960. Abbreviations: CRC, colorectal cancer; Polyps, adenomatous polyps in the colorectum; BRC, breast cancer. *We considered an amnestic report of colorectal cancer more reliable when the diagnosis had been made after 1960.

criteria for familial breast cancer [i.e., at least two first- or second-degree screening was done in blood-derived DNA of at least the colorectal relatives (DGR) with breast cancer of whom at least one was diagnosed cancer case with the youngest age at diagnosis for whom DNA was before age 60 y]. The evaluated Dutch Foundation for Detection of available (index case). CHEK2 1100delC screening was done on blood- Hereditary Tumors cohort (cohort I) included 114 HNPCC/HNPCC- derived DNA of the index case by allele-specific oligonucleotide related and 91 familial adenomatous polyposis (FAP)/FAP-related hybridization. This method includes PCR amplification of CHEK2 families that had been reported as part of another CHEK2 1100delC (ENSG00000183765) exon 10, application of the amplified products study (6). The evaluated Erasmus Medical Center cohort (cohort II) to nylon filters, and hybridization under high stringency to [32P] included 123 HNPCC/HNPCC-related and 41 FAP/FAP-related fami- oligonucleotides that are complementary to the CHEK2 1100delC or lies. All cases have consented to search for cancer susceptibility genes CHEK2 wild-type sequence. Amplification of exons 9 through 14 by and the Medical Ethical Review Board at Erasmus Medical Center has long-range PCR and subsequent sequencing of a nested PCR product approved the study. using primers flanking exon 10 confirmed all positive CHEK2 Population controls. The 909 population-matched controls all 1100delC cases. CHEK2 1100delC screening methods are described originated from the southwestern Netherlands and included a in detail in reference (1). hospital-based cohort of 184 spouses of heterozygous cystic fibrosis Statistical analysis. The difference between CHEK2 1100delC mutation carriers ascertained through the department of Clinical carriers in colorectal cancer cases and controls was analyzed using Genetics at Erasmus Medical Center, a population-based cohort of Fisher’s Exact Test. Odds ratios and 95% confidence intervals were 460 persons without cancer after age 55 y from the Erasmus Rotterdam calculated from two-by-two tables. All analyses were done with SPSS Health and the Elderly Study and a cohort of 265 randomly selected version 11. blood donors (5). Mutation screening of colorectal cancer families. The complete coding sequences of the APC, MUTYH, MLH1, MSH2, and MSH6 Results and Discussion genes were analyzed for mutations, including all known Dutch founder mutations, deletions, and rearrangements, in a routine clinical genetics Characterization of colorectal cancer families. The 369 diagnostic setting, as described (6, 7). For each family, mutation colorectal cancer families screened for CHEK2 1100delC were

Table 2. Prevalence of CHEK2 1100delC among colorectal cancer families from the southwestern Netherlands

Case cohorts CHEK2 1100delC+/total tested (%) Cohort I Cohort II Cohort I+II

Controls 9/909 (1.0) FAP/FAP-related families 0/91 (0.0) 0/41 (0.0) 0/132 (0.0) APC mutation positive 0/640/22 0/86 MUTYH mutation positive 0/6 0/40/10 >20 polyps 0/21 0/15 0/36 HNPCC/HNPCC-related families 4/114 (3.5) 6/123 (4.9) 10/237 (4.1) MLH1 mutation positive 1/29 0/9 1/38 MSH2 mutation positive 0/26 0/8 0/34 MSH6 mutation positive 1/40/7 1/11 >1 CRC <50 y Not included 2/23 2/23 z2 CRC 1st DGRs Not included 3/36 3/36 z2 CRC 1st DGRs with z1 CRC <50 y 2/55 1/40 3/95 P [HNPCC (related) vs controls] 0.05 0.005 0.002

NOTE: Cohort I, cohort of colorectal cancer cases registered at the Dutch Foundation for Detection of Hereditary Tumors; data on cohort I have also been published in reference 6. Cohort II, cohort of colorectal cancer cases registered at Erasmus Medical Center. Abbreviations: CRC, colorectal cancer; <50 y, diagnosed before age 50 y.

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Table 3. Summary of reported CHEK2 1100delC genetic screens in colorectal cancer cases

Area (reference) CHEK2 1100delC+/total tested (%) Population Familial OR (95% CI) Unselected controls cases with CRC cases with CRC

NL-SW (present study) 9/909 (1.0) 10/237 (4.2) 4.3 (1.7-10.7) UK-SE (17) 21/4,037 (0.5)c 3/149 (2.0) 3.9 (1.2-13.3)b Finland (16) f36/1,885 (1.9) 2/149 (1.3) 0.7 (0.2-2.9)b 15/513 (2.9) NL-N (12) 1/230 (0.4) 7/236 (3.0) 7.0 (0.9-57.4)b 5/498 (1.0) Spain (19) 0/400 (0.0) 0/182 (0.0) — Sweden (13) 5/760 (0.7) 2/192 (1.0) 1.6 (0.3-8.3)b 6/644 (0.9) Poland (10, 11) 12/5,496 (0.2) 5/1,085 (0.5) Sweden (15) 3/300 (1.0) USA-PA (14) 1/153 (0.7) UK-SE (18) 21/4,037 (0.5)c

NOTE: The summary includes data from the present study and 10 studies that have thus far been published on CHEK2 1100delC in colorectal cancer cases (10 – 19). Colorectal cancer families from southwestern Netherlands were excluded for families that fulfilled our familial breast cancer criteria. The Finnish data set included nine cases with a personal or family history of breast cancer (with one CHEK2 1100delC case). The breast cancer history of the familial case cohorts from the southeastern United Kingdom and northern Netherlands are not known. Abbreviations: NL-SW, southwestern Netherlands; UK-SE, southeastern United Kingdom; NL-N, northern Netherlands; US-PA, Pennsylvania area in the United States of America; AMS/Bethesda, Amsterdam and Bethesda criteria for HNPCC; y, years of age at diagnosis. OR, odds ratio from two-by-two tables; 95% CI, (approximate) 95% confidence interval. *P values for familial colorectal cancer cases versus matched population controls, using Fisher’s Exact Test. cControls were obtained from reference (5). b95% CI is unreliable due to small numbers.

classified as FAP (MIM 175100) and FAP-related families or as families had index cases that met the revised Bethesda criteria HNPCC (MIM 120435) and HPNCC-related families. Of the for MSI screening (8, 9). The cancer incidences among the 132 FAP/FAP-related families, 86 (65%) had a pathogenic MMR mutation–negative HNPCC/HNPCC-related families are germline mutation in APC (MIM 175100), 10 (8%) had a detailed in Table 1, showing that the majority of families had at pathogenic germline mutation in MUTYH (MIM 604933), and least three colorectal cancer cases and, thus, can be assigned as another 36 (27%) families included cases that had been high-risk colorectal cancer families. diagnosed with >20 adenomatous polyps. The 237 HNPCC/ CHEK2 1100delC confers HNPCC/HNPCC-related colorectal HNPCC-related families were classified according to the cancer. Genetic screening for CHEK2 1100delC revealed that presence of a pathogenic germline mismatch repair (MMR) none of 132 FAP/FAP-related cases carried the variant (Table 2). gene mutation or otherwise by distribution and mode of In contrast, 10 of 237 (4.2%) HNPCC/HNPCC-related cases inheritance of colorectal cancer cases in the family. The 83 carried CHEK2 1100delC compared with only 9 of 909 (1.0%) MMR mutation–positive families included 38 (46%) MLH1 of population controls, implying a strong association of the (MIM 120436), 34 (41%) MSH2 (MIM 120435), and 11 variant with familial colorectal cancer (P = 0.002; Table 2). Our (13%) MSH6 (MIM 600678) mutation–positive HNPCC results thus indicate that CHEK2 1100delC confers a colorectal families. Analysis of microsatellite instability (MSI) was done cancer risk. Moreover, we show that this risk is associated with in approximately one-third of these families showing that 22 HNPCC/HNPCC-related colorectal cancer rather than FAP/ (81%) index cases had an MSI-high, 4 (15%) had an MSI-low, FAP-related colorectal cancer. and 1 (4%) had an MSI-stable phenotype. Extensive mutational Progressive insight in CHEK2 cancer susceptibility has screening of MLH1, MSH2, and MSH6 had failed to identify revealed that various CHEK2 gene variants confer only low to pathogenic mutations, deletions, or rearrangements in 154 moderate cancer risks and that the prevalences of these variants HNPCC/HNPCC-related families. These 154 MMR mutation– are highly variable among populations. These characteristics negative families were classified by either the presence of at severely hamper evaluation of CHEK2 cancer risks. In an initial least two first DGRs with colorectal cancer of whom at least one screen for CHEK2 1100delC in familial colorectal cancer cases, was diagnosed before age 50 y (n = 95; 62%) or by the presence for example, we had found some suggestion of an HNPCC/ of at least two first DGRs with colorectal cancer but none of HNPCC-related colorectal cancer risk for the variant (6). them diagnosed before age 50 y (n = 36; 23%) or by the However, the familial colorectal cancer cases in this screen presence of a single colorectal cancer case diagnosed before age had been collected through the International Concerted Action 50 y (n = 23; 15%). MSI data were available for 100 (65%) Polyp Prevention and the Dutch Foundation for Detection of MMR mutation–negative HNPCC/HNPCC-related families. Hereditary Tumors, including 114 Dutch cases, 50 German The majority of index cases (74%) among these families had cases, 37 American cases, and several smaller cohorts from an MSI-stable phenotype. MSI-high and MSI-low phenotypes other countries. In retrospect, this case cohort was not only too were reported for 18% and 8% HNPCC/HNPCC-related divers regarding its geographic origins but also had not families, respectively. Fifty-eight (38%) of the MMR muta- appropriately been stratified for population controls. The case tion–negative families were classic HNPCC families as they cohort had included six CHEK2 1100delC mutant colorectal fulfilled the revised Amsterdam criteria, and another 73 (47%) cancer cases, of which four originated from the Netherlands

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Table 3. Summary of reported CHEK2 1100delC genetic screens in colorectal cancer cases (Cont’d)

CHEK2 1100delC+/total tested (%) P* Criteria familial cases OR (95% CI) Cases with OR (95% CI) CRC & BRC

0.002 AMS/Bethesda HNPCC, diagnosed <50 y and/or z2 CRC first DGRs 0.05 5-100 polyps and APC/MYH negative 1.5 (0.8-2.8) 1.0 z2 CRC first DGRs 2.3 (0.3-20.0)b 0.07 AMS/Bethesda HNPCC, diagnosed <50 y and/or z2 CRC second DGRs AMS/Bethesda HNPCC or HNPCC like 1.4 (0.4-4.7)b 0.6 z2 CRC and MLH1/MSH2 negative 2.1 (0.7-6.0)b 2/75 (2.7) 2.7 (0.5-16.5)b 0/24(0.0) 0/20 (0.0) and the other two from Germany. When now properly (MLH1 and MSH6; both reported earlier in ref. 6). Four compared with the Dutch population frequency of 1.0%, the CHEK2 1100delC families fulfilled the revised Amsterdam 3.5% frequency of CHEK2 1100delC among the 114 Dutch criteria for HNPCC disease, and five other families had index HNPCC/HNPCC-related cases was significantly increased cases that met the revised Bethesda criteria. Together, the (P = 0.05; cohort I in Table 2). In the current study, we sought 10 CHEK2 1100delC colorectal cancer families included to further substantiate these initial findings and collected all 35 colorectal cancer cases, 9 cases with polyps, and 21 cases available familial colorectal cancer cases from the Rotterdam with other tumor types (detailed in Table 4), implying that the Family Cancer Clinic at Erasmus Medical Center. Indeed, CHEK2 1100delC families can be classified as high-risk CHEK2 1100delC was again identified in HNPCC/HNPCC- colorectal cancer families. related cases but not in FAP/FAP-related cases, with 6 CHEK2 We also genotyped CHEK2 1100delC in all nonindex cases 1100delC cases among 123 HNPCC/HNPCC-related cases from the CHEK2 1100delC families of whom DNA was (4.9% and P = 0.005; cohort II in Table 2). Clearly, reliable available, including four cases with colorectal cancer, five cases evaluation of CHEK2 cancer risks requires sufficiently large and with polyps, and four cases with other cancers in first, second, homogeneous case cohorts that are appropriately matched for or third DGRs from the main cancer-prone branch of the population controls. Upon combining both Dutch colorectal families (Table 4). One of four colorectal cancer cases carried cancer case cohorts, we were now able to provide strong CHEK2 1100delC, three of five cases with polyps were CHEK2 evidence that CHEK2 1100delC confers a colorectal cancer risk 1100delC positive, and also one of four other cancers carried (4.1% and P = 0.002; Table 2). CHEK2 1100delC. As expected, cosegregation was better among To date, the colorectal cancer risk of CHEK2 1100delC has first DGRs, with three CHEK2 1100delC–positive cases who been evaluated in 908 familial colorectal cancer cases and in had polyps and one case who was diagnosed with ovarian 2,740 unselected colorectal cancer cases, derived from 10 cancer among six affected first DGRs (no DNA was available independent studies (reviewed in Table 3; refs. 10–19). As a of first DGRs with colorectal cancer). Altogether, our analysis whole, there was some suggestion that CHEK2 1100delC may thus shows incomplete cosegregation of the CHEK2 1100delC confer a colorectal cancer risk. Yet, none of the reported studies genotype with the cancer phenotype in these families, suggest- had sufficient statistical power to show, beyond doubt, that ing the presence of an additional cancer susceptibility allele or CHEK2 1100delC is associated with colorectal cancer. Unfor- alleles. tunately, the inclusion criteria for the colorectal cancer cases Although our current study design does not allow for an differed substantially among the reported studies and CHEK2 accurate estimate of the colorectal cancer risk conferred by 1100delC population frequencies were also highly variable, CHEK2 1100delC, the observed 4.3 odds ratio does not inducing us to refrain from meta-analysis of the combined account for the high-risk colorectal cancer inheritance pattern results. Our current study therefore is the very first to establish observed in the CHEK2 1100delC families. The high-risk an HNPCC/HNPCC-related colorectal cancer risk for the inheritance pattern together with the incomplete cosegregation CHEK2 1100delC variant. One other CHEK2 variant (I157T) of the CHEK2 1100delC variant suggests a polygenic colorectal has also been associated with colorectal cancer, in both the cancer susceptibility model, similar to the current ideas on Finnish and the Polish populations (10, 11, 20). The colorectal CHEK2 –related breast cancer susceptibility (1–5). Consistent cancer risk of CHEK2 is thus not limited to the 1100delC with a polygenic model, three of the CHEK2 1100delC variant. Similar to what has recently been done for other breast colorectal cancer families had not inherited CHEK2 1100delC cancer genes (21–25), the full spectrum of CHEK2 –associated through the main cancer-prone family branch (Table 4). cancer risks should therefore be established by whole CHEK2 Further support for a polygenic CHEK2 model involves the gene screens, in large sample cohorts that preferably also dramatic and unprecedented high CHEK2 1100delC prevalence include cancer cases of other tumor types. among Dutch families with HBCC compared with families with CHEK2 1100delC and polygenic cancer susceptibility. The 10 only breast cancer or colorectal cancer (18% versus each 4%; CHEK2 1100delC colorectal cancer families that we here have refs. 1, 6). It seems that at least two cancer susceptibility alleles identified included 8 MMR mutation–negative HNPCC/ in addition to CHEK2 1100delC are inherited in these HBCC HNPCC-related families and 2 families with a MMR mutation families. One thus might wonder whether CHEK2 is a breast

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Table 4. Cancer histories of CHEK2 1100delC colorectal cancer families

Family idInclusion Index = delC+ 1st DGRs 2ndDGRs 3rdDGRs Other family criterion (MSI status) branch

EMC16517 CRC <50 y CRC:35 Father double other Ca 1 CRC (<1960) 1 BRC:43 Mother other (MSI stable) 1 polyps: <50 2 other Ca Ca (delC+) 2nd DGR: 1 other Ca

EMC19398 z2 CRC 1st DGRs CRC:55 Father double CRC:79/91 1 BRC:74Mother BRC:75 (MSI stable) 1 CRC:50 2nd DGR: 1 CRC:83 EMC21829 z2 CRC 1st DGRs CRC:53 1 CRC:59 (MSI stable) 1 other Ca

EMC22131 CRC <50 y and CRC:41 Mother CRC:59 1 CRC Father unaffected z2 CRC 1st DGRs (MSI stable) 2 polyps: 41/47 2 other Ca (delC+) 2nd DGR: 2 other Ca EMC23748 CRC <50 y CRC:46 1 CRC:60 (MSI stable)

EMC50100 MLH1 positive CRC:34 Mother CRC:43 1 CRC:43 1 CRC: 43 Other Ca:55 Unaffected sibs (2 delC+) 1 other Ca 3 CRC (1 delC-) (MSI high) 1 other Ca (delC-)

EMC52210 z2 CRC 1st DGRs CRC:53 Father other Ca 2nd DGR: 1 CRC:56 2 CRC:54/62 CRC:65 (MSI low) 1 polyps:28 (delC+) 1 other Ca

NA15 CRC <50 y and CRC:45 Mother other Ca 1 CRC (delC+) 2 CRC:47/58 z2 CRC 1st (n.a.) (delC+) 1 CRC:42 (2 delC-, with DGRs Unaffected sibs (1 delC+) 1 other Ca 2 delC+ unaffected sibs) 1 CRC:58 1 polyps (delC-)

NA22 MSH6 positive CRC:65 Father CRC:69 1 polyps:40 Mother (MSI-low) 1 CRC/other Ca:45/54 (delC-) unaffected 2 polyps: 56/66 (1 delC+) (delC+) 3 other Ca: 45/47/57 (2 delC-)

NA211 CRC <50 y and CRC:48 Mother polyps:70 (delC+) 1 BRC<60 Father other Ca z2 CRC 1st DGRs (MSI stable) 1 CRC:45

NOTE: Detailed are the affected relatives from the main cancer-prone branch of the CHEK2 1100delC family, with the other family branch summarized. Families EMC50100, NA15, NA22, and NA211 have been reported previously (6). The number of relatives with a particular tumor type are indicated before the tumor type, with the age at diagnosis for the colorectal cancer, adenomatous polyps in the colorectum, or breast cancer cases, after the semicolon, when known. Genetic screening results for CHEK2 1100delC are indicated between brackets, including delC+ – unaffected sibs. Abbreviations: BRC, breast cancer; CRC, colorectal cancer; other Ca, cancer other than colorectal cancer or breast cancer; n.a., not available. cancer gene, a colorectal cancer gene, or a multiorgan gene—as suggests that the MMR genes might also be involved in breast was rightly suggested before (10, 20). Or, alternatively, is it the cancer families with the HBCC phenotype. additional cancer susceptibility alleles that determine organ specificity? In the HBCC families, one of these would then Disclosure of Potential Conflicts of Interest determine the breast cancer phenotype, whereas the other determines the colorectal cancer phenotype. In this scenario, No potential conflicts of interest were disclosed. CHEK2 1100delC would be a modifier that only increases cancer risks for carriers of the other susceptibility alleles. Acknowledgments Comprehension of the exact nature of polygenic CHEK2 cancer We thank the members of colorectal cancer families for their participation in this susceptibility clearly awaits identification of the additional research, all contributing members of the Dutch Stichting Opsporing Erfelijke cancer susceptibility alleles. Our finding that CHEK2 1100delC Tumoren and the Rotterdam Family Cancer Clinic, and Anja Wagner and Anja de specifically associates with HNPCC-related colorectal cancer Snoo for their kind help in compiling colorectal cancer pedigrees.

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Marijke Wasielewski, Hans Vasen, Juul Wijnen, et al.

Clin Cancer Res 2008;14:4989-4994.

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