Cytochrome P450 17A1and Catechol O-Methyltransferase

Human Cancer Biology

Cytochrome P450 17A1 and Catechol O-Methyltransferase Polymorphisms and Age at Lynch Syndrome Colon Cancer Onset in Newfoundland Peter T. Campbell,1, 4 Laura Edwards,3 John R. McLaughlin,1, 2 Jane Green,3 H. Banfield Younghusband,3 and Michael O.Woods3

Abstract Purpose: Lynch syndrome is a cancer predisposition syndrome which includes colon cancer. It is caused by inherited defects in DNA mismatch repair genes. Sporadic colon cancers are influenced by exogenous hormones (e.g., postmenopausal hormones); we hypothesized that polymorphisms which influence endogenous hormones would therefore modify age at colon cancer onset among Lynch syndrome mutation carriers. Experimental Design: We genotyped 146 Caucasian Lynch syndrome mutation carriers for a 5¶-untranslated region polymorphism in cytochrome P450 17A1 (CYP17; c.-34T!C) and an exon 4 polymorphism in catechol O-methyltransferase (COMT ;c.472G!A); 50 mutation carriers had developed colon or rectal cancer at last contact. We used m2 tests to assess differences in counts. Kaplan-Meier survival curves and Cox proportional hazard models assessed age at onset of colorectal cancer stratified by CYP17 and COMT genotypes. Results: Homozygous carriers of the CYP17 C allele were diagnosed with colorectal cancer 18 years earlier than homozygous carriers of the T allele. Hazard ratios identified that, relative to homozygous carriers of theTallele (T/T), carriers of one copy (T/C) and two copies (C/C) of the rare allele were, respectively, at1.9-fold and 2.9-fold increased the risk of colon cancer at any age. The COMT rare allele suggested a nonstatistically significant trend of decreased colon cancer risk. Conclusions:ThisstudyshowedthatapolymorphisminCYP17 (c.-34T!C) modifies age at onset of Lynch syndrome. Because of the high risk of colorectal cancer among this group, knowledge of the CYP17 genotype is warranted for genetic counseling and risk assessment. Future work should assess polymorphisms associated with steroidhormones in Lynch syndromemutationcarriers.

The incidence and mortality rates for colorectal cancer in the gastrointestinal, upper urologic, and female reproductive tracts Canadian province of Newfoundland and Labrador rank among (3). Lynch syndrome is caused by germ line mutations in genes the highest in the world (1), partly explained by a high pre- involved with postreplicative nucleotide mismatch repair; valence of familial cancer (2). Lynch syndrome is an autosomal f90% of the causative mutations occur in MLH1 (located on dominant genetic syndrome characterized by early age at colon chromosome 3p21.3) or MSH2 (located on chromosome 2p22- cancer diagnosis and the common occurrence of tumors in the 21; ref. 4). Loss of DNA repair ability leads to microsatellite instability in tumor tissue, a hallmark of Lynch syndrome (5). Penetrance of MSH2 germ line mutations is high but variable. The consistent finding of lower penetrance for colon Authors’ Affiliations: 1Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 2Division of Preventive Oncology, Cancer cancer in women than in men with the same mismatch repair Care Ontario,Toronto, Ontario, Canada; 3Discipline of Genetics, Memorial University defects (6–10) suggests that steroidal hormones, such as of Newfoundland, St. John’s, Newfoundland and Labrador, Canada; and 4Cancer estrogen or testosterone, might modify risk. Exogenous estro- Prevention Program, Fred Hutchinson Cancer Research Center, Seattle,Washington gens (postmenopausal hormones and oral contraceptives) Received 12/18/06; revised 2/13/07; accepted 3/30/07. likely reduce the risk of sporadic colon cancer (11, 12). More Grant support: Canadian Institutes of Health Research (CRT 43821) and the Newfoundland Cancer Treatment and Research Foundation. National Cancer specific to Lynch syndrome, oral contraceptives and postme- Institute of Canada Doctoral Fellowship (no. 13523), with funds from the Canadian nopausal hormones are linked with decreased microsatellite Cancer Society (P.T. Campbell). National Cancer Institute of Canada Post-Doctoral instability colorectal cancer risk (13). Recent work by our group Fellowship (no.13493),with funds from the Canadian Cancer Society (M.O.Woods). suggests that hormonal contraceptives and postmenopausal 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 hormones are associated with decreased colorectal cancer risk with 18 U.S.C. Section 1734 solely to indicate this fact. among women from families that meet the Amsterdam or Requests for reprints: Michael O. Woods, Discipline of Genetics, Faculty of revised Bethesda criteria for Lynch syndrome.5 Medicine,HealthSciencesCentre,Room4333,MemorialUniversityof Newfoundland, 300 Prince Philip Drive, St. John’s, Newfoundland and Labrador, Canada A1B 3V6. Phone: 709-777-7334; Fax: 709-777-7497; E-mail: [email protected]. 5 Campbell PT, Newcomb P, Gallinger S, Cotterchio M, McLaughlin JR. Exogenous F 2007 American Association for Cancer Research. hormones and colorectal cancer risk in Canada: associations stratified by clinically doi :10.1158/1078-0432.CCR-0 6-29 87 defined familial risk. Cancer Causes and Controls. In press 2007.

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Common genetic polymorphisms have been reported to bp fragment of CYP17 was amplified using the following primers: influence endogenous hormone levels (14, 15). Polymor- forward 5¶-TTCTTCCACAAGGCAAGAGA-3¶; reverse 5¶-TTGGGCCAA- ¶ A CYP17 phisms in the sex steroid synthesis and metabolism genes AACAAATAAGC-3 . The 25 L PCR reaction for included cytochrome P450 17A1 (CYP17) and catechol O-methyltrans- 100 ng of genomic DNA, 1 reaction buffer, 3.0 mmol/L of MgCl2, 0.2 mmol/L of each deoxynucleotide triphosphate, 0.04 units/ALof ferase (COMT) have been studied extensively in relation to risk Taq polymerase, and 0.6 Amol/L each of forward and reverse primers. of breast cancer (16–19), and to a lesser extent, cancers of the The region containing the COMT exon 4 polymorphism was amplified ovary (20), endometrium (21), and prostate (22, 23). using the primers: forward 5¶-TACTGTGGCTACTCAGCTGTGC-3¶; and CYP17 encodes a protein involved in the production of reverse 5¶-GTGAACGTGGTGTGAACACC-3¶. The 20 AL PCR reaction for precursors to testosterone, estrone, and estradiol. A common COMT included 200 ng of genomic DNA, 1 reaction buffer, 0.2 mmol/L single base pair substitution (c.-34T!C) in the 5¶ untranslated of each deoxynucleotide triphosphate, 0.05 units/AL of Taq polymerase, region of CYP17 creates an additional promoter site and and 0.2 Amol/L each of forward and reverse primers. increases its transcription (24). Relative to the common allele The thermocycler conditions used were 35 cycles of denaturation j j (T), the rare allele (C) correlates with higher serum levels of for 1 min at 94 C, annealing for 1 min at 57 C, and extension for j j various sex steroids (e.g., testosterone, progesterone, estrone, 1 min at 72 C. Initial denaturation (95 C for 5 min) and final extension (72jC for 10 min) steps were also used. After amplifica- and estradiol; refs. 25–28). A A Msp COMT tion, 3.3 L of digestion buffer, 0.66 L of restriction enzyme A1 encodes an enzyme responsible for metabolizing (New England BioLabs), and 0.33 AL of bovine serum albumin were ! catechol estrogens into their less active derivatives (29). A G A added to each 25 AL sample of the CYP17 PCR product. Digestion of transition in exon 4 of COMT creates a valine-to-methionine the total mixture occurred for f12 h at 37jC. Added to each 20 AL substitution; the substitution was reported to decrease protein sample of the COMT PCR product were 3 AL of digestion buffer and activity and stability by 2-to 3-fold in vitro (30, 31). The rare 1.5 AL of restriction enzyme NlaIII (New England BioLabs). Digestion allele (MET) was associated with higher concentrations of of the total mixture occurred for 1 h at 37jC. The digested products several sex hormones in both premenopausal (32) and were separated using agarose gel electrophoresis and visualized using postmenopausal women (28). ethidium bromide staining. Restriction fragments were detected as To our knowledge, only one study has examined the previously reported (16, 24, 36). The presence of a single 459 bp fragment for CYP17 indicated the homozygous common genotype influence of one of these polymorphisms (COMT) with risk (T/T); fragments of 459, 335, and 124 bp indicated heterozygosity of sporadic colorectal cancer (33), and no study has been (T/C); and fragments of 335 and 124 bp indicated the homozygous conducted among confirmed Lynch syndrome mutation rare genotype (C/C). For COMT, the presence of the MET allele (rare) carriers. Given the putative evidence for a link between was shown by a 96 bp fragment; the VAL allele (common) was indicated steroidal hormone exposures and colorectal cancer, the current by a 114 bp fragment. Genotypes were determined blinded to the interest was to identify whether polymorphisms in CYP17 and subjects’ cancer status. All genotyping was repeated by automated COMT modified Lynch syndrome age at colon cancer onset in a sequencing to confirm the original results. Discrepancies between the sample of 146 confirmed MSH2 mutation carriers. In addition two techniques occurred in three samples. The sequencing results to the reported influences of these polymorphisms on were taken as the gold standard. endogenous steroid levels, they were also selected for study Hardy-Weinberg equilibrium was tested among both genotypes, stratified by outcome, and in the total sample. Age at first colon cancer because both rare alleles were reported to be sufficiently was the outcome of interest in this study. Kaplan-Meier survival curves common in Caucasian populations (15, 34–37). were used to assess age at first colon cancer diagnosis, stratified by genotype. Homogeneity between survival curves was assessed with the Materials and Methods log-rank test. Censored observations occurred where a subject had no colon or rectal cancer diagnosis at last follow-up, or had been Over the last 25 years, members of more than 100 nuclear families diagnosed with colon polyps upon screening, or had been diagnosed with extensive colorectal cancers were referred to the Provincial with extracolonic cancer. Censoring was implemented in the latter two Medical Genetics Program at Memorial University of Newfoundland situations because the natural history of Lynch syndrome was likely in St. John’s, Newfoundland and Labrador, Canada. Members of more altered. The median age at diagnosis represents the age at which 50% of than 50 of these families received MSH2 germ line mutation screening the sample was colon cancer–free. Cox proportional hazard models for Lynch syndrome (6). Twelve families harbored a founder mutation were used to estimate hazard ratios (HR) and 95% confidence intervals in MSH2 (c.942+3A!T). One of these families was used in the (95% CI): age at colon cancer onset was the modeled outcome, whereas original linkage study of the 2p locus (38). A second mutation in genotype, sex, and MSH2 mutation type were included as covariates. MSH2 was recently identified, c.646-?_2802+?del (a genomic deletion We selected 92 DNA samples from population-based controls in of exons 4-16), in a very large kindred (39). A third mutation in Newfoundland to compare allele frequencies in the current study with MSH2, c.1277-?_1386+?del (a genomic deletion of exon 8), was that of the general population. Controls were identified through identified in five families (39). random-digit dialing and frequency-matched on age and sex to the case Genomic DNA was extracted from leukocytes using a common population and were unaffected by any cancer. These analyses were salting out procedure (40). Techniques for MSH2 mutation detection conducted to assess potential population stratification in this study. All were reported previously (6, 39). For the current study, we selected all analyses were conducted with the SAS software package, version 9.1 archived mutation-positive DNA samples for which we had data on age (SAS Institute). and site of cancer diagnoses, colon screening history, polyp detection, and vital status (n = 161). From those 161 samples, 15 were excluded because of low DNA yield. Written informed consent was obtained Results from all subjects for use of their DNA samples for research purposes MSH2 consistent with this study. The ethics review board of the Memorial As shown in Table 1, 50 of the 146 mutation carriers University of Newfoundland approved this study. developed colon cancer at last follow-up. The majority of CYP17 and COMT genotypes were determined by PCR and RFLP the total sample was female (59%). The majority of the techniques as previously described (20), with slight adaptation. A 459 colon cancer sample was male (58%). All participants were

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with the Provincial Medical Genetics Program. Colon cancers Table 1. Demographic and genetic characteristics were proportionately more common among carriers of the of the study sample c.1277-?_1386+?del mutation (54% affected) than among the c.646-?_2802+?del (40% affected) or c.942+3A!T (26% Measure Colon No colon Total, m2 P cancer, cancer, n = 146 affected) mutations ( = 7.1, = 0.03). n =50 n =96 (%)* Age at colon cancer onset did not differ by COMT genotype in the entire sample or when stratified by sex (Table 2; Fig. 1). Sex MSH2 Male 29 31 60 (41) HRs and CIs, including variables for sex, and allele, were Female 21 65 86 (59) consistent with these findings (Val/Met versus Val/Val HR, 0.89; Age at colon cancer 95% CI, 0.41-1.91; Met/Met versus Val/Val HR, 0.73; 95% CI, diagnosis or censoring 0.31-1.71). Mean (SD)39.8 (8.9) 39.6 (12.2) 39.6 (11.2) Minimum and maximum 19-63 19-82 19-82 Age at colon cancer onset differed among the entire sample COMT genotype when stratified by CYP17 genotype. In the entire sample, the Val/Val 10 26 36 (25) median age at colon cancer diagnosis among CYP17 T/T, Val/Met 23 45 68 (46) T/C, and C/C subjects was 63, 48, and 45 years, respectively Met/Met 17 25 42 (29) CYP17 genotype (Table 2; Fig. 2). After stratifying by sex, risk was attenuated T/T 13 42 55 (38) toward null in both groups. Among the entire sample, T/C 28 47 75 (51) multivariable HRs and 95% CIs were consistent with the C/C 9 7 16 (11) Kaplan-Meier analyses (T/C versus T/T HR, 1.89; 95% CI, 0.94- hMSH2 germ line 3.75; C/C versus T/T HR, 2.85; 95% CI, 1.13-7.16). mutation type c.942+3A!T 23 64 87 (60) c.646-?_2802+?del 14 21 35 (24) Discussion (exon 4-16 del) c.1277-?_1386+?del 13 11 24 (16) Our data suggested that a common polymorphism in CYP17 (exon 8 del) modified age at colon cancer onset among MSH2 germ line mutation carriers. Compared with homozygote carriers of the *Parentheses denote percentages, unless otherwise noted. common allele (T/T), risk of colon cancer was increased by nearly 2-fold among heterozygote carriers (T/C) and risk was further increased by nearly 3-fold among homozygote carriers Caucasian. Mean age at colon cancer diagnosis was slightly of the rare allele (C/C). These results suggest a gene-dosage younger among males (38 years) than females (43 years), and (or additive) effect for the C allele (P for linear trend = 0.02). the difference was statistically significant according to a t test In our data, a common COMT polymorphism was not asso- (P = 0.043). Mean age at colon cancer diagnosis and age at ciated with age at colon cancer onset; however, homozygous censoring were similar between the two outcome groups, as carriers of the rare allele (MET/MET) relative to homozygous shown in Table 1 (P = 0.89). carriers of the common allele (VAL/VAL) experienced a COMT and CYP17 genotype frequencies did not differ by sex nonsignificant 27% reduction in risk of colorectal cancer at (COMT: m2 = 0.49, P = 0.78; CYP17: m2 = 2.7, P = 0.25). COMT any given age. and CYP17 rare alleles were similar in the current study and These findings for CYP17 were consistent with previous 92 controls selected from the general population (COMT: m2 = reports of the effects of polymorphisms in other genes among 2.37, P = 0.31; CYP17: m2 = 0.015, P = 0.99). Among the Lynch syndrome mutation carriers. For example, clinic-based entire sample, and in the unaffected group, both COMT data from the United States showed that carriers of a variant and CYP17 genotypes were in Hardy-Weinberg equilibrium. allele in cyclin D1 developed Lynch syndrome an average of The c.942+3A!T MSH2 mutation was most common in 11 years earlier than noncarriers (41). Similar work from the our sample (60%), owing to the greater duration of contact same group showed that Lynch syndrome age at onset was

Table 2. Kaplan-Meier survival results for age at onset, stratified by COMT and CYP17 genotypes

Median age at onset*( n) Log-rank C2 P Homozygous common Heterozygous Homozygous rare COMT genotype Total sample 47 (36)49 (68)48(42)0.034 0.98 Males 47 (13)41 (29)43(18)0.23 0.89 Females NA (23)58 (39)56(24)0.41 0.81 CYP17 genotype Total sample 63 (55)48 (75)45(16)6.12 0.047 Males 63 (27)39 (26)41(7)4.27 0.118 Females NA (28)58 (49)45(9)3.31 0.19

Abbreviation: NA, not available (<50% of the category was affected by colon cancer). *Median age at onset was defined as the point at which 50% of the samples were unaffected by a first colon cancer diagnosis.

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Fig. 1. COMT genotype and age at colon cancer onset.

modified by rare alleles in NAT2 (42), p53 (43), DNMT3b (44), cancers of the ovary (20), endometrium (21), and prostate and IGF1 (45). Work in Germany reported that polymorphisms (22, 23) were similarly inconsistent and controversial. Landi in RNASEL (46) and p53 (47) modified age at onset of Lynch et al. (33) reported no association between the current COMT syndrome. Work from South Africa recently reported that polymorphism and risk of sporadic colon cancer in a case- variants in GSTT1 and GSTM1 were associated with earlier age control study. Given the relatively small sample size in our at onset of Lynch syndrome among a homogeneous sample of study, and the suggestive trend reported herein, future studies MLH1 mutation carriers (48). We found that COMT did not of this allele are warranted. significantly modify Lynch syndrome age at onset; similarly, These polymorphisms are plausible candidates for colon others have reported that age at onset of Lynch syndrome was cancer studies because of their effects on altered endogenous not modified by polymorphisms in ATM (49), GSTM1 (50), sex hormone levels. Given the higher levels of endogenous CHEK2 (51), p53 (52), and cyclin D1 (53, 54). estrone (55), estradiol (25, 55), and progesterone (25, 55) To our knowledge, no previous study has examined the effect associated with the CYP17 C allele relative to the T allele, of the CYP17 or COMT polymorphisms on colon cancer risk combined with the consistent evidence that supplementation among Lynch syndrome mutation carriers. Furthermore, we with these hormones decreases the risk of colorectal cancer in are not aware of any studies which have evaluated the risk women (11, 12), our finding of a deleterious effect for the C of sporadic colon cancer with the CYP17 genotype. The CYP17 allele was partly unexpected. This unexpected finding might be c.-34T!C polymorphism has been examined extensively in explained by pleiotropy: whereas C allele–associated increases breast cancer with earlier studies, suggesting an increased risk of in estrogens may decrease risk of colorectal cancer in women, disease from the C allele (16, 17), whereas more recent studies the C allele has also been associated with increased levels and meta-analyses do not support this link (18, 19). Evidence of testosterone, androstenedione, and SHBG (28, 55–57). for a link between the CYP17 c.-34T!C polymorphism and Several of these hormones have been implicated in colon

Fig. 2. CYP17 genotype and age at colon cancer onset.

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tumorigenesis (58–63). Supplemental estrogens in males One potential bias in this study was from the reported effect caused insulin resistance and hyperinsulinemia (64); markers of the C allele on postmenopausal hormone use; female carriers of insulin resistance and diabetes are both major risk factors with the C/C relative to the T/T genotype were previously for colorectal cancer (65), supporting the link between the C reported to be about half as likely to use postmenopausal allele and increased colorectal cancer risk in males. Alternative- hormones (72). Although we do not have data on postmeno- ly, the C allele may be in linkage disequilibrium with another, pausal hormone use, we feel this potential for bias was likely unknown, polymorphism that confers risk on colon cancer. minimal. The women in this cohort were relatively young and We found no evidence to support this alternative explanation colon cancers and censoring occurred at relatively young ages in the literature or in online repositories of gene sequence data. (mean age at colon cancer diagnosis among females, 42.8 years; The strengths of this study include that it was conducted mean age at censoring among females, 40.2 years). All but 3 of among participants who largely share common geographic and the 21 female colon cancers occurred prior to age 50 years. environmental conditions; this homogeneity should, by design, Postmenopausal hormones were largely irrelevant in this hold other potentially confounding issues to a minimum and sample because their cancers occurred, on average, about one likely decrease the risk of population stratification. Addition- decade prior to menopause. Of the censored women, 10 of 65 ally, all subjects in this study shared deleterious defects in the were older than 50 years. In the absence of questionnaire or same gene. Although the environmental and genetic homoge- pharmacy record data, we cannot exclude the possibility that neity strengthens the internal validity of this study, the external some of them used postmenopausal hormones, and we cannot validity is weakened, further highlighting the need for future rule out that postmenopausal hormone use might have differed studies in other populations. Frequencies of the rare alleles according to CYP17 genotype. Although anecdotal evidence (COMT, 52%; CYP17, 37%) in this study were similar to from clinic staff suggests that exogenous hormone use in this previous reports among Caucasian populations in the United population is very low. Kingdom, United States, and Canada (15, 34–37, 66–71), Given the dramatic increased lifetime risk of colon and strengthening the external validity in this study. Furthermore, extracolonic cancers among germ line mutation carriers linked the frequencies of the rare alleles in the current study were with Lynch syndrome, knowledge of genetic and environmen- similar to a randomly selected sample of 92 population-based tal modifiers is needed for risk counseling and targeted controls from Newfoundland (COMT, 48%; CYP17, 37%), prevention strategies. This study found that a common allele supporting the fact that population stratification did not in CYP17 modified age at colon cancer onset among MSH2 account for these results. Ideally, future studies would also mutation carriers. Future studies are needed to confirm this collect data on lifestyle and demographic data; it was not association; examination of other polymorphisms involved possible for us to collect this information. with steroid production and metabolism is also warranted.

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