Polymorphic TP53BP1 and TP53 Gene Interactions Associated With

Cancer Prevention

Polymorphic TP53BP1 and TP53 Gene Interactions Associated with Risk of Squamous Cell Carcinoma of the Head and Neck Kexin Chen,1Zhibin Hu,1Li-E Wang,1 Wei Zhang,2 Adel K. El-Naggar,2 Erich M. Sturgis,1, 3 and Qingyi Wei1

Abstract Purpose: Tumor protein 53-binding protein 1 (TP53BP1) and TP53 interact during TP53- mediated transcriptional activation and during checkpoint activation in response to DNA damage. Because suboptimal repair of tobacco-induced DNA damage is associated with risk of squamous cell carcinoma of the head and neck (SCCHN), we hypothesized that potentially functional polymorphisms inTP53BP1 and TP53 may contribute jointly to SCCHN risk. Experimental Design: In a case-control study, DNA samples from age- and sex-matched SCCHN patients (n = 818) and cancer-free controls (n = 821) were genotyped for the presence of three variants of TP53BP1 (T-885G, Glu353Asp, and Gln1136 Lys) and three variants of TP53 (Arg72Pro, PIN3, and MspI). Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Results: Although none of these six genetic variants alone was associated with SCCHNrisk, the combined TP53BP1 genotypes were associated with a significant, dose response ^ dependent decrease in SCCHN risk among carriers of TP53 Pro72Pro, TP53 PIN3del/del, and TP53 Msp1AA genotypes (trend test: P = 0.024, 0.016, and 0.016, respectively). Furthermore,TP53BP1 variant haplotype GGC carriers who were alsoTP53 variant homozygotes had a significantly lower risk of SCCHN than did TP53BP1 haplotype TCA carriers (adjusted OR, 0.48; 95% CI, 0.25-0.94 for TP53 Pro72Pro; adjusted OR, 0.17; 95% CI, 0.04-0.69 for TP53 PIN3del/de; and adjusted OR, 0.16;95%CI,0.04-0.65forTP53 Msp1AA).There was statistical evidence of interaction between TP53BP1 and TP53 diplotypes (P =0.017). Conclusion: Our data suggest that TP53BP1 variants may have protective effects on SCCHN risk but such effects were confined toTP53 variant allele/haplotype carriers.

Squamous cell carcinoma of the head and neck (SCCHN), previous studies have shown that SCCHN risk is associated which includes cancers of the oral cavity, pharynx, and with suboptimal repair of tobacco-induced DNA damage (5) larynx, is relatively common worldwide (1). Major risk and low expression of DNA repair genes (6, 7). Although factors for SCCHN are tobacco smoke and alcohol use. most of the major SCCHN susceptibility genes remain Tobacco carcinogens cause various kinds of DNA damage (2) unknown, it is known that variations in genes involved in that may lead to mutations in critical genes, such as DNA repair (2, 8, 9) and cell cycle control (10–12) may oncogenes and the tumor suppressor gene TP53 (3, 4). contribute to tobacco-induced SCCHN. However, the fact that some smokers and drinkers do not The tumor suppressor gene TP53 encodes a key cellular develop SCCHN suggests that a spectrum of genetic component that helps maintain genomic stability by (a) susceptibility exists in the general population (1). Our arresting the cell cycle long enough to allow DNA repair, (b) inducing apoptosis, or (c) both (13, 14). Somatic mutations that inactivate the TP53 gene have been found in at least half of all human tumors (15, 16), suggesting that loss of TP53 function plays an important role in carcinogenesis. Authors’ Affiliations: Departments of 1Epidemiology, 2Pathology, and 3Head These mutations may either be acquired or occur naturally in and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, the form of common genetic variants, such as the non- Houston, Texas Received 2/23/07; revised 4/10/07; accepted 5/3/07. synonymous single nucleotide polymorphism (SNP) at codon 72 72 Grant support: NIH grants ES 11740 (Q.Wei), CA100264 (Q.Wei), and CA16672 72 (Arg Pro). The Arg Pro SNP has been extensively (The University of Texas M. D. Anderson Cancer Center). studied for its association with cancer risk, although the The costs of publication of this article were defrayed in part by the payment of page findings have ranged from conflicting (17) to conclusive advertisement charges. This article must therefore be hereby marked in accordance (17–27). with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Current address for K. Chen: Department of Epidemiology, Cancer Institute To function properly, the TP53 protein must interact with and Hospital, Tianjin Medical University, Tianjin, China. many other proteins. One of the TP53-regulated genes is Requests for reprints: Qingyi Wei, Department of Epidemiology,The University TP53-binding protein 1 (TP53BP1) that encodes a nuclear of Texas M. D. Anderson Cancer Center, Unit 1365, 1515 Holcombe Boulevard, protein of 1,972 amino acids that contains numerous Houston, TX 77030. Phone: 713-792-3020; Fax: 713-563-0999; E-mail: qwei@ mdanderson.org. phosphatidylinositol-like kinase phosphorylation sites (S/TQ) F 2007 American Association for Cancer Research. and two NH2-terminal BRCT motifs (28). TP53BP1 takes part doi:10.1158/1078-0432.CCR-07-0469 in both DNA repair and cell cycle control and interacts

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Table 1. Logistic regression analysis of associations between TP53BP1 and TP53 polymorphisms and risk of SCCHN

Polymorphism No. (%) P* OR (95% CI) Adjusted OR (95% CI)c Cases (n = 818) Controls (n = 821) TP53BP1 T-885G (rs1869258) TT 444 (54.3) 437 (53.2) 0.786 1.00 1.00 TG 302 (36.9) 316 (38.5) 0.94 (0.77-1.16) 0.96 (0.77-1.19) GG 72 (8.8) 68 (8.3) 1.04 (0.73-1.49) 1.01 (0.69-1.46) TG + GG 374 (45.7) 384 (46.8) 0.670 0.96 (0.79-1.16) 0.97 (0.79-1.18) G allele frequency 0.273 0.275 0.929 TP53BP1 Glu353Asp (C>G; rs560191) CC 427 (52.2) 424 (51.6) 0.913 1.00 1.00 CG 322 (39.4) 323 (39.3) 0.99 (0.81-1.22) 0.99 (0.80-1.22) GG 69 (8.4) 74 (9.0) 0.93 (0.65-1.32) 0.88 (0.61-1.27) CG + GG 391 (47.8) 397 (48.3) 0.822 0.98 (0.81-1.19) 0.97 (0.79-1.18) G allele frequency 0.2810.287 0.732 TP53BP1 Gln1136Lys (A>C; rs2602141) AA 430 (52.6) 433 (52.7) 0.734 1.00 1.00 AC 322 (39.4) 330 (40.2) 0.98 (0.80-1.20) 0.96 (0.77-1.18) CC 66 (8.1) 58 (7.1) 1.15 (0.79-1.67) 1.10 (0.74-1.62) AC + CC 388 (47.5) 388 (47.3) 0.944 1.01 (0.83-1.22) 0.98 (0.80-1.20) C allele frequency 0.278 0.272 0.730 TP53BP1 combined genotypes Other genotypes 733 (89.6) 730 (88.9) 0.651 1.00 1.00 Any variant homozygotes 85 (10.4) 91 (11.1) 0.93 (0.68-1.27) 0.89 (0.64-1.24) TP53 Arg72Pro (G>C; rs1042522) Arg/Arg 442 (54.0) 442 (53.8) 0.508 1.00 1.00 Arg/Pro 313 (38.3) 327 (39.8) 0.96 (0.78-1.17) 0.99 (0.80-1.22) Pro/Pro 63 (7.7) 52 (6.3) 1.21 (0.82-1.79) 1.27 (0.84-1.90) Arg/Pro + Pro/Pro 376 (46.0) 379 (46.1) 0.936 0.99 (0.82-1.21) 1.02 (0.84-1.25) Pro allele frequency 0.268 0.262 0.727 TP53PIN3 (16-bp insertion/deletion; rs17878362) ins/ins 607 (74.2) 630 (76.7) 0.440 1.00 1.00 ins/del 194 (23.7) 178 (21.7) 1.13 (0.90-1.43) 1.15 (0.90-1.47) del/del 17 (2.1) 13 (1.6) 1.36 (0.65-2.82) 1.39 (0.65-2.98) ins/del + del/del 211 (25.8) 191 (23.3) 0.234 1.15 (0.92-1.44) 1.17 (0.92-1.48) del allele frequency 0.139 0.124 0.223 TP53MspI (G>A; rs1625895) GG 603 (73.7) 631 (76.9) 0.144 1.00 1.00 GA 191 (23.4) 176 (21.4) 1.14 (0.90-1.43) 1.16 (0.91-1.48) AA 24 (2.9) 14 (1.7) 1.79 (0.92-3.50) 1.71 (0.85-3.44) GA + AA 215 (26.3) 190 (23.1) 0.140 1.18 (0.95-1.48) 1.20 (0.95-1.52) A allele frequency 0.146 0.124 0.073 TP53 combined genotypes Other genotypes 750 (91.7) 765 (93.2) 0.253 1.00 1.00 Any variant homozygotes 68 (8.3) 56 (6.8) 1.24 (0.86-1.79) 1.26 (0.86-1.84)

*Two-sided v 2 test for differences in the frequency distributions of genotypes, combined genotypes, or alleles between cases and controls. cAdjusted for age, sex, smoking status, and alcohol consumption status.

specifically with the DNA-binding core domain of TP53 of these three potentially functional TP53BP1 SNPs to be to enhance TP53-mediated transcriptional activation (29). associated with increased breast cancer risk, particularly among It also helps mediate the DNA damage checkpoint by TP53Pro72Pro homozygotes. However, this study did not cooperating with damage sensors and signal transducers include two other TP53 SNPs known to be associated with (30, 31). cancer risk: TP53PIN3 (a 16-bp insertion/deletion variant in TP53BP1 is polymorphic. Of over 178 SNPs reported to TP53 intron 3 associated with lung cancer risk; ref. 24) and date, 70 are relatively common (e.g., minor allele frequency TP53MspI (a 1798G>A SNP in TP53 intron 6 associated with >0.05) but only 1 in promoter (i.e., T-885G) and 2 non- colon cancer risk; ref. 27). We hypothesized that interactions 353 1136 4 synonymous (i.e., Glu Asp and Gln Lys). A recent between variants of TP53BP1 and TP53 may collectively Chinese study of breast cancer (32) found variant genotypes contribute to SCCHN risk. To test this hypothesis, we conducted a case-control study in which we genotyped TP53BP1 variants T-885G, Glu353Asp, and Gln1136Lys SNPs and TP53 variants Arg72Pro, PIN3, and MspI SNPs in SCCHN 4 http://egp.gs.washington.edu/data/tp53bp1/tpbp1.csnps.txt patients and cancer-free controls.

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Materials and Methods described previously (24, 32). The laboratory personnel doing the genotyping analyses were blinded to the subjects’ case-control status. Similar numbers of case and control DNA samples were assayed on Study subjects. Our recruitment of study subjects has been described each 96-well PCR plate. Approximately 10% of the DNA samples were in detail elsewhere (11). In brief, we identified all patients whose newly reanalyzed, and the results of both sets of analyses were 100% diagnosed, untreated SCCHN was histologically confirmed at The concordant. University of Texas M. D. Anderson Cancer Center between May 1995 Statistical analysis. The case and control groups were compared in and March 2005. Excluded were any patients with a second primary terms of selected demographic variables, smoking status, and alcohol SCCHN tumor, a primary tumor of the nasopharynx or sinonasal tract, use. Differences were evaluated using the v2 test. The associations a primary tumor outside the upper aerodigestive tract, cervical between genotypes or diplotypes of the selected polymorphisms metastasis of unknown origin, or any histopathologic diagnosis other and SCCHN risk were estimated by computing the odds ratios (OR) than SCCHN. and 95% confidence intervals (95% CI) from both univariate and Cancer-free control subjects were recruited from among visitors at multivariate unconditional logistic regression analyses. An analytic the clinics of our institution. Excluded as potential control subjects software program (PHASE 2.0; ref. 33) was used to infer haplotype were any persons genetically related to any enrolled case subject or to frequencies based on observed genotypes. For each individual case any other control subject. Potential control subjects were asked to or control, ‘‘diplotype’’ was defined as the most probable haplotype complete a short questionnaire to (a) determine their willingness to pair inferred using the PHASE 2.0 program. Potential gene-gene participate in research studies and (b) obtain demographic informa- interactions were evaluated by logistic regression analysis and F tion for frequency matching to the cases by age ( 5 years), sex, and maximum likelihood testing as follows: the changes in deviance ethnicity. (-2 log likelihood) between the models were compared in terms of After giving informed consent, all eligible subjects who agreed to main effects with or without the interaction term. All statistical participate were interviewed to collect additional information about analyses were done using Statistical Analysis System software (v.9.1.3; risk factors, such as tobacco smoking and alcohol use. Each study SAS Institute). subject had 30 mL of blood drawn for later biomarker testing. Because relatively few minority subjects were recruited in this study, only non- Hispanic whites were included in the current analysis. The research Results protocol was approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. A total of 835 cases and 854 controls of non-Hispanic whites Genotyping. Genotyping analyses were done on genomic DNA F obtained from the study subjects. Six SNPs were targeted for analysis: frequency matched for age ( 5 years) and sex was recruited. TP53BP1 T-885G, Glu353Asp, and Gln1136Lys SNPs and TP53 Because of the poor quality of their DNA samples, 17 of the Arg72Pro, PIN3, and MspI SNPs. The materials, methods, and PCR case subjects and 33 of the control subjects did not have usable conditions for genotyping these six genetic variants have been genotyping data, which were consequently excluded from the

Table 2. Frequency of inferred haplotypes of TP53BP1 and TP53 based on observed genotypes and their association with risk of SCCHN

Haplotype No. chromosomes (%)* OR (95% CI)c TP53BP1 TP53BP1 TP53BP1 Cases Controls T-885G Glu353Asp (C>G) Gln1136Lys (A>C) T C A 1,112 (67.97) 1,099 (66.93) 1.00 G G C 377 (23.04) 364 (22.17) 1.00 (0.84-1.19) T G C 36 (2.20) 26 (1.58) 1.32 (0.78-2.24) T C C 22 (1.34) 26 (1.58) 0.79 (0.43-1.44) G G A 27 (1.65) 42 (2.56) 0.69 (0.41-1.14) T G A 20 (1.22) 39 (2.38) 0.50 (0.28-0.87) G C A 23 (1.41) 16 (0.97) 1.59 (0.81-3.12) G C C 19 (1.16) 30 (1.83) 0.65 (0.36-1.20) P = 0.032b

TP53 Arg72Pro TP53PIN3 (16-bp TP53MspI (G>A) (G>C) insertion/deletion)

Arg ins G 1,148 (70.17) 1,178 (71.74) 1.00 Pro ins G 217 (13.26) 233 (14.19) 0.98 (0.79-1.20) Pro del A 192 (11.74) 174 (10.60) 1.16 (0.92-1.45) Arg del G 23 (1.41) 15 (0.91) 1.59 (0.80-3.14) Arg ins A 22 (1.34) 15 (0.91) 1.35 (0.68-2.68) Pro ins A 21 (1.28) 12 (0.73) 1.92 (0.91-4.05) Pro del G 9 (0.55) 12 (0.73) 0.83 (0.34-2.01) Arg del A 4 (0.24) 3 (0.18) 1.15 (0.24-5.41) P = 0.345b

*Data are presented as no. (%) of total chromosomes for cases (total chromosomes, N = 1,636) and controls (total chromosomes, N = 1,642), respectively. cOR adjusted for age, sex, smoking status, and alcohol use. bTwo-sided v 2 test.

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Demographic and exposure main effect of any single genetic variant on SCCHN risk, we variables were further adjusted for in multivariate logistic did note that the main effect of haplotypes/diplotypes of the regression analyses. The most frequent SCCHN was cancer TP53BP1 SNPs on SCCHN risk seemed to be modified by the of the pharynx (46.8%, 383 of 818) followed by cancer of TP53 Arg72Pro SNP, particularly in TP53 variant homozygotes the oral cavity (30.1%, 246 of 818) and larynx (23.1%, 189 and haplotypes/diplotypes. The finding of an interaction, but of 818). in a different direction, was also reported in Chinese breast The genotype frequency distributions of the six selected cancer patients (32), although any conclusions drawn from polymorphisms in the controls were consistent with the these two studies are obviously limited by differences in ethnic Hardy-Weinberg equilibrium: TP53BP1 T-885G (P = 0.311), diversity and cancer sites. Moreover, the present finding, as they Glu353Asp (P = 0.271), and Gln1136Lys (P = 0.650) and TP53 are based on a limited number of possible interactions, needs Arg72Pro (P = 0.411), PIN3 (P = 0.916), and MspI (P = 0.670). to be validated in larger studies that allow for robust subgroup In the single-locus analysis (Table 1), none of the six variants analyses. was associated with SCCHN risk. That the effects of TP53BP1 on cancer risk might depend on Further linkage disequilibrium analysis revealed high but the status of TP53 is biologically plausible. Studies of the incomplete linkage disequilibrium among the three loci in association between TP53 polymorphisms and cancer risk have TP53BP1 (r2 = 0.684, D¶ = 0.851 for T-885G and Glu353Asp; produced inconsistent results (34). It has been variously r2 = 0.681, D¶ = 0.833 for T-885G and Gln1136Lys; and r2 = suggested that the wild-type TP53 Arg72 allele enhances tumor 0.615, D¶ = 0.815 for Glu353Asp and Gln1136Lys) and the three development (via increased inactivation of TP53) in cells loci in TP53 (r2 = 0.295, D¶ = 0.860 for Arg72Pro and PIN3; expressing the mutated TP53 protein but inhibits tumor r2 = 0.295, D¶ = 0.860 for Arg72Pro and MspI; and r2 = 0.721, development (via increased apoptotic ability) in cells express- D¶ = 0.849 for PIN3 and MspI). We estimated eight inferred ing the wild-type TP53 protein (34), that the TP53PIN3 variant haplotypes for both TP53BP1 and TP53. Of these haplotypes, causes alternative splicing and RNA instabilization (27), and two common TP53BP1 haplotypes [i.e., TCA (66.9%) and GGC that the TP53MspI variant influences apoptosis and cell (22.2%)] and three common TP53 haplotypes [Arg-ins-G survival (35). Together, these suggest that the joint effect of (71.7%), Pro-ins-G (14.2%), and Pro-del-A (10.6%)] these three TP53 polymorphisms on cancer risk may be more accounted for 89.1% and 95.8%, respectively, of the 1,642 significant than the individual effect of any one of them alone. chromosomes in control subject DNA; however, only one rare Indeed, cells bearing the TP53 haplotype that contains all three TP53BP1 haplotype (i.e., TGA) was associated with a signifi- variant TP53 alleles (Pro-del-A, the so-called ‘‘mutant’’ MMM cantly reduced risk of SCCHN (adjusted OR, 0.50; 95% CI, haplotype) are associated not only with lung cancer risk but 0.28-0.87; Table 2). also with a decreased capacity for apoptosis and DNA repair Because altered risk was associated with the number of (24). Therefore, the association of this Pro-del-A haplotype TP53BP1 variant alleles only in TP53 variant carriers, we also with decreased SCCHN risk and the interaction between the stratified and analyzed the TP53BP1 haplotypes by TP53 TP53BP1 variant diplotypes and the TP53 diplotypes that carry genotype. Compared with the most common TP53BP1 it suggest that the TP53BP1 variant alleles may evolutionarily haplotype TCA, the TP53BP1 haplotype GGC containing all compensate for the adverse effects of the TP53 variant alleles/ variant alleles was consistently associated with a significantly haplotype. However, these findings need to be validated in reduced SCCHN risk only in TP53 variant homozygotes larger studies. Additionally, we found no significant effect of (adjusted OR, 0.48; 95% CI, 0.25-0.94 for TP53Pro72Pro; the TP53 Pro-del-A haplotype by itself but a profound effect of adjusted OR, 0.17; 95% CI, 0.04-0.69 for TP53PIN3del/del; the homozygous TP53 Pro-del-A genotype on the effect of the and adjusted OR, 0.16; 95% CI, 0.04-0.65 for TP53Msp1AA; TP53BP1 diplotype on cancer risk. Table 3). It is known that the p53 codon 72 variants have markedly Finally, we analyzed diplotypes using TP53BP1 GGC and different apoptotic potential by differentially activating p53- TP53 Pro-del-A as the variant haplotypes. Because too few responsive promoters. For example, the Arg72 allele has a higher carriers of the TP53BP1 diplotype GGC/GGC also carried the apoptotic potential than the Pro72 allele because Arg72 has an TP53 Pro-del-A/Pro-del-A diplotype, this group was combined enhanced association with MDM2 and CRM1 and a greater with the heterozygotes of the TP53BP1 haplotype GGC. ability to localize to the mitochondria (36); earlier study also Diplotypes of one or two copies of the TP53BP1 haplotype suggested that Arg72 allele enhanced the ability of mutant p53 GGC harboring all three TP53BP1 variant alleles were to bind p73 and neutralized p73-induced apoptosis (37). associated with a significantly reduced SCCHN risk, if the Therefore, it is likely that TP53 and TP53BP1 variant allele or carrier had two copies of the TP53 variant haplotype Pro-del-A haplotype may enhance their protein interaction in the absence (adjusted OR, 0.08; 95% CI, 0.01-0.50) but with a nonsig- of TP53 mutations, a hypothesis consistent with a protective nificantly increased risk, if the carrier had zero copies of effect observed in this study. Larger studies are needed to test the TP53 variant haplotype Pro-del-A (adjusted OR, 1.10; this hypothesis. 95% CI, 0.87-1.38]); this interaction was statistically significant To date, only two case-control studies have investigated the (P = 0.017; Table 4). role of TP53BP1 variants in cancer susceptibility. One was a

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Table 3. Association between inferred haplotypes of TP53BP1 and risk of SCCHN by TP53 genotypes

TP53BP1 haplotype TP53BP1 TP53BP1 TP53BP1 No. chromosomes (%)* OR (95% CI)c T-885G Glu353Asp (C>G) Gln1136Lys (A>C) Cases Controls TP53 Arg72Arg T C A 604 (68.3) 586 (66.3) 1.00 G G C 210 (23.8) 190 (21.5) 1.03 (0.81-1.30) Other haplotypesb 70 (7.9) 108 (12.2) 0.66 (0.47-0.92) TP53 PIN3 ins/ins T C A 819 (67.5) 844 (67.0) 1.00 G G C 288 (23.7) 276 (21.9) 1.07 (0.88-1.31) Other haplotypesb 107 (8.8) 140 (11.1) 0.81 (0.62-1.08) TP53 MspI GG T C A 810 (67.2) 844 (66.9) 1.00 G G C 293 (24.3) 279 (22.1) 1.09 (0.89-1.33) Other haplotypesb 103 (8.5) 139 (11.0) 0.83 (0.62-1.10)

*Data are presented as no. (%) of case subjects (n = 818) and control subjects (n = 821), respectively. cAdjusted for age, sex, smoking status, and alcohol use. bThe combination of all haplotypes with a frequency of <0.05.

relatively large German study of 353 breast cancer patients and with that in the German case-control study (47.6% for CC, 960 control subjects that found no overall association between 42.5% for CG, and 9.9% for GG in controls; P = 0.233; ref. 36) four TP53BP1 SNPs (i.e., D353E, G412S, K1136Q, and than to that in the Chinese study (30.9% for CC, 50.9% for 1347_1352delTATCCC) and breast cancer risk (38). The other CG, and 18.2% for GG; P < 0.0001; ref. 32). The frequency was the Chinese study of 404 breast cancer cases and 472 cancer- distribution of TP53 Arg72Pro genotypes among the control free controls that found no significant main effect of any subjects in our current study was also significantly different from TP53BP1 genotype (of T-885G, Glu353Asp, and Gln1136Lys) or that in the Chinese study (P < 0.0001; ref. 32). Another possible haplotype (except for GGC) on risk but an increased risk reason for the difference between the Chinese findings and ours associated with the combined genotypes in TP53 variant is the type of cancer studied. SCCHN and breast cancer likely Pro72Pro homozygotes only (32). However, we noticed that involve fundamentally different pathways of DNA repair. the allele/haplotype frequency distribution of both TP53BP1 Indeed, the nucleotide excision repair pathway seems to be and TP53 variant genotypes in the Chinese study differed more relevant in the etiology of SCCHN (6, 7), whereas DNA dramatically from that in ours and that our study had a much double-strand break repair, as suggested by the roles of BRCA1 smaller number of TP53 variant homozygotes and diplotypes and BRCA2 (39), seems to be more relevant in the etiology of containing two copies of the TP53 mutant haplotype, thus breast cancer (22). limiting the statistical power of our study. One possible reason In summary, our data from a relatively large, although for the difference in frequency distribution between studies is racially homogenous, case-control population suggest that ethnicity. The distribution of TP53BP1 Glu353Asp genotype none of the TP53BP1 and TP53 SNPs we studied affects frequencies in our U.S. non-Hispanic white population (51.6% individually the risk of SCCHN. However, the data also suggest for CC, 39.3% for CG, and 9.0% for GG) was more comparable that gene-gene interaction between TP53BP1 and TP53 may

Table 4. Analysis of associations between TP53BP1 diplotypes and risk of SCCHN as stratified by TP53 diplotype

TP53BP1 TP53 diplotype diplotype Other haplotypes/ Other haplotypes/Pro-del-A Pro-del-A/Pro-del-A P* other haplotypes Cases Controls OR (95% CI)c Cases Controls OR (95% CI)c Cases Controls OR (95% CI)c Other haplotypes/ 380 408 1.00 101 91 1.00 14 3 1.00 other haplotypes Other haplotypes/ 263 250 1.10 (0.87-1.38) 57 61 0.83 (0.52-1.32) 3 8 0.08 (0.01-0.50) 0.017 GGC or GGC/GGC

*P value for interaction. cAdjusted for age, sex, smoking status, and alcohol use.

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Table 3. Association between inferred haplotypes of TP53BP1 and risk of SCCHN by TP53 genotypes (Cont’d)

Genotypes of selected TP53 polymorphisms No. chromosomes (%)* OR (95% CI)c No. chromosomes (%)* OR (95% CI)c Cases Controls Cases Controls TP53 Arg72Pro TP53 Pro72Pro 420 (67.1) 453 (69.3) 1.00 88 (69.8) 60 (57.7) 1.00 142 (22.7) 142 (21.7) 1.11 (0.84-1.46) 25 (19.8) 32 (30.8) 0.48 (0.25-0.94) 64 (10.2) 59 (9.0) 1.17 (0.79-1.74) 13 (10.3) 12 (11.5) 0.59 (0.24-1.50) TP53 PIN3 ins/del TP53 PIN3 del/del 268 (69.1) 244 (68.5) 1.00 25 (73.5) 11 (42.3) 1.00 85 (21.9) 78 (21.9) 0.91 (0.63-1.31) 4 (11.8) 10 (38.5) 0.17 (0.04-0.69) 35 (9.0) 34 (9.6) 0.93 (0.55-1.58) 5 (14.7) 5 (19.2) 0.39 (0.09-1.68) TP53 MspI GA TP53 MspI AA 270 (70.7) 243 (69.0) 1.00 32 (66.7) 12 (42.9) 1.00 79 (20.7) 75 (21.3) 0.87 (0.60-1.26) 5 (10.4) 10 (35.7) 0.16 (0.04-0.65) 33 (8.6) 34 (9.7) 0.83 (0.49-1.42) 11 (22.9) 6 (21.4) 0.57 (0.15-2.12) alter the risk of SCCHN, a notion that warrants further Acknowledgments evaluation in larger studies. In any case, our findings warrant functional elucidation of the six SNPs we have studied here to We thank Margaret Lung, Kathryn Patterson, and Leanel Fairly for their assistance in recruitingthesubjects;ZhenshengLiu,XiaodongZhai,andJiachunLufor their technical better understand the mechanisms underlying carcinogenesis in support;Yawei Qiao, Jianzhong He, and Kejing Xu for their laboratory assistance;Mon- SCCHN. ica Domingue for manuscript preparation; andJude Richard, ELS, for scientific editing.

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www.aacrjournals.org 4305 Clin Cancer Res 2007;13(14) July 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2007 American Association for Cancer Research. Polymorphic TP53BP1 and TP53 Gene Interactions Associated with Risk of Squamous Cell Carcinoma of the Head and Neck

Kexin Chen, Zhibin Hu, Li-E Wang, et al.

Clin Cancer Res 2007;13:4300-4305.

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