Cancer Epidemiology Research Cooperative (CERC)
Program in Epidemiology
Division of Public Health Sciences
Dr. Madeleine is an Assistant Member in the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center, and a Research Assistant Professor in the Department of Epidemiology, School of Public Health, at the University of Washington. She received an MPH in Epidemiology from Yale University and a PhD in Epidemiology from the University of Washington.
Research Interests
Dr. Madeleine's major research focus is the molecular epidemiology of pathogens and the immune response to them that may be associated with cancer development and prognosis. She is also interested in the role that chronic subclinical immune disregulation (such as occurs with age, obesity, physical inactivity, hormone use, and UV exposure) may play in carcinogenesis.
Current Studies
Recent Publications
Maley SN, Schwartz SM, Johnson LG, Malkki M, Du Q, Daling JR, Li SS, Zhao LP, Petersdorf EW, Madeleine MM. Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study. Int J Immunogenet. 2009; 36:367-375.
CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.
Carter JJ, Paulson KG, Wipf GC, Miranda D, Madeleine MM, Johnson LG, Lemos BD, Lee S, Warcola AH, Iyer JG, Nghiem P, Galloway DA. Association of Merkel Cell Polyomavirus-Specific Antibodies With Merkel Cell Carcinoma. J Natl Cancer Inst. 2009; 101:1510-1522.
Merkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma. Multiplex antibody-binding assays were used to assess levels of antibodies against polyomaviruses in plasma. MCPyV VP1 antibody levels were determined in plasma from 41 patients with Merkel cell carcinoma and 76 matched control subjects. MCPyV DNA was detected in tumor tissue specimens by quantitative polymerase chain reaction. Seroprevalence of polyomavirus-specific antibodies was determined in 451 control subjects. MCPyV strain-specific antibody recognition was investigated by replacing coding sequences from MCPyV strain 350 with those from MCPyV strain w162. We found that 36 (88%) of 41 patients with Merkel cell carcinoma carried antibodies against VP1 from MCPyV w162 compared with 40 (53%) of the 76 control subjects (odds ratio adjusted for age and sex = 6.6, 95% confidence interval [CI] = 2.3 to 18.8). MCPyV DNA was detectable in 24 (77%) of the 31 Merkel cell carcinoma tumors available, with 22 (92%) of these 24 patients also carrying antibodies against MCPyV. Among 451 control subjects from the general population, prevalence of antibodies against human polyomaviruses was 92% (95% CI = 89% to 94%) for BK virus, 45% (95% CI = 40% to 50%) for JC virus, 98% (95% CI = 96% to 99%) for WU polyomavirus, 90% (95% CI = 87% to 93%) for KI polyomavirus, and 59% (95% CI = 55% to 64%) for MCPyV. Few case patients had reactivity against MCPyV strain 350; however, indistinguishable reactivities were found with VP1 from strain 350 carrying a double mutation (residues 288 and 316) and VP1 from strain w162. Infection with MCPyV is common in the general population. MCPyV, but not other human polyomaviruses, appears to be associated with Merkel cell carcinoma.
Bodelon C, Madeleine MM, Voigt LF, Weiss NS. Is the incidence of invasive vulvar cancer increasing in the United States? Cancer Causes Control 2009; 20:1779-1782.
In order to document incidence rates of vulvar cancer, specifically invasive vulvar cancer, from 1973 to 2004 in the United States, nine US cancer registries from the Surveillance, Epidemiology, and End Results (SEER) databases were used to identify women aged 15-84 years, who were first diagnosed with vulvar cancer during 1973-2004. Age-adjusted incidence rates and annual percentage changes were calculated for different time periods, stage of the disease, age, race, and geographic area. During 1973-2004, the incidence of in situ vulvar tumors increased by an average of 3.5% per year (95% CI: 2.9%, 4.1%), while the incidence of invasive tumors increased 1.0% per year (95% CI: 0.6%, 1.4%). An increasing incidence was observed for localized and regional invasive tumors. To at least some degree, the rise of incidence rates of incidence tumors was evident in every age category, race, and geographic region. Incidence rates of invasive vulvar cancer have increased in the United States during the last three decades. The reasons for this increase are unknown.
Klug SJ, Ressing M, Koenig J, Abba MC, Agorastos T, Brenna SM, Ciotti M, Das B, Del Mistro A, Dybikowska A, Giuliano AR, Gudleviciene Z, Gyllensten U, Haws AL, Helland A, Herrington CS, Hildesheim A, Humbey O, Jee SH, Kim JW, Madeleine MM, Menczer J, Ngan HY, Nishikawa A, Niwa Y, Pegoraro R, Pillai M, Ranzani G, Rezza G, Rosenthal AN, Roychoudhury S, Saranath D, Schmitt VM, Sengupta S, Settheetham-Ishida W, Shirasawa H, Snijders PJ, Stoler MH, Suárez-Rincón AE, Szarka K, Tachezy R, Ueda M, van der Zee AG, von Knebel Doeberitz M, Wu MT, Yamashita T, Zehbe I, Blettner M. TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol 2009;10:772-784.
Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies.
Edelstein ZR, Madeleine MM, Hughes JP, Johnson LG, Schwartz SM, Galloway DA, Carter JJ, Koutsky LA. Age of diagnosis of squamous cell cervical carcinoma and early sexual experience. Cancer Epidemiol Biomarkers Prev 2009;18:1070-1076.
Given the established links among young age at first intercourse (AFI), number of sex partners, high-risk human papillomavirus infection, and squamous cell cervical cancer (SCC), we hypothesized that women diagnosed with SCC at younger ages would be more likely to report young AFI than women diagnosed later in life. We performed a population-based investigation among invasive SCC cases who were diagnosed between 1986 and 2004, were ages 22 to 53 years, and lived in the metropolitan Seattle-Puget Sound region (n = 333). Using multivariate linear regression, we estimated coefficients and 95% confidence intervals (95% CI) to assess the association between age at SCC diagnosis and AFI (<15, 15-18, > or =19 years) and number of sex partners at age <20 years (0, 1, 2-4, 5-14, > or =15), accounting for birth year and other factors. Interactions were assessed using the likelihood ratio test. The interval between AFI and SCC diagnosis ranged from 4 to 35 years. In a multivariate model, compared with SCC cases reporting AFI > or =19, the mean age of diagnosis was 3.1 years younger for SCC cases reporting AFI <15 (95% CI, -5.8 to -0.5) and 2.6 years younger for SCC cases reporting AFI 15 to 18 (95% CI, -4.6 to -0.6). Although number of sex partners at age <20 years was associated with age at SCC diagnosis in a crude analysis, the association was not independent of AFI. However, in the AFI > or =19 and <15 groups, differences in effect were seen by number of sex partners at age <20 years (P(interaction) = 0.08), with the association remaining strong and significant only in the AFI <15 group that had > or =2 partners at age <20 years (coefficient, -4.2; 95% CI, -6.3 to -2.1). Among younger and middle-aged women with SCC, early age of diagnosis was associated with early AFI, although the effect appeared to be modified by number of sex partners at age <20 years.
De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer. 2009;124:1626-1636.
This meta-analysis investigated human papillomavirus (HPV) prevalence in vulvar, vaginal and anal intraepithelial neoplasia (VIN, VAIN, AIN) grades 1-3 and carcinoma from 93 studies conducted in 4 continents and using PCR assays. Overall HPV prevalence was 67.8%, 85.3% and 40.4% among 90 VIN1, 1,061 VIN2/3 and 1,873 vulvar carcinomas; 100%, 90.1% and 69.9% among 107 VAIN1, 191 VAIN2/3 and 136 vaginal carcinomas; and 91.5%, 93.9% and 84.3% among 671 AIN1, 609 AIN2/3 and 955 anal carcinomas, respectively. HPV16 was found more frequently (>75%) and HPV18 less frequently (<10%) in HPV-positive vulvar, vaginal and anal carcinomas than in cervical carcinoma. HPV6 and 11 were common in VIN1 and AIN1, but not in VAIN1. HPV prevalence in vulvar carcinoma varied most by histological type (69.4% in warty-basaloid and 13.2% in keratinized type) and was also higher in women 60 years or younger and in studies carried out in North America. HPV prevalence in anal carcinoma was higher among women (90.8%) than men (74.9%), but no difference by gender emerged in North America. The majority of AIN2/3 derived from studies of HIV-positive individuals and/or men who have sex with men. Among AIN2/3, HIV infection was associated with higher HPV prevalence, more multiple-type infections and a relative under-representation of HPV16. In conclusion, approximately 40% of vulvar, 60% of vaginal and 80% of anal carcinoma may be avoided by prophylactic vaccines against HPV16/18. This proportion would be similar for the corresponding high-grade lesions of the vagina and anus, but higher for VIN2/3 (75%) than for vulvar carcinoma.
Lanoy E, Dores GM, Madeleine MM, Toro JR, Fraumeni JF Jr, Engels EA. Epidemiology of nonkeratinocytic skin cancers among persons with AIDS in the United States. AIDS 2009;23:385-393.
Immunosuppression may increase risk for some skin cancers. We evaluated skin cancer epidemiology among persons with AIDS. We linked data from population-based US AIDS and cancer registries to evaluate risk of nonkeratinocytic skin cancers (melanoma, Merkel cell carcinoma, and appendageal carcinomas, including sebaceous carcinoma) in 497,142 persons with AIDS. Standardized incidence ratios (SIRs) were calculated to relate skin cancer risk to that in the general population. We used logistic regression to compare risk according to demographic factors, CD4 cell count, and a geographic index of ultraviolet radiation exposure. From 60 months before to 60 months after AIDS onset, persons with AIDS had elevated risks of melanoma (SIR = 1.3, 95% confidence interval 1.1-1.4, n = 292 cases) and, more strongly, of Merkel cell carcinoma (SIR = 11, 95% confidence interval 6.3-17, n = 17) and sebaceous carcinoma (SIR = 8.1, 95% confidence interval 3.2-17, n = 7). Risk for appendageal carcinomas increased with progressive time relative to AIDS onset (P trend = 0.03). Risk of these skin cancers was higher in non-Hispanic whites than other racial/ethnic groups, and melanoma risk was highest among men who have sex with men. Melanoma risk was unrelated to CD4 cell count at AIDS onset (P = 0.32). Risks for melanoma and appendageal carcinomas rose with increasing ultraviolet radiation exposure (P trend <10 and P trend = 10, respectively). Among persons with AIDS, there is a modest excess risk of melanoma, which is not strongly related to immunosuppression and may relate to ultraviolet radiation exposure. In contrast, the greatly increased risks for Merkel cell and sebaceous carcinoma suggest an etiologic role for immunosuppression.
Hussain SK, Madeleine MM, Johnson LG, Du Q, Malkki M, Wilkerson HW, Farin FM, Carter JJ, Galloway DA, Daling JR, Petersdorf EW, Schwartz SM. Cervical and vulvar cancer risk in relation to the joint effects of cigarette smoking and genetic variation in interleukin 2. Cancer Epidemiol Biomarkers Prev 2008;17:1790-1709.
Cigarette smoking is an established cofactor to human papillomavirus (HPV) in the development of cervical and vulvar squamous cell carcinoma (SCC), and may influence risk through an immunosuppressive pathway. Genetic variation in interleukin 2 (IL2), associated in some studies with the inhibition of HPV-targeted immunity, may modify the effect of smoking on the risk of HPV-related anogenital cancers. We conducted a population-based case-only study to measure the departure from a multiplicative joint effect of cigarette smoking and IL2 variation on cervical and vulvar SCC. Genotyping of the four IL2 tagSNPs (rs2069762, rs2069763, rs2069777, and rs2069778) was done in 399 cervical and 486 vulvar SCC cases who had been interviewed regarding their smoking history. Compared with cases carrying the rs2069762 TT genotype, we observed significant departures from multiplicativity for smoking and carriership of the TG or GG genotypes in vulvar SCC risk [interaction odds ratio (IOR), 1.67; 95% confidence interval (CI), 1.16-2.41]. Carriership of one of three diplotypes, together with cigarette smoking, was associated with either a supramultiplicative (TGCT/GGCC; IOR, 2.09; 95% CI, 0.98-4.46) or submultiplicative (TTCC/TGTC; IOR, 0.37; 95% CI, 0.16-0.85 or TGCT/TGCC; IOR, 0.37; 95% CI, 0.15-0.87) joint effect in vulvar cancer risk. For cervical SCC, departure from multiplicativity was observed for smokers homozygous for the rs2069763 variant allele (TT versus GG or GT genotypes; IOR, 1.87; 95% CI, 1.00-3.48), and for carriership of the TTCC/TTCC diplotype (IOR, 2.08; 95% CI, 1.01-4.30). These results suggest that cervical and vulvar SCC risk among cigarette smokers is modified by genetic variation in IL2.
