Kathryn L. Terry

CA125 has proven to be the most promising biomarker for ovarian cancer screening. However, results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound (TVU) to usual care have shown no clinically important difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity, which could be due in part to its expression on variety of tissues, including the lung, pancreas, stomach, liver, endometrium, and breast. In addition, CA125 levels vary between individuals based on demographic, reproductive, and lifestyle characteristics. We hypothesize that, independent of ovarian cancer, genetic variation may influence CA125 levels and identification of genetic predictors of CA125 may be used to develop individualized cut-off points, in combination with personal characteristics, to improve the predictive value of CA125 as an ovarian cancer screening biomarker. Furthermore, studies showing that CA125 binds to natural killer cells and monocytes, dampening immune response, suggest that CA125 may contribute to ovarian cancer progression through immune dysregulation. Thus, identifying genetic variants associated with CA125 levels could add another layer of understanding of the biologic role of elevated CA125 in ovarian cancer progression. To test our hypothesis, we evaluated the association between common germline genetic variants across the genome in relation to serum levels of CA125 among 347 women without ovarian cancer recruited as population-based controls in the New England Case Control Study, a population-based study of ovarian cancer that enrolled participants between 1992 and 2008 in eastern Massachusetts and New Hampshire. We used linear regression to identify SNPs associated with CA125 using the Rare variant (RV) test. To account for multiple testing, a p-value threshold of 5x10-8 was used. We adjusted for age and three principal components to account for potential population stratification. While there were no GWAS-significant SNPs, rs12602627 on chromosome 17 was associated with a 75% increase in CA125 per additional variant allele of rs12602627 (p=6.47x10-8). Furthermore, there were two SNPs (rs12602169 and rs73990427) in close proximity that were nearly GWAS significant (p=7.12x10-8 and 8.97x10-8, respectively). rs12602627 explained 8% of the variability of CA125. Monocyte to macrophage differentiation associated (MMD) is the closest gene to rs12602627. MMD encodes a protein expressed in differentiated mature macrophages and is involved in macrophage activation, suggesting it may play an important role in immune response. This is the first GWAS study to assess SNPs directly associated with circulating levels of CA125 in women without ovarian cancer. Validation studies are currently under way. Results from these analyses may provide important insights into genetic determinants of CA125 levels, improved ovarian cancer screening, and better understanding of how CA125 contributes to ovarian cancer pathogenesis and progression. *Coauthors. Citation Format: Naoko Sasamoto, Lai Jiang, Allison F. Vitonis, Raina N. Fichorova, Paul Pharaoh, Daniel W. Cramer, Peter Kraft, Kathryn L. Terry. Genome-wide association study of cancer antigen 125. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B19.

(Abstracted from Cancer Epidemiol Biomarkers Prev 2016;25(7):1114–1124) It is estimated that 5% of women in the United States and 10% to 50% of women worldwide are physically inactive. Previous studies have demonstrated that recreational physical activity is associated with decreased risks of developing breast, colon, and endometrial cancers.

Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):983–6)

Background: The etiology of uterine leiomyoma (or fibroids) is poorly understood. Sex steroid hormones and growth factors have been hypothesized to play a role in their development, and anthropometric characteristics may influence uterine leiomyoma risk. Methods: We analyzed prospectively-collected data from the Nurses’ Health Study II, a cohort of 116,609 female registered nurses age 25 to 42 years at baseline. Incidence of uterine leiomyoma and anthropometric characteristics were assessed every 2 years. We calculated hazard ratios and 95% confidence intervals adjusted for known and suspected risk factors for uterine leiomyoma. Results: Uterine leiomyomas were associated with current body mass index, change in weight since age 18, and waist-to-hip ratio. However, there was little evidence of their association with body mass index at age 18, childhood or adolescent body size, or adult height. Conclusion: Body mass and weight gain in adulthood may increase the risk of uterine leiomyoma, but body mass in early life does not.

Mutation of the breast cancer–associated gene 1 (BRCA1) plays an important role in familial breast cancer. Although hypermethylation of the BRCA1 promoter has been observed in sporadic breast cancer, its exact role in breast cancer initiation and association with breast cancer risk is unknown. The frequency of BRCA1 promoter hypermethylation was tested in (a) 14 primary breast cancer biopsies and (b) the initial random periareolar fine-needle aspiration (RPFNA) cytologic samples obtained from 61 asymptomatic women who were at increased risk for breast cancer. BRCA1 promoter hypermethylation was assessed from nucleotide −150 to nucleotide +32 relative to the transcription start site. RPFNA specimens were stratified for cytologic atypia using the Masood cytology index. BRCA1 promoter hypermethylation was observed at similar frequency in nonproliferative (normal; Masood ≤10: 18%, 2 of 11), hyperplastic (Masood 11-13: 15%, 6 of 41), and atypical cytology (Masood 14-17: 22%, 4 of 18; P = 0.79). BRCA1 promoter hypermethylation was not associated with (a) family history of breast or ovarian cancer or (b) calculated Gail or BRCAPRO risk score. BRCA1 promoter hypermethylation was associated with (a) age (P = 0.028) and (b) the combined frequency of promoter hypermethylation of the retinoic acid receptor-β2 (RARB) gene, estrogen receptor-α (ESR1) gene, and p16 (INK4A) gene (P = 0.003). These observations show that BRCA1 promoter hypermethylation (a) is not associated with breast cancer risk as measured by mathematical risk models and (b) does not predict mammary atypia in RPFNA cytologic samples obtained from high-risk women. (Cancer Epidemiol Biomarkers Prev 2007;16(1):50–6)

Epidemiologic studies have consistently found an association between the timing of menarche and menopause and the risk of breast cancer.¹ These events affect the number of lifetime ovulatory cycles and consequently influence exposure to ovarian hormones. Thus, fewer lifetime ovulatory cycles might reduce breast cancer risk.^2,3

Biological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with ≥22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (≥22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (<22 CAG repeats).