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It is unclear whether the different histologic subtypes of epithelial ovarian carcinoma have different risk factors. We investigated the relationships between selected epidemiologic variables (i.e., parity, family history of ovarian cancer, oral contraceptive use, a history of tubal ligation and noncontraceptive estrogen use) and the major histologic subtypes of epithelial ovarian cancer in a hospital-based case-control study of adult women at Roswell Park Cancer Institute in Buffalo, NY, USA. Multivariate unconditional logistic regression models were used for statistical analysis. We observed a pattern of increased risk associated with family history and a pattern of risk reduction associated with parity, noncontraceptive estrogen use and tubal ligation across all histologic subtype groups. However, we did not observe a consistent pattern of risk associated with oral contraceptive use. These results provide some additional support for the hypothesis that the effects of various ovarian cancer risk factors may differ according to the histologic subtype.

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Background: Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) and acetaminophen all have biologic effects that might reduce the risk of ovarian cancer. However, epidemiologic data on this question are mixed.Methods: A population-based, case-control study in western Pennsylvania, eastern Ohio, and western New York State included 902 women with incident epithelial ovarian cancer who were diagnosed between February 2003 and November 2008 as well as 1802 matched controls. Regular use (at least 2 tablets per week for 6 months or more) of aspirin, NA-NSAIDs, and acetaminophen before the reference date (9 months before interview date) was assessed by in-person interview. We used logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).Results: The OR for aspirin use was 0.81 (95% CI = 0.63-1.03). Decreased risks were found among women who used aspirin continuously (0.71 [0.54-0.94]) or at a low-standardized daily dose (0.72 [0.53-0.97]), who used aspirin for the prevention of cardiovascular disease (0.72 [0.57-0.97]), who used aspirin more recently, or who used selective cyclooxygenase-2 inhibitors (0.60 [0.39-0.94]). No associations were observed among women using nonselective NA-NSAIDs or acetaminophen.Conclusions: Risk reductions of ovarian cancer were observed with use of aspirin or selective cyclooxygenase-2 inhibitors. However, the results should be interpreted with caution due to the inherent study limitations and biases. [ABSTRACT FROM AUTHOR]

We wished to examine variables associated with pregnancy desire among pregnant adolescents from low socioeconomic backgrounds. This study analyzed 335 charts at a state-funded family planning clinic. Participants were adolescents who had a positive pregnancy test at the clinic on the day of the survey. Logistic regression was utilized to determine differences in pregnancy desire. We found that Hispanic teens were more than twice as likely to desire pregnancy as African American teens (adjusted odds ratio [AOR], 2.22; 95% confidence interval [CI], 1.22-3.65), and adolescents who were not in school were almost twice as likely as those who were in school full-time to desire pregnancy (AOR, 1.83; 95% CI, 1.08-3.09). Hispanic teens who were not in school were 12 times more likely to desire pregnancy than African American teens who were in school full-time (odds ratio [OR], 11.47; 95% CI, 3.68-35.75). Adolescent pregnancy desire is significantly associated with educational status and racial background. Developing culturally appropriate interventions to encourage continued education and asking about community and familial norms are essential steps in addressing this issue. [ABSTRACT FROM AUTHOR]

Our objective was to examine differences in contraceptive choice among female adolescents from low socioeconomic backgrounds both before and after an appointment for reproductive health care at a community-based, state-funded, family planning clinic. This study utilized data collected from 4237 charts from young women attending a family planning clinic. Logistic regression was utilized to examine variables associated with the following main questions: (1) the selection of use or nonuse of contraception; (2) the selection of barrier versus hormonal contraception; and (3) within those who selected hormonal contraception, the preference for injectable versus oral hormonal methods. We found that race, age, school status, and type of health insurance were all associated with contraceptive decision-making among female adolescents. Some but not all of these associations remained after the clinic visit, which included no-cost contraception. [ABSTRACT FROM AUTHOR]

A number of epidemiological studies have suggested that diet may affect the etiology of prostate cancer, but few have investigated the impact of phytochemical intakes on this cancer. We conducted a case-control study of diet and prostate cancer in western New York involving 433 men with primary, histologically confirmed prostate cancer and 538 population-based controls, frequency matched to cases on age and county of residence. Diet was assessed with a detailed food-frequency questionnaire. We calculated daily intakes of nutrients and the phytochemicals beta-sitosterol, campesterol, stigmasterol, total phytosterols, total lignan precursors, quercetin, and kaempferol based on published food composition data. Odds ratios (ORs) and 95% confidence intervals (CIs) describing the association of prostate cancer risk with selected nutrients, phytochemicals, and food groups were estimated with unconditional logistic regression. Compared with men in the lowest quartile of intake, reduced risks were observed for men in the highest quartile of intake of vitamin C (OR = 0.49; 95% CI = 0.33-0.74), beta-carotene (OR = 0.53; 95% CI = 0.36-0.79), alpha-carotene (OR = 0.67; 95% CI = 0.47-0.97), lutein (OR = 0.55; 95% CI = 0.37-0.81), lycopene (OR = 0.62; 95% CI = 0.42-0.92), total lignan precursors (OR = 0.66; 95% CI = 0.47-0.94), quercetin (OR = 0.64; 95% CI = 0.44-0.92), and total vegetables (OR = 0.53; 95% CI = 0.36-0.79), but weak increased risks were observed for snacks and sweets (OR = 1.46; 95% CI = 0.95-2.23). Estimates associated with nutrients and phytochemicals were attenuated after adjustment for total vegetable intake. Nevertheless, our results support the hypothesis that a phytochemical-rich, plant-based diet is of importance in reducing risks of hormone-related neoplasms. [ABSTRACT FROM AUTHOR]

Although cigarette smoking is a clear risk factor for lung cancer, the other determinants of lung cancer risk among smokers are less clear. Tea and coffee contain catechins and flavonoids, which have been shown to exhibit anticarcinogenic properties. Conversely, caffeine may elevate cancer risk through a variety of mechanisms. The current study investigated the effects of regular consumption of black tea and coffee on lung cancer risk among 993 current and former smokers with primary incident lung cancer and 986 age-, sex-, and smoking-matched hospital controls with non-neoplastic conditions. Results indicated that lung cancer risk was not different for those with the highest black tea consumption (>or=2 cups/day) compared with nondrinkers of tea [adjusted odds ratio (aOR)=0.90; 95% confidence interval (CI)=0.66-1.24]. However, elevated lung cancer risk was observed for participants who consumed 2-3 cups of regular coffee daily (aOR=1.34; 95% CI=0.99-1.82) or >or=4 cups of regular coffee daily (aOR=1.51, 95% CI=1.11-2.05). In contrast, decaffeinated coffee drinking was associated with decreased lung cancer risk for both participants who consumed or=2 cups/day (aOR=0.64; 95% CI=0.51-0.80). These results suggest that any chemoprotective effects of phytochemicals in coffee and tea may be overshadowed by the elevated risk associated with caffeine in these beverages. [ABSTRACT FROM AUTHOR]

Cruciferous vegetables contain anticarcinogenic isothiocyanates (ITCs), particularly the potent sulforaphane, which may decrease risk of prostate cancer through induction of phase II enzymes, including glutathione S-transferases (GSTs). We evaluated this hypothesis in a population-based, case-control study of prostate cancer, including 428 men with incident prostate cancer and 537 community controls. An in-person interview included an extensive food-frequency questionnaire. Genotyping for deletions in GSTM1 and GSTT1 was performed in a subset of men who provided blood. Intakes of cruciferous vegetables and of broccoli, the greatest source of sulforaphane, were associated with decreased prostate cancer risk at all levels above the lowest consumers [adjusted 4th quartile odds ratio (OR)=0.58; 95% confidence interval (CI)=0.38, 0.89, and 0.72 (95% CI=0.49, 1.06)], respectively. In relation to genotypes, there was a nonsignificant increase in risk with the GSTT1 null genotype (OR=1.51; 95% CI=0.98, 2.31) but no effects of GSTM1 genotype. However, men with GSTM1-present genotype and high broccoli intake had the greatest reduction in risk (OR=0.49; 95% CI=0.27, 0.89). Our findings provide evidence that two or more servings per month of cruciferous vegetables may reduce risk of prostate cancer, especially among men with GSTM1-present alleles, and are consistent with a role of dietary ITCs as chemopreventive agents against prostate cancer. [ABSTRACT FROM AUTHOR]

The etiology of testicular cancer (TC) remains largely unknown. Few studies have investigated the role diet may play in the etiology of TC. We report on a hospital-based case-control study of TC and selected nutrients and food groups. Cases included 117 patients with primary, incident TC treated at Roswell Park Cancer Institute between 1982 and 1998. A total of 334 hospital controls were frequency matched on age to cases. Cases were categorized by histology (seminoma, nonseminoma, and mixed germ cell TC), and multinomial logistic regression and unconditional logistic regression were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) comparing each histological type with the controls. For nonseminoma and mixed germ cell TC, vitamin E intake was suggestive of reduced risk (OR = 0.51, 95% CI = 0.15-1.76 and OR = 0.36, 95% CI = 0.01-1.31, respectively); for seminoma, it was suggestive of an increased risk (OR = 2.94, 95% CI = 0.99-8.78). Fat intakes were not associated with nonseminoma or mixed germ cell risk; high saturated, animal, and total fat intakes were suggestive of an increase in risk of seminoma. Overall, diet was not associated with TC. However, risk seemed to differ by histology, suggesting that seminoma, nonseminoma, and mixed germ cell TC may have different etiologies. We suggest that future investigations should continue to stratify cases by histology. [ABSTRACT FROM AUTHOR]

The Chernobyl nuclear accident on 26th April, 1986, led to a massive release of radionuclides into the environment. Although vast areas of Europe were affected by Chernobyl-related ionising radiation, the accident had the greatest impact in Belarus, Ukraine, and the Russian Federation. Epidemiological studies that have investigated the link between the Chernobyl accident and cancer have largely focused on malignant diseases in children, specifically thyroid cancer and leukaemia. There is good evidence to suggest that rates of thyroid cancer in children from the countries that were formally part of the Soviet Union have risen as a consequence of the Chernobyl accident. The findings for childhood leukaemia are less conclusive. Overall rates for this disease do not seem to have been affected by the Chernobyl-related ionising radiation, but there may be a larger risk of infant leukaemia in contaminated areas of Europe. Among adult populations, there is no strong evidence to suggest that risk of thyroid cancer, leukaemia, or other malignant disease has increased as a result of the Chernobyl accident. [ABSTRACT FROM AUTHOR]

Data from a community-based screening campaign were analyzed to assess compliance with colorectal cancer (CRC) screening guidelines among both average risk adults and those at increased risk because of having a first-degree relative (FDR) with CRC (FDR+). The prevalence of screening compliance was low in both groups. The authors also found that individuals with FDR+ returned a free fecal occult blood test at a slightly higher rate than those without FDR+s. Despite higher screening rates among individuals with FDR+s, interventions may need to target this high-risk group to increase compliance with CRC screening recommendations. [ABSTRACT FROM AUTHOR]

In a hospital-based case-control study, we examined dietary intakes of selected nutrients and food groups and ovarian cancer risk among 496 women with primary, histologically confirmed epithelial ovarian cancer and 1,425 women with nonneoplastic diagnoses, ages 20-87 years, admitted to Roswell Park Cancer Institute between 1982 and 1998. Data on diet and other relevant risk factors in the few years before admission were collected with a self-administered questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression adjusting for age, education, region of residence, regularity of menstruation, family history of ovarian cancer, parity, age at menarche, oral contraceptive use, and energy intake. Women in the highest vs. the lowest quartile of total energy had a weak increase in risk (OR = 1.25, 95% CI = 0.90-1.73). Significantly reduced risks were associated with higher intakes of dietary fiber (OR = 0.57, 95% CI = 0.38-0.87), vitamin A (OR = 0.66, 95% CI = 0.45-0.98), carotenoid (OR = 0.64, 95% CI = 0.43-0.93), vitamin E (OR = 0.58, 95% CI = 0.38-0.88), beta-carotene (OR = 0.68, 95% CI = 0.46-0.98), and total fruit and vegetable intake (OR = 0.62, 95% CI = 0.42-0.92). Our findings suggest that a diet high in plant foods may be important in reducing risk of ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: The American Cancer Society recommends physicians inform average risk women about endometrial cancer (EC) risk on reaching menopause, but new diagnoses are rising fastest in women <50 years. Educating these women about EC risks requires knowledge of risk factors. However, EC in young women is rare and challenging to study in single study populations., Methods: We included 13,846 incident EC patients (1,639 < 50 years) and 30,569 matched control individuals from the Epidemiology of Endometrial Cancer Consortium. We used generalized linear models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 6 risk factors and EC risk. We created a risk score to evaluate the combined associations and population attributable fractions of these factors., Results: In younger and older women, we observed positive associations with BMI and diabetes, and inverse associations with age at menarche, oral contraceptive use, and parity. Current smoking was associated with reduced risk only in women ≥50 years (PHet<0.01). BMI was the strongest risk factor [OR≥35 vs <25 kg/m2=5.57 (95% CI:4.33-7.16) for <50 years; OR≥35 vs <25 kg/m2=4.68 (95% CI : 4.30-5.09) for ≥50 years; PHet=0.14]. Possessing ≥4 risk factors was associated with ∼9-fold increased risk in women <50 years and ∼4-fold increased risk in women ≥50 years (PHet<0.01). Together, 59.1% of ECs in women <50 and 55.6% in women ≥50 were attributable to these factors., Conclusions: Our data confirm younger and older women share common EC risk factors. Early educational efforts centered on these factors may help mitigate the rising EC burden in young women., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: There is compelling evidence that CD4 + and CD8 + T cells are dysfunctional in multiple myeloma, compromising their ability to control disease progression. Pre-clinical models suggest that exercise represents a non-pharmacologic means to reduce immune exhaustion, but no studies to date have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in multiple myeloma patients., Patients and Methods: The current study includes 24 multiple myeloma patients who participated in a six-month physical activity intervention, consisting of supervised strength training (n = 12) and unsupervised home-based walking arms (n = 12). Comprehensive flow cytometry was utilized to assess the frequency of CD4 + and CD8 + T cells and subpopulations expressing the markers of exhaustion PD-1, TIGIT, TIM3 and/or LAG3. Ratios of exhausted to non-exhausted cell populations, and percentages of exhausted to total populations of the same lineage, were calculated for the baseline and final timepoints., Results: Eighteen of 20 exhaustion measures were lower at the end of the intervention than at baseline, and several were significantly or borderline significantly reduced in the entire sample or in one of the arms. The entire sample saw improvements in the ratios of CD4 + TIGIT + to non-exhausted CD4 + (0.7 [0.6] to 0.6 [0.4], P = .04) and CD8 + PD1 + to non-exhausted CD8 + (1.8 [2.6] to 1.5 [2.0], P = .06), and in total exhausted CD8 + as a percent of total CD8 + (72.9 [21.9] to 68.3 [19.6], P < .01)., Conclusions: This pilot study suggests that physical activity induces changes in MM patients' immune systems, potentially rendering a less exhausted T cell state., Competing Interests: Disclosure JH serves on the advisory boards of Adaptive, Amgen, Angitia, Axxess Networks, Bristol Myers Squibb, GlaxoSmithKline, Janssen Biotech, Oncopeptides, ONCOtracker, Prothena, Sanofi, and Skyline; has given talks at Amgen, BeiGene, Beijing Medical Award Foundation, Curio Science, and Janssen Biotech; and serves on the data and safety monitoring board of Janssen Biotech. JMJ, JDT, AG, KBM, MH, HJ, BW, HM, PKW, KA, RC, and SA declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10 -8 ) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10 -5 ). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors., Methods: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors., Results: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy., Conclusions: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association., Impact: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10 -8 ). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC., (© 2024. The Author(s).)

Abstract: Monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma, is associated with shorter lifespan and cardiac, renal, neurologic, and immune-related comorbidities. There is little known about modifiable risk factors for this condition. To determine whether the risk of MGUS is associated with dietary factors in a racially diverse population, we conducted a US population-based case-control study from the National Health and Nutrition Examination Survey (1988-2004), which included 373 individuals with MGUS and 1406 matched controls. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. Unconditional multivariable logistic regressions were used to model associations between intake of several food groups and MGUS, with odds ratios (ORs) and 95% confidence intervals (CIs) reported for the highest relative to the lowest quantile of intake. Daily gram intake of several food and beverage groups were significantly associated with MGUS. MGUS was inversely associated with whole-grain bread, oats, and rice (OR, 0.70; 95% CI, 0.48-1.00; P < .05), fruits (excluding juice) and vegetables (OR, 0.69; 95% CI, 0.52-0.93; P = .02), vegetables (OR, 0.75; 95% CI, 0.56-0.99; P < .05), tomatoes (OR, 0.72; 95% CI, 0.51-1.00; P < .05), and cruciferous vegetables (OR, 0.44; 95% CI, 0.26-0.74; P < .01). Direct associations were observed for sugar-sweetened beverages (OR, 1.34; 95% CI, 1.00-1.78; P < .05), sugar-sweetened soft drinks (OR, 1.41; 95% CI, 1.01-1.96; P = .04), and artificially sweetened soft drinks (OR, 1.55; 95% CI, 1.04-2.33; P = .03). Our study shows that diet is potentially a modifiable risk factor for MGUS., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC., Methods: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source., Results: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes., Conclusions: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors., Methods: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial., Results: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59)., Conclusions: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations., (© The Author(s) 2023. Published by Oxford University Press.)

Importance: Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups., Objective: To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer., Design, Setting, and Participants: We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022., Exposures: Frequent aspirin use, defined as daily or almost daily use for 6 months or longer., Main Outcomes and Measures: The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS., Results: There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype., Conclusions and Relevance: The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.

Pancreatic cancer (PanCa) is a highly fatal malignancy with few modifiable risk and prognostic factors. This study investigates the association between cola, diet cola, and non-cola soft drink consumption and PanCa risk and mortality. A retrospective study was conducted using data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA), including 213 PanCa patients and 852 cancer-free controls. Data were collected using a self-administered questionnaire, including a 46-item food frequency questionnaire (FFQ). Multivariable logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) of cola, diet cola, and non-cola soft drink consumption and PanCa risk. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs of cola, diet cola, and non-cola soft drink consumption and PanCa mortality. Stratified analyses were conducted by sex, body mass index (BMI), and smoking status. We observed significant 55% increased odds of PanCa among patients consuming ≥1 regular cola per day (OR: 1.55, 95% CI: 1.01-2.39). We also observed non-significant 38% increased hazard of mortality among patients consuming ≥1 regular cola per day (HR: 1.38, 95% CI: 0.91-2.07). We conclude that regular cola consumption is a modifiable lifestyle that may be associated with PanCa risk and mortality following diagnosis.

Purpose: Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors., Methods: Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2)., Results: Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design ( P = .48) or histotype ( P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P -heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90)., Conclusion: This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort., Methods: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types., Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types., Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis., Design: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium., Setting: Population-based., Patient(s): We included 8,500 women with ovarian cancer, 13,592 control women., Intervention(s): Ten well-established ovarian cancer risk factors., Main Outcome Measure(s): Risk of ovarian cancer for women with and without endometriosis., Result(s): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m 2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m 2 ; an increased risk was observed for a BMI ≥30 kg/m 2 , although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively)., Conclusion(s): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs., (© 2021. The Author(s).)

Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects., Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data., Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54)., Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival., Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer., (©2021 American Association for Cancer Research.)