Demographic, Clinical, and Behavioral Factors Associated With Electronic Nicotine Delivery Systems Use in a Large Cohort in the United States.

Introduction: Our primary purpose is to understand comorbidities and health outcomes associated with electronic nicotine delivery systems (ENDS) use. Methods: Study participants were Kaiser Permanente (KP) members from eight US regions who joined the Kaiser Permanente Research Bank (KPRB) from September 2015 through December 2019 and completed a questionnaire assessing demographic and behavioral factors, including ENDS and traditional cigarette use. Medical history and health outcomes were obtained from electronic health records. We used multinomial logistic regression to estimate odd ratios (ORs) and 95% confidence intervals (CIs) of current and former ENDS use according to member characteristics, behavioral factors, and clinical history. We used Cox regression to estimate hazard ratios (HRs) and 95% CIs comparing risk of health outcomes according to ENDS use. Results: Of 119 593 participants, 1594 (1%) reported current ENDS use and 5603 (5%) reported past ENDS use. ENDS users were more likely to be younger, male, gay or lesbian, and American Indian / Alaskan Native or Asian. After adjustment for confounding, current ENDS use was associated with current traditional cigarette use (OR = 39.55; CI:33.44-46.77), current marijuana use (OR = 6.72; CI:5.61-8.05), history of lung cancer (OR = 2.64; CI:1.42-4.92), non-stroke cerebral vascular disease (OR = 1.55; CI:1.21-1.99), and chronic obstructive pulmonary disease (OR = 2.16; CI:1.77-2.63). Current ENDS use was also associated with increased risk of emergency room (ER) visits (HR = 1.17; CI: 1.05-1.30) and death (HR = 1.84; CI:1.02-3.32). Conclusions: Concurrent traditional cigarette use, marijuana use, and comorbidities were prevalent among those who used ENDS, and current ENDS use was associated with an increased risk of ER visits and death. Additional research focused on health risks associated with concurrent ENDS and traditional cigarette use in those with underlying comorbidities is needed.

Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries.

The chr12q24.13 locus encoding OAS1-OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

Retrospective assessment of barriers and access to genetic services for hereditary cancer syndromes in an integrated health care delivery system.

BACKGROUND: A critical step in access to genetic testing for hereditary cancer syndromes is referral for genetic counseling to assess personal and family risk. Individuals meeting testing guidelines have the greatest need to be evaluated. However, referrals to genetics are underutilized in US patients with hereditary cancer syndromes, especially within traditionally underserved populations, including racial and ethnic minorities, low-income, and non-English speaking patients. METHODS: We studied existing processes for referral to genetic evaluation and testing for hereditary cancer risk to identify areas of potential improvement in delivering these services, especially for traditionally underserved patients. We conducted a retrospective review of 820 referrals to the Kaiser Permanente Northwest (KPNW) genetics department containing diagnosis codes for hereditary cancer risk. We classified referrals as high- or low-quality based on whether sufficient information was provided to determine if patients met national practice guidelines for testing. Through chart abstraction, we also assessed consistency with practice guidelines, whether the referral resulted in a visit to the genetics department for evaluation, and clinical characteristics of patients receiving genetic testing. RESULTS: Most referrals (n = 514, 63%) contained sufficient information to assess the appropriateness of referral; of those, 92% met practice guidelines for genetic testing. Half of referred patients (50%) were not offered genetic evaluation; only 31% received genetic testing. We identified several barriers to receiving genetic evaluation and testing, the biggest barrier being completion of a family history form sent to patients following the referral. Those with a referral consistent with testing guidelines, were more likely to receive genetic testing than those without (39% vs. 29%, respectively; p = 0.0058). Traditionally underserved patients were underrepresented in those receiving genetic evaluation and testing relative to the overall adult KPNW population. CONCLUSIONS: Process improvements are needed to increase access to genetic services to diagnose hereditary cancer syndromes prior to development of cancer.

Molecular markers of risk of subsequent invasive breast cancer in women with ductal carcinoma in situ: protocol for a population-based cohort study.

INTRODUCTION: Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of invasive breast cancer (IBC). Many DCIS patients are either undertreated or overtreated. The overarching goal of the study described here is to facilitate detection of patients with DCIS at risk of IBC development. Here, we propose to use risk factor data and formalin-fixed paraffin-embedded (FFPE) DCIS tissue from a large, ethnically diverse, population-based cohort of 8175 women with a first diagnosis of DCIS and followed for subsequent IBC to: identify/validate miRNA expression changes in DCIS tissue associated with risk of subsequent IBC; evaluate ipsilateral IBC risk in association with two previously identified marker sets (triple immunopositivity for p16, COX-2, Ki67; Oncotype DX Breast DCIS score); examine the association of risk factor data with IBC risk. METHODS AND ANALYSIS: We are conducting a series of case-control studies nested within the cohort. Cases are women with DCIS who developed subsequent IBC; controls (2/case) are matched to cases on calendar year of and age at DCIS diagnosis. We project 485 cases/970 controls in the aim focused on risk factors. We estimate obtaining FFPE tissue for 320 cases/640 controls for the aim focused on miRNAs; of these, 173 cases/346 controls will be included in the aim focused on p16, COX-2 and Ki67 immunopositivity, and of the latter, 156 case-control pairs will be included in the aim focused on the Oncotype DX Breast DCIS score®. Multivariate conditional logistic regression will be used for statistical analyses. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Boards of Albert Einstein College of Medicine (IRB 2014-3611), Kaiser Permanente Colorado, Kaiser Permanente Hawaii, Henry Ford Health System, Mayo Clinic, Marshfield Clinic Research Institute and Hackensack Meridian Health, and from Lifespan Research Protection Office. The study results will be presented at meetings and published in peer-reviewed journals.

Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1 . We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

Financial burden and quality of life among early-onset colorectal cancer survivors: A qualitative analysis.

BACKGROUND: Colorectal cancer (CRC) diagnosed at ages <50 years old (early-onset CRC) has been increasing in the United States, resulting in a growing number of early-onset CRC survivors who may face significant financial and quality of life (QOL) challenges. OBJECTIVE: Identify themes from a patient advocate discussion about the impact of CRC on financial burden and QOL among early-onset CRC survivors. METHODS: We conducted a semi-structured, stakeholder discussion among 14 early-onset CRC survivors and one caregiver who were members of an advocacy group. The discussion focused on the financial and overall QOL impacts of CRC. The meeting was recorded, transcribed and coded in ATLAS.ti, using a thematic analysis approach. RESULTS: Cancer stage at diagnosis among advocates with CRC ranged from 2 to 4; about half of the attendees had no evidence of disease, and about half were undergoing treatment. Employment (career trajectory, lost wages, health insurance/benefits, performance) emerged as the dominant theme of the financial impacts discussion. Lifestyle impacts of disease and survivorship included both emotional and physical side-effects. Diagnosis experience, missing information about CRC treatment and side-effects, financial stress and strain on relationships were the primary themes for the overall QOL impacts. CONCLUSION: Given the growing incidence of CRC in those under 50, it is particularly important for providers to be aware of these patients' financial, emotional and QOL needs, and to develop care plans that specifically address these areas of concern for early-onset CRC survivors.

Melanoma incidence, recurrence, and mortality in an integrated healthcare system: A retrospective cohort study.

BACKGROUND: Numerous studies have examined melanoma incidence and survival, but studies on melanoma recurrence are limited. We examined melanoma incidence, recurrence, and mortality among members of Kaiser Permanente Colorado (KPCO) between January 1, 2000 and December 31, 2015. METHODS: Age-adjusted incidence rates were computed to examine trends among KPCO members aged 21 years and older. Cox proportional hazards models were used to examine factors associated with recurrence and mortality. RESULTS: Our cohort included 1931 cases of invasive melanoma. Incidence rates increased over time and were higher than SEER rates; however, the increase was limited to early stage disease. In multivariable models, stage at initial diagnosis, gender, and age were associated with melanoma recurrence. Men were more likely to have a recurrence than women (adjusted hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.19-2.43), and for each decade of increasing age, the adjusted HR = 1.20 (95% CI: 1.06-1.37). Factors associated with all-cause mortality included stage (HR = 12.87, 95% CI: 6.63-24.99, for stage IV vs stage I), male gender (HR = 1.42, 95% CI: 1.12-1.79), older age at diagnosis, lower socioeconomic status, and comorbidity index. For melanoma-specific mortality, results were similar, with one exception: age was not associated with melanoma-specific death (HR = 1.09, 95% CI: 0.94-1.25, P = 0.253). CONCLUSIONS: Data derived from an insured patient population, such as KPCO, have the potential to enhance our understanding of emerging trends in melanoma. This is the first population-based study in the United States to examine patient characteristics associated with risk of recurrence. Men have an increased risk of both recurrence and death, and thus may benefit from more intensive follow-up than women.

Developing an Algorithm to Identify History of Cancer Using Electronic Medical Records.

INTRODUCTION/OBJECTIVE: The objective of this study was to develop an algorithm to identify Kaiser Permanente Colorado (KPCO) members with a history of cancer. BACKGROUND: Tumor registries are used with high precision to identify incident cancer, but are not designed to capture prevalent cancer within a population. We sought to identify a cohort of adults with no history of cancer, and thus, we could not rely solely on the tumor registry. METHODS: We included all KPCO members between the ages of 40-75 years who were continuously enrolled during 2013 (N=201,787). Data from the tumor registry, chemotherapy files, inpatient and outpatient claims were used to create an algorithm to identify members with a high likelihood of cancer. We validated the algorithm using chart review and calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for occurrence of cancer. FINDINGS: The final version of the algorithm achieved a sensitivity of 100 percent and specificity of 84.6 percent for identifying cancer. If we relied on the tumor registry alone, 47 percent of those with a history of cancer would have been missed. DISCUSSION: Using the tumor registry alone to identify a cohort of patients with prior cancer is not sufficient. In the final version of the algorithm, the sensitivity and PPV were improved when a diagnosis code for cancer was required to accompany oncology visits or chemotherapy administration. CONCLUSION: Electronic medical record (EMR) data can be used effectively in combination with data from the tumor registry to identify health plan members with a history of cancer.

Identification of Stevens-Johnson syndrome and toxic epidermal necrolysis in electronic health record databases.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) carry a high mortality risk. While identifying clinical and genetic risk factors for these conditions has been hindered by their rarity, large electronic health databases hold promise for identifying large numbers of cases for study, especially with the introduction in 2008 of ICD-9 codes more specific for these conditions. OBJECTIVE: The objective of this study is to estimate the validity of ICD-9 codes for ascertaining SJS/TEN in 12 collaborating research units in the USA, covering almost 60 million lives. METHODS: From the electronic databases at each site, we ascertained potential cases of SJS/TEN using ICD-9 codes. At five sites, a subset of medical records was abstracted and standardized criteria applied by board-certified dermatologists to adjudicate diagnoses. Multivariate logistic regression was used to identify factors independently associated with validated SJS/TEN cases. RESULTS: A total of 56 591 potential cases of SJS/TEN were identified. A subset of 276 charts was selected for adjudication and 39 (of the 276) were confirmed as SJS/TEN. Patients with the ICD-9 codes introduced after 2008 were more likely to be confirmed as cases (OR 3.32; 95%CI 0.82, 13.47) than those identified in earlier years. Likelihood of case status increased with length of hospitalization. Applying the probability of case status to the 56 591 potential cases, we estimated 475-875 to be valid SJS/TEN cases. CONCLUSION: Newer ICD-9 codes, along with length of hospitalization, identified patients with a high likelihood of SJS/TEN. This is important for identification of subjects for future pharmacogenomics studies.

Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Variability in reexcision following breast conservation surgery.

CONTEXT: Health care reform calls for increasing physician accountability and transparency of outcomes. Partial mastectomy is the most commonly performed procedure for invasive breast cancer and often requires reexcision. Variability in reexcision might be reflective of the quality of care. OBJECTIVE: To assess hospital and surgeon-specific variation in reexcision rates following partial mastectomy. DESIGN, SETTING, AND PATIENTS: An observational study of breast surgery performed between 2003 and 2008 intended to evaluate variability in breast cancer surgical care outcomes and evaluate potential quality measures of breast cancer surgery. Women with invasive breast cancer undergoing partial mastectomy from 4 institutions were studied (1 university hospital [University of Vermont] and 3 large health plans [Kaiser Permanente Colorado, Group Health, and Marshfield Clinic]). Data were obtained from electronic medical records and chart abstraction of surgical, pathology, radiology, and outpatient records, including detailed surgical margin status. Logistic regression including surgeon-level random effects was used to identify predictors of reexcision. MAIN OUTCOME MEASURE: Incidence of reexcision. RESULTS: A total of 2206 women with 2220 invasive breast cancers underwent partial mastectomy and 509 patients (22.9%; 95% CI, 21.2%-24.7%) underwent reexcision (454 patients [89.2%; 95% CI, 86.5%-91.9%] had 1 reexcision, 48 [9.4%; 95% CI, 6.9%-12.0%] had 2 reexcisions, and 7 [1.4%; 95% CI, 0.4%-2.4%] had 3 reexcisions). Among all patients undergoing initial partial mastectomy, total mastectomy was performed in 190 patients (8.5%; 95% CI, 7.2%-9.5%). Reexcision rates for margin status following initial surgery were 85.9% (95% CI, 82.0%-89.8%) for initial positive margins, 47.9% (95% CI, 42.0%-53.9%) for less than 1.0 mm margins, 20.2% (95% CI, 15.3%-25.0%) for 1.0 to 1.9 mm margins, and 6.3% (95% CI, 3.2%-9.3%) for 2.0 to 2.9 mm margins. For patients with negative margins, reexcision rates varied widely among surgeons (range, 0%-70%; P = .003) and institutions (range, 1.7%-20.9%; P < .001). Reexcision rates were not associated with surgeon procedure volume after adjusting for case mix (P = .92). CONCLUSION: Substantial surgeon and institutional variation were observed in reexcision following partial mastectomy in women with invasive breast cancer.

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

Menstrual cycle variability and the likelihood of achieving pregnancy.

The menstrual cycle is an important indicator of underlying hormonal function. Although menstrual cycle variability (sometimes referred to as 'regularity') is associated with a variety of demographic, behavioral, occupational, and environmental factors, as well as with several chronic diseases, few studies have examined its association with fecundity. We investigated whether a woman's menstrual cycle variability was associated with the likelihood of her achieving pregnancy. In this prospective study, we analyzed 3,536 menstrual cycles from 401 women (aged 19-41) recruited from 1990-1994. The women provided daily diaries recording menstrual bleeding, intercourse, and birth control use. Urine samples were assayed for human chorionic gonadotropin to identify early pregnancies during each menstrual cycle. Each woman's menstrual cycle variability was defined by the standard deviation of her cycle lengths during followup. The median follow-up was eight cycles. The outcome was her per-cycle probability of pregnancy. We found that women with high menstrual cycle variability had a reduced (51% lower) per cycle probability of pregnancy (fecundity ratio: 0.49; 95% confidence interval: 0.31, 0.77) compared with women with minimal variability. This relationship was independent of a woman's age and her mean cycle length. Thus, researchers and clinicians using menstrual cycle characteristics as indicators of endocrine or reproductive health should include measures of cycle variability in addition to the more commonly examined cycle length.

Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.

BACKGROUND: Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis. METHODS: We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (>or=T3b, N1, or M1) and high-grade (Gleason sum >or=8) prostate cancer, respectively. RESULTS: The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer. CONCLUSION: In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P < 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer.

Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence.

The interconversion of folates by the one-carbon metabolism pathway is essential for the synthesis of precursors used in DNA synthesis, repair, and methylation. Perturbations in this pathway can disrupt these processes and are hypothesized to facilitate carcinogenesis. We investigated associations of 25 candidate polymorphisms in nine one-carbon metabolism genes with risk of postmenopausal breast cancer using 502 cases and 505 controls from the Cancer Prevention II Nutrition Cohort. Four single nucleotide polymorphisms (SNP) in three different genes were significantly associated with breast cancer. The nonsynonymous R134K SNP in methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthase [MTHFD1; odds ratio (OR), 1.40; 95% confidence interval (95% CI), 1.06-1.85 for CT + TT] and an intronic SNP in formyltetrahydrofolate dehydrogenase (FTHFD; OR, 2.23; 95% CI, 1.09-4.54 for CC) were associated with a significant increase in risk. Significantly decreased risk was associated with an intronic SNP in FTHFD (OR, 0.75; 95% CI, 0.58-0.98 for CT + CC) and the A360A SNP in cystathionine beta-synthase (CBS; OR, 0.63; 95% CI, 0.41-0.96 for TT). The presence of at least one variant from both the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C SNPs was also associated with increased risk (OR, 2.16; 95% CI, 1.34-3.48 for 677 CT + TT/1,298 AC + CC). Investigations into interactions of the associated SNPs with each other and with dietary factors yielded inconclusive results. Our findings indicate that genetic variation in multiple one-carbon metabolism genes may influence risk of postmenopausal breast cancer and may involve changes in methyl donor synthesis. However, larger studies are needed to further examine gene/gene and gene/diet interactions in this pathway.

Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study.

INTRODUCTION: Vitamin D receptor (VDR) polymorphisms have been inconsistently associated with breast cancer risk. Whether risk is influenced by polymorphisms in other vitamin D metabolism genes and whether calcium or vitamin D intake modifies risk by genotype have not been evaluated. METHODS: We conducted a nested case-control study within the Cancer Prevention Study II Nutrition Cohort of associations between breast cancer and four VDR single-nucleotide polymorphisms (SNPs), Bsm1,Apa1,Taq1, and Fok1, a poly(A) microsatellite, and associated haplotypes (baTL and BAtS). We also examined one SNP in the 24-hydroxylase gene (CYP24A1) and two in the vitamin D-binding protein (group-specific component [GC]) gene. Participants completed a questionnaire on diet and medical history at baseline in 1992. This study includes 500 postmenopausal breast cancer cases and 500 controls matched by age, race/ethnicity, and date of blood collection. RESULTS: Incident breast cancer was not associated with any genotype examined. However, women with the Bsm1 bb SNP who consumed greater than the median intake of total calcium (> or = 902 mg/day) had lower odds of breast cancer compared to women with the Bb or BB genotype and less than the median calcium intake (odds ratio 0.61, 95% confidence interval 0.38 to 0.96; p(interaction) = 0.01). Similar interactions were observed for Taq1 (T allele) and the poly(A) (LL) repeat. CONCLUSION: We found no overall association between selected vitamin D pathway genes and postmenopausal breast cancer risk. However, certain VDR gene polymorphisms were associated with lower risk in women consuming high levels of calcium, suggesting that dietary factors may modify associations by VDR genotype.

Menstrual cycle characteristics: associations with fertility and spontaneous abortion.

BACKGROUND: Epidemiologists often use menstrual cycle patterns as indicators of endocrine function in environmental and occupational studies, yet few studies have considered whether menstrual cycle characteristics are associated with fertility or pregnancy outcome. METHODS: We prospectively studied 470 women to determine whether cycle length or bleed length were associated with fertility or spontaneous abortion. Women completed daily diaries with information on menstrual bleeding, intercourse, birth control use, and covariates. For each menstrual cycle, women collected at least 2 urine samples, which were assayed for human chorionic gonadotropin to define early pregnancies. Women were followed for 1 year or until the end of a clinical pregnancy. RESULTS: Cycles with lengths of 30 to 31 days preceded cycles with the highest fecundity. Shorter cycles were less likely to be followed by conception (fecundity ratio [FR] = 0.6; 95% confidence interval [CI] = 0.4-1.0). Compared with 30- to 31-day cycles, conceptions after shorter and longer cycles were more likely to be spontaneously aborted (for shorter cycles, odds ratio [OR] = 3.0 [95% CI = 0.9-9.6] and for longer cycles, OR = 3.0 [0.9-10.6]). Cycles with 5 days of menstrual bleeding had the highest fecundity. Cycles with up to 4 days of bleeding had lower fecundity (for bleed lengths of 4 days, FR = 0.5 [0.3-0.8] and for bleed lengths less than 4 days, FR = 0.6 [0.3-0.9]). Spontaneous abortion was less likely after bleeds greater than 5 days (OR = 0.4 [0.1-1.1]) when compared with 5-day bleeds. CONCLUSIONS: Menstrual cycle characteristics appear to be associated with fertility and spontaneous abortion.

Genetic variation in the HSD17B1 gene and risk of prostate cancer.

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.

Aspirin and other nonsteroidal anti-inflammatory drugs and breast cancer incidence in a large U.S. cohort.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, has consistently been associated with reduced risk of breast cancer in case-control studies. However, results from prospective studies have been less consistent. We examined the association between NSAID use and breast cancer incidence, adjusting for multiple breast cancer risk factors among 77,413 women in the Cancer Prevention Study II Nutrition Cohort. During follow-up from 1992 to 2001, we observed 3,008 cases of incident breast cancer. Information on NSAID use was obtained from a questionnaire completed at enrollment in 1992 or 1993 and was updated using follow-up questionnaires in 1997 and 1999. NSAID use was modeled using time-dependent variables to update exposure status. Neither current total NSAID use (aspirin and other NSAIDs combined) nor current aspirin use were associated with breast cancer incidence even at relatively high levels of use [rate ratio (RR), 1.07; 95% confidence interval (95% CI), 0.96-1.21 for > or =60 NSAID pills per month compared with no reported use of NSAIDs; RR, 1.01; 95% CI, 0.84-1.20 for > or =60 aspirin per month compared with no reported use of aspirin]. Even long-duration regular use (> or =30 pills per month for > or =5 years) was not associated with breast cancer incidence (RR, 1.05; 95% CI, 0.88-1.26 for total NSAIDs; RR, 0.88; 95% CI, 0.69-1.12 for aspirin). Although we cannot exclude a small reduction in breast cancer risk associated with NSAID use, the results of this study provide evidence against a large reduction in risk.

The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics.

BACKGROUND: Large-scale, prospective cohort studies have played a critical role in discovering factors that contribute to variability in cancer risk in human populations. Epidemiologists and volunteers at the American Cancer Society (ACS) were among the first to establish such cohorts, beginning in the early 1950s and continuing through the present, and these ACS cohorts have made landmark contributions in many areas of epidemiologic research. METHODS AND RESULTS: The Cancer Prevention Study II Nutrition Cohort was established in 1992 and was designed to investigate the relation between diet and other lifestyle factors and exposures and the risk of cancer, mortality, and survival. The cohort includes over 84,000 men and 97,000 women who completed a mailed questionnaire in 1992. New questionnaires are sent to surviving cohort members every other year to update exposure information and to ascertain new occurrences of cancer; a 90% response rate was achieved for follow-up questionnaires in 1997 and 1999. Reported cancers are verified through medical records, registry linkage, or death certificates. The cohort is followed actively for all cases of incident cancer and for all causes of death. Through a collaborative effort among ACS national and division staff, volunteers, and the American College of Surgeons, blood samples were collected from a subgroup of 40,000 cohort members and are in storage at a central repository for future investigation of dietary, hormonal, genetic, and other factors and cancer risk. Collection of DNA samples from buccal cells in an additional 50,000 cohort members is underway currently and will be completed in 2002. CONCLUSIONS: This new cohort of both men and women promises to be particularly valuable for the study of cancer occurrence, mortality, and survival as they relate to obesity and weight change, physical activity at various points in life, vitamin supplement use, exogenous hormone use, other medications (such as aspirin and nonsteroidal anti- inflammatory drugs) and cancer screening modalities.