Lauren R. Teras

Weight Gain, Body Mass Index, Hormone Replacement Therapy, and Postmenopausal Breast Cancer in a Large Prospective Study

Excess adiposity and hormone replacement therapy (HRT) are important contributors to postmenopausal breast cancer risk. HRT has been shown to modify the association between body weight and breast cancer risk, although few studies are sufficiently large to examine the risk of breast cancer associated with body mass index (BMI) and weight gain separately among current HRT users and nonusers. This study includes 1,934 incident breast cancer cases occurring among 62,756 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort. Age-adjusted incidence rates were calculated, and Cox proportional hazards models were used to examine the association of BMI and adult weight gain (since age 18 years) with breast cancer risk stratified by HRT use. Total adult weight gain strongly predicted breast cancer risk among former and never HRT users (P for trend < 0.0001). Weight gain of 21–30 pounds was associated with a rate ratio of 1.4 (95% confidence interval 1.1–1.8); rates doubled among women gaining >70 pounds compared with women who maintained their weight within 5 pounds of their weight at age 18. After accounting for weight gain, neither recent BMI nor BMI at age 18 were independent predictors of risk. Among current HRT users, no association was seen between breast cancer and either BMI or weight gain. Adult weight gain is strongly associated with postmenopausal breast cancer only among non-HRT users in this study. These data illustrate the importance of examining breast cancer risk factors separately by HRT use; the effects of other risk factors may be attenuated or obscured among women taking HRT.

2016 US lymphoid malignancy statistics by World Health Organization subtypes.

Collectively, lymphoid neoplasms are the fourth most common cancer and the sixth leading cause of cancer death in the United States. The authors provide contemporary lymphoid neoplasm statistics by subtype based on the 2008 World Health Organization classifications, including the most current US incidence and survival data. Presented for the first time are estimates of the total numbers of US lymphoid neoplasm cases by subtype as well as a detailed evaluation of incidence and survival statistics. In 2016, 136,960 new lymphoid neoplasms are expected. Overall lymphoma incidence rates have declined in recent years, but trends vary by subtype. Precursor lymphoid neoplasm incidence rates increased from 2001 to 2012, particularly for B‐cell neoplasms. Among the mature lymphoid neoplasms, the fastest increase was for plasma cell neoplasms. Rates also increased for mantle cell lymphoma (males), marginal zone lymphoma, hairy cell leukemia, and mycosis fungoides. Like incidence, survival for both mature T‐cell lymphomas and mature B‐cell lymphomas varied by subtype and by race. Patients with peripheral T‐cell lymphomas had among the worst 5‐year relative survival (36%‐56%, depending on race/sex), while those with mycosis fungoides had among the best survival (79%‐92%). For B‐cell lymphomas, 5‐year survival ranged from 83% to 91% for patients with marginal zone lymphoma and from 78% to 92% for those with hairy cell leukemia; but the rates were as low as 47% to 63% for patients with Burkitt lymphoma and 44% to 48% for those with plasma cell neoplasms. In general, black men had the lowest survival across lymphoid malignancy subtypes. These contemporary incidence and survival statistics are useful for developing management strategies for these cancers and can offer clues regarding their etiology. CA Cancer J Clin 2016;66:443–459.

Adult weight gain and histopathologic characteristics of breast cancer among postmenopausal women

Although the link between postmenopausal breast cancer and adiposity is well established, the association between weight gain and specific histopathologic characteristics of breast carcinoma has not been studied carefully.

Weight Cycling and Mortality in a Large Prospective US Study

Weight cycling has been associated with an increased risk of death in some studies, but few studies differentiated weight cycling initiated by intentional weight loss from that initiated by illness. The association of weight cycling with death was examined among 55,983 men and 66,655 women in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2008. A weight cycle was defined as an intentional loss of 10 or more pounds (≥4.5 kg) followed by regain of that weight, and the lifetime number of weight cycles was reported on a questionnaire administered at enrollment in 1992. A total of 15,138 men and 10,087 women died during follow-up, which ended in 2008. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression models. When the models were adjusted for age only, weight cycling was positively associated with mortality (P for trend < 0.0001). However, after adjustment for body mass index and other risk factors, low numbers of weight cycles (1-4 cycles) were associated with slightly lower mortality rates (hazard ratio (HR) = 0.93, 95% confidence interval (CI): 0.89, 0.97 in men and HR = 0.93, 95% CI: 0.89, 0.98 in women), whereas high numbers of weight cycles (≥20 cycles) were not associated with mortality (HR = 1.03, 95% CI: 0.89, 1.19 in men and HR = 0.99, 95% CI: 0.88, 1.12 in women). These results do not support an increased risk of mortality associated with weight cycling.

No Association between Polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, or ADIPOR2 and Postmenopausal Breast Cancer Risk

There is evidence that adipokines such as leptin and adiponectin may influence breast tumor development. We conducted a nested case-control study using women in the American Cancer Society Cancer Prevention Study II to examine the association between postmenopausal breast cancer and variability in the genes encoding leptin, the leptin receptor, adiponectin, adiponectin receptor 1, and adiponectin receptor 2. Using 648 cases and 659 controls, we found no statistically significant (P < 0.05) associations between breast cancer risk and any of the single nucleotide polymorphisms. Individual odds ratios ranged from 0.93 to 1.06. We found no evidence of effect modification by body mass index, adult weight gain, location of weight gain, or physical activity. Although we cannot rule out that these genes are involved in gene-gene or gene-environment interactions, our results suggest that individual single nucleotide polymorphisms in these genes do not substantially affect postmenopausal breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2553–7)

Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype.

Data from large prospective studies are needed to fully characterize the impact of exogenous hormones on breast cancer incidence by type of hormone preparation and histology of the cancer.

Improved imputation of common and uncommon SNPs with a new reference set

6 volume 44 | number 1 | january 2012 | nature genetics Statistical imputation of genotype data is an important statistical technique that uses patterns of linkage disequilibrium observed in a reference set of haplotypes to computationally predict genetic variants in silico1. Currently, the most popular reference sets are the publicly available International HapMap2 and 1000 Genomes data sets3. Although these resources are valuable for imputing a sizeable fraction of common SNPs, they may not be optimal for imputing data for the next generation of genome-wide association studies (GWAS) and SNP arrays, which explore a fraction of uncommon variants. We have built a new resource for the imputation of SNPs for existing and future GWAS, known as the Division of Cancer Epidemiology and Genetics (DCEG) Reference Set. The data set has genotypes for cancer-free individuals, including 728 of European ancestry from three large prospectively sampled studies4–6, 98 AfricanAmerican individuals from the Prostate, Lung, Colon and Ovary Cancer Screening Trial (PLCO), 74 Chinese individuals from a clinical trial in Shanxi, China (SHNX)7 and 349 individuals from the HapMap Project (Table 1). The final harmonized data set includes 2.8 million autosomal polymorphic SNPs for 1,249 individuals after rigorous quality control metrics were applied (see Supplementary Methods and Supplementary Tables 1 and 2). We compared the imputation performance of the DCEG Reference Set to that of the International HapMap and 1000 Genomes reference sets, which are available from the IMPUTE2 website (see URLs). We assessed imputation accuracy by taking directly genotyped SNP data from the DCEG Reference Set and masking subsets to simulate data from two low-cost commercial genotyping arrays commonly used in GWAS studies (Illumina Human Hap660 and Human OmniExpress). Probabilistic genotypes were imputed using both IMPUTE2 (ref. 8) and BEAGLE9 software and compared with the masked genotyped SNPs. Accuracy was measured using the squared Pearson correlation coefficient (R2) under an allelic dosage model (see Supplementary Methods). Using the new reference set, we observed higher imputation accuracy than that achieved with the combination of 1000 Genomes and HapMap data across a spectrum of minor allele frequencies (MAFs) (Fig. 1). Accuracy in individuals of European ancestry imputed from Hap660 or OmniExpress arrays, measured by the proportion of variants imputed with R2 > 0.8, improved by 34%, 23% and 12% for variants with MAFs of 3%, 5% and 10%, respectively. We estimated the difference in power to detect associations in GWAS design between an imputed data set and one composed of directly genotyped SNPs with the DCEG Reference Set by adapting a model developed by Park et al.10. When using Hap660 data for imputation, we observed detection rates of 92.9% when imputing with the DCEG Reference Set and 84.7% with the 1000 Genomes and HapMap reference sets relative to the detection rate attained with directly genotyped SNPs; for OmniExpress data, we observed detection rates of 93.9% and 86.2% for these reference sets, respectively. Because imputation accuracy depends on the similarity of haplotypes between reference and study populations, we examined an extreme scenario in which we used a reference population from Finland (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, ATBC) to impute genotypes using OmniExpress data from a US population of European ancestry (PLCO) (Supplementary Fig. 1). For common SNPs, there was minimal loss of imputation accuracy when using the reference population from Finland relative to the US-based Cancer Prevention Study II (CPSII) or a combined population of HapMap individuals from Utah of Northern and Western European ancestry (CEU) and from northern Italy (Toscans in Italy, TSI). This result suggests that, for common variants, a reference set of sufficient size can adequately predict common SNPs when there is a discrepancy in population ancestry, provided that comparable haplotypes are sufficiently represented. This observation should enable investigators to proceed more confidently with imputation without additional genotyping in related but not identical populations. Improved imputation of common and uncommon snps with a new reference set

Colorectal Cancer Incidence and Postmenopausal Hormone Use by Type, Recency, and Duration in Cancer Prevention Study II

The Womens Health Initiative randomized trials showed a reduction in colorectal cancer risk with the use of estrogen plus progesterone (E + P), but not with estrogen alone (E-only), after intervention periods <7 years. Using data from the Cancer Prevention Study II Nutrition Cohort, we examined associations of colorectal cancer risk with E-only and E + P, including analyses by recency and duration of hormone use. During 13.2 years of follow-up, 776 cases of invasive colorectal cancer occurred among 67,412 postmenopausal women participants. Cox proportional hazards models were used to estimate multivariate-adjusted relative risks (RR) and 95% confidence intervals (95% CI) of colorectal cancer for current and former hormone users according to hormone type and duration of use. Relative to women who never used postmenopausal hormones, current, but not former, use of E-only was associated with a reduced risk of colorectal cancer (RR 0.76; 95% CI, 0.59-0.97). Among current E-only users, duration of use was inversely and linearly associated with risk (Ptrend = 0.01). Use of E-only for <5 years was not associated with reduced risk, whereas use for ≥20 years was associated with a 45% reduction in risk (RR, 0.55; 95% CI, 0.36-0.86). There were no statistically significant associations between E + P and colorectal cancer risk. Our results suggest a strong inverse association of long-term use of E-only with colorectal cancer risk, underscoring the importance of collecting data on duration of hormone use in epidemiologic studies of postmenopausal hormones and risk of disease. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2835–41)

Work schedule, sleep duration, insomnia, and risk of fatal prostate cancer.

BACKGROUND Studies of breast cancer in women and laboratory studies provide evidence that shift work involving circadian rhythm disruption is a probable human carcinogen. However, evidence linking shift work and other circadian disruption factors to prostate cancer risk is limited. PURPOSE To examine associations of work schedule (i.e., rotating shift work, fixed night and fixed afternoon/evening shift work); sleep duration; and insomnia frequency with prostate cancer mortality. METHODS The Cancer Prevention Study-II is a large prospective cohort study of U.S. adults. Work schedule, sleep duration, insomnia frequency, and other information was self-reported in 1982. Among 305,057 employed men, aged ≥29 years who were cancer free at baseline, there were 4974 prostate cancer deaths during follow-up through 2010. In 2013, multivariable-adjusted relative risks (RRs) and 95% CIs were computed using Cox proportional hazards regression. RESULTS Work schedule and insomnia frequency were not associated with risk of fatal prostate cancer. Short sleep duration was associated with higher risk of prostate cancer during the first 8 years of follow-up, compared to 7 hours/night, the RRs (95% CIs) for 3-5 and 6 hours/night were 1.64 (1.06, 2.54), and 1.28 (0.98, 1.67), respectively. There was no association between sleep duration and fatal prostate cancer during later follow-up. CONCLUSIONS These results do not support associations of work schedule or insomnia frequency with prostate cancer mortality. The association between short sleep duration and higher risk of fatal prostate cancer only during the first 8 years of follow-up suggests that short sleep duration could affect later stages of prostate carcinogenesis.

Associations of Oral α-, β-, and γ-Human Papillomavirus Types With Risk of Incident Head and Neck Cancer

Importance Prospective studies are needed to examine the temporal relationship between oral human papillomavirus (HPV) detection and risk of head and neck squamous cell carcinoma (HNSCC). Moreover, the oral cavity contains a wide spectrum of α-, β-, and γ-HPV types, but their association with risk of HNSCC is unknown. Objective To prospectively examine associations between α-, β-, and γ-HPV detection in the oral cavity and incident HNSCC. Design A nested case-control study was carried out among 96 650 participants, cancer free at baseline, with available mouthwash samples in 2 prospective cohort studies: (1) the American Cancer Society Cancer Prevention Study II Nutrition Cohort and (2) the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident cases of HNSCC (n = 132) were identified during an average 3.9 years of follow-up in both cohorts. Three controls per case (n = 396) were selected through incidence density sampling and matched on age, sex, race/ethnicity, and time since mouthwash collection. Methods Through a next-generation sequencing assay, DNA from α-, β-, and γ-HPV types were detected. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% CIs, adjusting for smoking history, alcohol consumption, and detection of HPV-16 for β- and γ-HPVs. Main Outcomes and Measures Incident HNSCC, which includes cancers of the oropharynx, oral cavity, and larynx. Results A total of 132 participants developed HNSCC during the follow-up period (103 men and 29 women; average age at baseline, 66.5 years). Oral HPV-16 detection was associated with incident HNSCC (OR, 7.1; 95% CI, 2.2-22.6), with positive association for oropharyngeal SCC (OR, 22.4; 95% CI, 1.8-276.7), but not for oral cavity (OR, 4.5; 95% CI, 0.6-34.7) or laryngeal SCCs (OR, 0.11; 95% CI, 0.01-834.80). Detection of β1-HPV-5 and β2-HPV-38 types, as well as γ-11 and γ-12 species, had ORs for HNSCC that ranged from 2.64 to 5.45 (P < .01 for all comparisons). Detection of β1-HPV-5 type was associated with oropharyngeal (OR, 7.42; 95% CI, 0.98-56.82; P = .054), oral cavity (OR, 5.34; 95% CI, 1.51-18.80; P = .01), and laryngeal SCCs (OR, 2.71; 95% CI, 1.00-7.43; P = .05), whereas γ11- and γ12-HPV species were associated with both oral cavity (OR, 7.47; 95% CI, 1.21-46.17; P = .03; and OR, 6.71; 95% CI, 1.47-30.75; P = .01, respectively) and laryngeal SCCs (OR, 7.49; 95% CI, 1.10-51.04; P = .04 and OR, 5.31; 95% CI, 1.13-24.95; P = .03, respectively). Conclusions and Relevance This study demonstrates that HPV-16 detection precedes the incidence of oropharyngeal SCC. Associations of other HPVs, including γ11- and γ12-HPV species and β1-HPV-5 type suggest a broader role for HPVs in HNSCC etiology.