Cerhan, James R.

Abstract Background: Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are collectively classified as myeloproliferative neoplasms (MPN). Given that little is known about their etiology, we investigated the role of anthropometric, medical and lifestyle factors in the development of MPNs and the common subtypes (ET & PV) in a population-based cohort of women. Methods: The IWHS is a prospective cohort of Iowa women aged 55-69 years at enrollment in 1986. Participants completed 6 self-administered questionnaires between 1986-2004. This analysis includes 27370 women who completed the 1993 questionnaire, had no history of cancer, and were enrolled in Medicare at least 1 year. MPN cases through 2004 were identified by linkage to Medicare. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard regression, with age as the underlying time variable. Results: After >250,000 person-years of follow-up, 257 cases of MPNs were identified (172 ET, 64 PV and 21 MF). Height, body mass index (BMI) and waist-to-hip ratio were not associated with risk of MPN. In subtype analysis, BMI was positively associated with risk of ET (RR=1.52 for >29.3 vs <23.5 kg/m2; p-trend=0.042) but not PV. Physical activity (PA) showed a suggestive association with MPN (RR=0.74 for high vs low activity; p-trend=0.063), specific only to ET (RR=0.66; p-trend=0.04). Diabetes (DM) was positively associated with risk of MPN (RR=1.51; 95% CI 1.02-2.24), also specific only to ET (RR=1.82; 95% CI 1.16-2.84). Regular use of aspirin, but not other non-steroidal anti-inflammatory agents, was associated with a lower risk of MPN (RR=0.71; 95% CI 0.55-0.92); slightly stronger for ET (RR=0.68; 95% CI 0.50-0.93) than for PV (RR=0.84; 95% CI 0.50-1.43). There was no dose-response with frequency of use. Cigarette smoking was associated with risk of MPN, which was stronger for PV (RR=0.94 for former and RR=2.83 for current; p-trend=0.016) than for ET (RR=1.28 for former and RR=1.32 for current; p-trend=0.15). There were no associations with alcohol use. In a multivariate model for ET, the associations for BMI (RR=1.28; p-trend=0.21) and DM (RR=1.51; 95% CI 0.92-2.46) attenuated, while there was little change for PA (RR=0.66; p-trend=0.062) or aspirin use (RR=0.70; 95% CI 0.51-0.96). In PV, there was little impact on the association with smoking (RR=0.92 for former and RR=2.67 for current; p-trend=0.028) after adjustment for BMI, PA, DM and aspirin use. Conclusions: Risk factors were unique to the 2 most common types of MPN. ET was associated with obesity-related factors (PV was not), and PV was associated with current smoking (ET was not). Aspirin use had a stronger inverse association for ET. Our results suggest distinct etiologies of these PMN subtypes, and raises mechanistic hypotheses related to inflammation for ET and smoking-related carcinogenic pathways for PV. Citation Format: Alexis D. Leal, Carrie A. Thompson, Alice Wang, Robert A. Vierkant, Thomas M. Habermann, Julie A. Ross, Beth A. Virnig, James R. Cerhan. Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in the Iowa Women's Health Study (IWHS) cohort. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2013-2536

Abstract BACKGROUND: Biobanks collect and store biological samples and data from participants for use in research by multiple investigators. The Mayo Clinic Biobank was established by the Mayo Clinic Center for Individualized Medicine with a goal to support a wide array of health-related research studies at Mayo Clinic, including cancer studies. The Biobank is not focused on any particular disease, however, through annotation by questionnaires, the Mayo electronic medical record (EMR), and the Mayo Cancer Registry, it is a useful clinical research resource for cancer related studies. METHODS: Recruitment started in April 2009. Our goal is 50,000 enrollees. Eligible subjects are adult Mayo Clinic patients, U.S residents, and able to consent. Mailed invitations were sent to patients with appointments in certain Mayo Clinic departments. Each participant completed a health history questionnaire including a wide variety of health information as well as whether they or their 1st-degree relatives had ever been diagnosed with specific cancers. For self-reported cancers, subjects were asked to provide the age they were first diagnosed. Subjects also provided a blood sample and granted research access to clinically collected specimens and data from their Mayo Clinic record, at enrollment and into the future. All research projects utilizing samples from this resource are required to return to the Biobank the data generated from their projects. RESULTS: In the first three years, 21736 subjects consented to participate (30% response rate). Participants are 58% female, 95% White, and range in age from 18 to 97 with a median age of 62. At enrollment, 74% were residents in Minnesota, 6% in Iowa, 4% in Wisconsin, and 15% in the other states. Twelve percent reported being a current smoker, while 59% were never smokers. The most common self-reported cancers at baseline were non-melanoma skin cancer (n=2950), prostate cancer (n=1107), breast cancer (n=941), melanoma (n=692), colorectal cancer (n=296), cervical cancer (n=240), sarcoma (n=233), urinary/bladder (n=211), lymphoma (n=187), thyroid cancer (n=186), endometrial cancer (n=170), kidney cancer (n=163), lung cancer (n=145). Excluding non-melanoma skin cancer, 16188 (74%) (6516 male, 9672 female) self-reported being cancer free at baseline. Data will be presented on the frequency of incident cancers diagnosed since enrollment in the Biobank. To date, the Biobank has served as a source of controls for 17 cancer related studies on genetic susceptibility, including studies of the breast, colon, myeloma, brain, lung, pancreas, endometrium, and kidneys. CONCLUSIONS: The Mayo Clinic Biobank has quickly been established as a valuable resource for cancer researchers at Mayo Clinic - primarily as a source of controls for genetic studies. As the Biobank continues to grow in sample size and length of follow-up, it will also serve as a cohort study of cancer incidence embedded within an EMR of a large health organization. Citation Format: Janet E. Olson, Euijung Ryu, Kiley J. Johnson, Karen Maschke, Jody A. Morrisette, Mark Liebow, Paul Y. Takahashi, Ruchi G. Sharma, Kari S. Anderson, Matthew A. Hathcock, Jyotishman Pathak, Noralane M. Lindor, Timothy J. Beebe, Stephen N. Thibodeau, James R. Cerhan. The Mayo Clinic Biobank - A growing resource for cancer related studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2515. doi:10.1158/1538-7445.AM2013-2515

Abstract Background: Nitrate and nitrite are precursors of N-nitroso compounds, known animal and human carcinogens. Nitrate and nitrite are common in foods, such as vegetables and processed meats, and nitrate is a contaminant of drinking water. We previously reported an increased ovarian cancer risk associated with higher nitrate intake in public water supplies in the Iowa Women's Health Study. Here, we report results based on an additional 12 years of follow-up and we present results for dietary nitrate and nitrite intake. Methods: Among 28,555 postmenopausal women aged 55–69 y at baseline, we identified 315 incident epithelial ovarian cancers between 1986 and 2010. Dietary nitrate and nitrite intakes were assessed using a food frequency questionnaire at baseline. Information on drinking water source was obtained in 1989. Nitrate-nitrogen (NO3-N) levels in public water supplies (average level 1955-1988) and water sources (finished surface or ground water) were from a database of monitoring data for Iowa water utilities. Cox proportional hazards regression generated hazard ratios (HR) and 95% confidence intervals (CI). Because disinfection by-products (DBP) are higher in surface water and have been associated with increased risk for certain cancers, we determined whether the association between nitrate intake from drinking water and ovarian cancer risk differed by water source. Results: Neither total dietary nitrate nor nitrite intake was associated with ovarian cancer risk after adjusting for age, energy intake, family history of ovarian cancer, number of live births, and history of unilateral oophorectomy. Nitrate and nitrite intakes from animal or plant sources, or processed meats were not associated with ovarian cancer risk. Among women who drank public water, we observed an increased risk for ovarian cancer with higher average levels of NO3-N (ptrend=0.004). Compared with women in the lowest quartile of NO3-N levels (<0.36 mg/L), risk was 1.81 (95% CI=1.08-3.05) and 2.02 (95% CI=1.21-3.36) times higher in the third (1.0-2.5 mg/L) and fourth (>2.5 mg/L) quartiles, respectively. Ovarian cancer risk among private well water drinkers was elevated (HR=1.52, 95% CI=0.91-2.53) but not statistically significantly different from the referent group. When stratified by water source, the positive association between NO3-N levels in public water and ovarian cancer risk was confined to women who drank water from surface sources (ptrend=0.007; pinteraction=0.04). Conclusions: Dietary nitrate or nitrite intake was not associated with ovarian cancer risk. Our findings for nitrate intake from public water supplies suggest that nitrate intake from drinking water may increase ovarian cancer risk, particularly in the likely presence of other contaminants found in surface water. Further evaluation of DBP and other water contaminant levels on ovarian cancer risk in this population is warranted. Citation Format: Maki Inoue-Choi, Kristin E. Anderson, James R. Cerhan, Peter J. Weyer, Mary H. Ward. Dietary intake of nitrate and nitrite, nitrate in drinking water, and ovarian cancer risk among postmenopausal women in Iowa. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 149. doi:10.1158/1538-7445.AM2013-149

Abstract Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow up of 1.8 years (IQ range: 0.8-3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table. Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4174. doi:10.1158/1538-7445.AM2011-4174

Abstract Introduction. Up to now PCNSL incidence in the US was presumed to be increasing in all age groups independent of changes in nosology, new diagnostic techniques, and HIV infection. The intent of our study was, firstly, to extend our prior study of PCNSL incidence in the US (Olson et al, Cancer 2002;95:1504-10) with an additional decade of SEER data; and, secondly, to determine time trends during the HAART era in the US. Methods. PCNSL age-adjusted incidence rates from 1973-2007 were obtained from the nine SEER registries used in the Olson et al. study. Similarly, the same exclusion criteria were used to remove PCNSL most likely associated with HIV (never married males and females; persons of unknown marital status; all cases reported in the San Francisco registry). To assess the accuracy of the criteria in removing HIV associated cases, incidence rates of Kaposi sarcoma (KS) were assessed with and without the use of the same exclusion criteria. Results. The incidence of PCNSL in the general population decreased from 1995 to 2000. Following this decrease, the incidence stabilized and is now beginning to increase in the last 5 years. Stratifying the incidence rate by age group and employing the exclusion criteria, PCNSL incidence has remained stable in the 20-64 year old population, but has steadily increased in the 65+ population. Removing the exclusion criteria did not alter the data for the 65+ population but demonstrated a sharp drop in incidence after 1996 for the 20-64 year old population. Applying the same HIV exclusion criteria the incidence of KS resulted in no appreciable change in incidence rates over the same time frame. Conclusion. The incidence rate of PCNSL is increasing. This increase is driven by a continued increase in incidence among the 65+ population while the incidence for those aged 20-64 has stabilized during the same time frame. An effect of HAART on PCNSL incidence in the US is suggested by the decline in the incidence among the 20-64 year old population without the HIV exclusion criteria. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1926. doi:10.1158/1538-7445.AM2011-1926

Abstract Background: Allergic diseases signify immune dysregulation attributable to underlying genetics and environmental exposures. Associations between various allergies and hematopoietic cancers have been observed, albeit inconsistently; however, few prospective studies have examined the risk, and even fewer among older adults. Methods: We examined risk of incident hematopoietic cancers in those reporting allergic diseases in a population-based cohort of 22,601 older women (Iowa Women's Health Study). Self-reported allergic status, including asthma, hay fever, eczema, and/or other allergies, was determined via questionnaire in 1997 (mean age, 72 years; range, 63–81 years). Incident cancers were ascertained by linkage with the Iowa Cancer Registry from 1997 to 2011. Cox proportional hazards regression was performed to estimate multivariate-adjusted HR and 95% confidence intervals (CI) for myeloid (N = 177) and lymphoid (N = 437) malignancies, respectively. Results: Allergic diseases were not associated with risk of myeloid (HR, 1.00; 95% CI, 0.72–1.37) or lymphoid (HR, 0.99; 95% CI, 0.81–1.22) malignancies overall, or for most allergic and malignant subtypes examined. Self-reported asthma was positively associated with development of myelodysplastic syndrome (MDS; HR, 2.00; 95% CI, 0.93–4.32). In addition, there was a 30% to 40% decrease in risk of both lymphoid and myeloid cancers in those reporting rural residences but no association in those reporting urban residences; the interaction between residence and allergy was statistically significant for lymphoid malignancies (Pinteraction = 0.05). Conclusions and Impact: These results suggest that asthma may contribute to the pathogenesis of MDS, a finding consistent with the chronic antigen stimulation hypothesis. Susceptibility differences by location of residence are concordant with the hygiene hypothesis and merit additional exploration. Cancer Epidemiol Biomarkers Prev; 23(9); 1903–12. ©2014 AACR.

Key Points ALK-negative ALCLs have chromosomal rearrangements of DUSP22 or TP63 in 30% and 8% of cases, respectively. DUSP22-rearranged cases have favorable outcomes similar to ALK-positive ALCLs, whereas other genetic subtypes have inferior outcomes.

Abstract Motivation: Exome sequencing (exome-seq) data, which are typically used for calling exonic mutations, have also been utilized in detecting DNA copy number variations (CNVs). Despite the existence of several CNV detection tools, there is still a great need for a sensitive and an accurate CNV-calling algorithm with built-in QC steps, and does not require a paired reference for each sample. Results: We developed a novel method named PatternCNV, which (i) accounts for the read coverage variations between exons while leveraging the consistencies of this variability across different samples; (ii) reduces alignment BAM files to WIG format and therefore greatly accelerates computation; (iii) incorporates multiple QC measures designed to identify outlier samples and batch effects; and (iv) provides a variety of visualization options including chromosome, gene and exon-level views of CNVs, along with a tabular summarization of the exon-level CNVs. Compared with other CNV-calling algorithms using data from a lymphoma exome-seq study, PatternCNV has higher sensitivity and specificity. Availability and implementation: The software for PatternCNV is implemented using Perl and R, and can be used in Mac or Linux environments. Software and user manual are available at http://bioinformaticstools.mayo.edu/research/patterncnv/ , and R package at https://github.com/topsoil/patternCNV/ . Contact: Asmann.Yan@mayo.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Abstract Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology. Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements. Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers. Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention. Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.

BACKGROUNDThe 1996 National Cancer Institute Working Group (NCI‐WG 96) guidelines classified disease in individuals who had a B‐cell clone with chronic lymphocytic leukemia (CLL) immunophenotype as CLL if their absolute lymphocyte count was ≥5 × 109/L. The 2008 International Workshop on CLL guidelines (IWCLL 2008) classified disease as CLL if the absolute B‐cell count was ≥5 × 109/L or as monoclonal B‐cell lymphocytosis (MBL) if the absolute B‐cell count was <5 × 109/L. The objective of the current study of Olmsted County, Minnesota, was to assess the effects of these changes on incidence rates and presentation from 2000 to 2010.METHODSUsing diagnostic indices available through the Rochester Epidemiology Project and the Mayo CLL database, the authors identified all patients with newly diagnosed CLL and high‐count MBL from 2000 to 2010. Age‐specific and sex‐specific incidence rates were determined.RESULTSAccording to NCI‐WG 96 criteria, there were 115 patients with CLL and 8 patients with MBL during the period studied. Using the IWCLL 2008 classification, there were 79 patients with CLL and 40 patients with MBL. Rai stage distribution (low risk, intermediate risk, and high risk) using NCI‐WG 96 criteria was 60.9%, 33.9%, and 5.2%, respectively, compared with 43%, 49.4%, and 7.6%, respectively, using IWCLL 2008 criteria. The age‐adjusted and sex‐adjusted incidence rates (per 100,000) for CLL and MBL were 10.0 and 0.66, respectively, using NCI‐WG 96 criteria versus 6.8 and 3.5, respectively, using IWCLL 2008 criteria. The median time to treatment according to NCI‐WG 96 criteria was 9.2 years versus 6.5 years with IWCLL 2008 criteria.CONCLUSIONSUse of the IWCLL 2008 guidelines reduced the incidence of CLL, altered the distribution of initial Rai stage at diagnosis, and shortened the median time to treatment. Cancer 2014;120:2000–2005. © 2014 American Cancer Society.