Wang, Alice H.

Abstract Background: Obesity has been linked to NHL risk in some studies, and may be stronger for obesity in early adulthood (ages 18-20). There has only been limited evaluation of physical activity and risk of NHL, particularly physical activity earlier in life. The purpose of this study was to evaluate the association of body mass index (BMI), physical activity (PA), and NHL risk during adulthood and at age 18. Methods: Self-reported anthropometrics and PA were collected in a clinic-based study of 954 newly diagnosed NHL cases and 1146 controls enrolled at the Mayo Clinic from 2002-2008. PA variables included duration and frequency of mild, moderate, and strenuous PA two years prior to case diagnosis or control selection, strenuous activity at age 18 (any vs. none), and height and weight at both time periods. An overall PA index was estimated by weighting the reported duration and frequency of each PA intensity by the average energy requirement (defined in METs) to obtain an average MET-minutes/week for each participant. BMI was calculated as weight (kg) divided by height (m) squared. Odds Ratios (OR), 95% confidence intervals (CI), and test for trend were estimated using unconditional logistic regression adjusted for the age, gender, and residence. Continuous variables were divided into quartiles according to the distribution among the controls; results are reported for the highest vs. lowest category or quartile unless otherwise specified. Results: The mean age at diagnosis/enrollment was 61 for both cases and controls; 47% and 43% of the cases and controls, respectively, were female. The most common NHL subtypes were CLL/SLL (32%), follicular lymphoma (FL; 26%), and diffuse large B-cell lymphoma (DLBCL; 21%). BMI 2 years prior to diagnosis was not associated with NHL risk (OR=1.21, p-trend=0.13), while there was a positive association with BMI at age 18 (OR=1.40, p-trend=0.001). There was no association of the PA index with risk (OR=0.91, p-trend=0.29). Furthermore, frequency of walking (OR=0.71, p-trend 0.43), mild (OR=1.30, p-trend=0.64), moderate (OR=0.99, p-trend=0.75), and strenuous (OR=0.77, p-trend=0.20) PA were not associated with NHL risk when evaluated individually. However, there was a suggestive weak inverse association between strenuous activity at age 18 and NHL risk (OR=0.85, 95% CI 0.71-1.05). On exploratory analysis, the association of BMI at age 18 with NHL risk was specific to DLBCL (OR=1.84, p-trend=0.002) and CLL/SLL (OR=1.25, p-trend=0.044) but not FL; all other results were similar across these subtypes. Conclusions: We did not observe an association between adult BMI and NHL risk; however a higher BMI in early adulthood was associated with NHL risk, consistent with limited prior reports. We found little evidence to support an association between PA in either early adulthood or later in life and NHL risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1833.

Abstract Background: The t(14;18)(q32;q21) translocation is the most commonly observed chromosomal translocation in non–Hodgkin's lymphoma (NHL), resulting in constitutive Bcl-2 expression and apoptosis inhibition. In addition, germline variation in both BCL2L11 (BIM) and CASP9, known regulators of apoptosis, has recently been linked to NHL risk. We conducted a comprehensive evaluation of 36 apoptosis pathway genes with risk of NHL. Methods: We genotyped 226 single-nucleotide polymorphisms (SNP) from 36 candidate genes in a clinic-based study of 441 newly diagnosed NHL cases and 475 frequency-matched controls. We used principal components analysis to assess gene-level associations, and logistic regression to assess SNP-level associations. MACH was used for imputation of SNPs in BCL2L11 and CASP9. Results: In gene-level analyses, BCL2L11 (P = 0.0019), BCLAF1 (P = 0.0097), BAG5 (P = 0.026), and CASP9 (P = 0.0022) were associated with NHL risk after accounting for multiple testing (tail strength, 0.38; 95% confidence interval, 0.05-0.70). Two of the five BCL2L11 tagSNPs (rs6746608 and rs12613243), both genotyped BCLAF1 tagSNPs (rs797558 and rs703193), the single genotyped BAG5 tagSNP (rs7693), and three of the seven genotyped CASP9 tagSNPs (rs6685648, rs2020902, and rs2042370) were significant at P < 0.05. We successfully imputed BCL2L11 and CASP9 SNPs previously linked to NHL, and replicated all four BCL2L11 and two of three CASP9 SNPs. Conclusion: We replicated the association of BCL2L11 and CASP9 with NHL risk at the gene and SNP level, and identified novel associations with BCLAF1 and BAG5. Impact: Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted. Cancer Epidemiol Biomarkers Prev; 19(11); 2847–58. ©2010 AACR.

AbstractObesity is a controversial risk factor for colorectal cancer (CRC) in older women. We evaluated associations between multiple body size parameters and incident CRC in the prospective, population-based Iowa Women's Health Study (IWHS). IWHS participants, ages 55 to 69 years, provided data regarding height; weight; weight at ages 50, 40, 30, 18 years; hip circumference; and waist circumference at baseline (1986). Derived variables included body mass index (BMI), waist-to-hip ratio (WHR), and “overweight years” (OWY; conceptually similar to cigarette pack-years). Incident CRC cases (n = 1,464) were ascertained from the State Health Registry of Iowa, through 2005. Multivariable Cox regression models were fit to estimate body size–associated CRC risks. Among 36,941 women (619,961 person-years), baseline height, weight, BMI, hip circumference, waist circumference, and WHR were all positively associated with incident CRC (Ptrend ≤ 0.003 for each). Baseline BMI yielded the highest CRC risk estimates (obese III versus normal, RR = 1.56; 95% CI = 1.10–2.22; Ptrend < 0.001) and was more closely associated with distal than proximal tumors (Ptrend < 0.001 versus 0.06). Conversely, height was more closely associated with proximal than distal tumors (Ptrend < 0.001 versus 0.04). Other body size parameters were less predictive of incident CRC. These data strongly support a positive association between increased body size and CRC risk among older women. Further investigation of when increased body size has the greatest effect on CRC risk (i.e., early adulthood versus later adulthood) might also be informative, particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis. Cancer Prev Res; 3(12); 1608–20. ©2010 AACR.

Abstract Elevated B-cell–activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non–Hogkin lymphoma (NHL) risk. We genotyped 9 tagSNPs within TNFSF13B in a clinic-based study of 441 NHL cases and 475 matched controls and evaluated the association of individual SNPs with risk of NHL; 3 tagSNPs were significant (P < 0.05). When categorized into low-, moderate-, and high-risk groups based on risk alleles, we found the permutation-corrected odds ratio for the trend to be 1.43 (P = 0.0019) for risk of B-cell NHL, 1.69 (P = 0.0093) for diffuse large B-cell lymphoma, 1.43 (P = 0.029) for follicular lymphoma, and 1.06 (P = 0.21) for chronic lymphocytic leukemia/small lymphocytic lymphoma. The mean serum BAFF level in those who carried the low-risk alleles was 2 ng/mL compared with 4.3 ng/mL in those with the high-risk alleles (P = 0.02). Taken together, our data suggest that genetic variation in the TNFSF13B gene is significantly associated with NHL risk and elevated serum BAFF levels. [Cancer Res 2009;69(10):4217–24]

Abstract Non-Hodgkin's lymphoma (NHL) is a cancer closely associated with immune function, and the tumor necrosis factor (TNF) G-308A promoter polymorphism, which influences immune function and regulation, was recently reported by the InterLymph Consortium to be associated with NHL risk. TNF signaling activates the nuclear factor-κB (NF-κB) canonical pathway, leading to transcriptional activation of multiple genes that influence inflammation and immune response. We hypothesized that, in addition to TNF signaling, common genetic variation in genes from the NF-κB canonical pathway may affect risk of NHL. We genotyped 54 single nucleotide polymorphisms (SNP) within TNF, lymphotoxin A LTA, and nine NF-κB genes from the canonical pathway (TNFRSF1A, TRADD, TRAF2, TRAF5, RIPK1, CHUK, IKBKB, NFKB1, and REL) in a clinic-based study of 441 incident cases and 475 frequency-matched controls. Tagging SNPs were selected from HapMap supplemented by putative functional SNPs for LTA/TNF. We used principal components and haplo.stats to model gene-level associations and logistic regression to model SNP-level associations. Compared with the wild-type (GG), the AA genotype for the TNF promoter polymorphism G-308A (rs1800629) was associated with increased risk of NHL [odds ratio (OR), 2.14; 95% confidence interval (95% CI), 0.94-4.85], whereas the GA genotype was not (OR, 1.00; 95% CI, 0.74-1.34). This association was similar for follicular lymphoma and diffuse large B-cell lymphoma. A previously reported LTA/TNF haplotype was also associated with NHL risk. In gene-level analysis of the NF-κB pathway, only NFKB1 showed a statistically significant association with NHL (P = 0.049), and one NFKB1 tagSNP (rs4648022) was associated with NHL risk overall (ordinal OR, 0.59; 95% CI, 0.41-0.84; Ptrend = 0.0037) and for each of the common subtypes. In conclusion, we provide additional evidence for the role of genetic variation in TNF and LTA SNPs and haplotypes with risk of NHL and also provide some of the first preliminary evidence for an association of genetic variation in NFKB1, a downstream target of TNF signaling, with risk of NHL. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3161–9)

Abstract Background: Early adolescent weight may affect the risk of postmenopausal breast cancer, and this association may be modified by a family history of breast or ovarian cancer in a first-degree relative, and/or estrogen (ER) and progesterone (PR) receptor status of the disease. Methods: Relative weight at age 12 years (above, below, or average weight compared with peers) and family history were ascertained using a mailed questionnaire in 1986, in the Iowa Women's Health Study, a prospective cohort study of postmenopausal women. Incident breast cancer cases (including ER and PR status) were identified using the Iowa Surveillance, Epidemiology, and End Results Cancer Registry. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression, and were adjusted for breast cancer risk factors, including body mass index at age 18 years and body mass index at study baseline. Results: Through 2003, 2,503 cases of postmenopausal breast cancer were identified among 35,941 women in the analytic cohort. Compared with women with average weight at age 12 years, there was no association of below average weight with risk of breast cancer (RR, 1.02; 95% CI, 0.92-1.13), whereas women with above average weight had a lower risk (RR, 0.85; 95% CI, 0.74-0.98). There was no evidence of an interaction between weight at age 12 years and family history (P = 0.44). The inverse association of above average weight with risk of breast cancer was strongest for PR− tumors (RR, 0.62; 95% CI, 0.43-0.89), intermediate for ER+ (RR, 0.80; 95% CI, 0.67-0.96) and ER− (RR, 0.77; 95% CI, 0.50-1.19) tumors, and weakest for PR+ tumors (RR, 0.90; 95% CI, 0.74-1.09). These associations were not modified by a family history (all P > 0.18). In a joint ER/PR analyses, the strongest inverse association with above average weight at age 12 years was seen for ER+/PR− (RR, 0.49; 95% CI, 0.29-0.85). Conclusion: Above average weight at age 12 years was inversely associated with risk of postmenopausal breast cancer, and was not modified by a family history of the disease. The inverse association was strongest for ER+/PR− tumors. (Cancer Epidemiol Biomarkers Prev 2008;17(2):374–8)

Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P ≤ .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P ≤ .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.