Citations

Abstract Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10−8), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10−9). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

Purpose We determined whether the association between breast density and breast cancer risk and cancer severity differs according to menopausal status and postmenopausal hormone therapy (HT) use. Methods We collected data on 587,369 women who underwent 1,349,027 screening mammography examinations; 14,090 women were diagnosed with breast cancer. We calculated 5-year breast cancer risk from a survival model for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, age, menopausal status, and current HT use, assuming a body mass index of 25 kg/m 2 . Odds of advanced (ie, IIb, III, IV) versus early (ie, I, IIa) stage invasive cancer was calculated according to BIRADS density. Results Breast cancer risk was low among women with low density (BIRADS-1): women age 55 to 59 years, 5-year risk was 0.8% (95% CI, 0.6 to 0.9%) for non-HT users and 0.9% (95% CI, 0.7% to 1.1%) for estrogen and estrogen plus progestin users. Breast cancer risk was high among women with very high density (BIRADS-4), particularly estrogen plus progestin users: women age 55 to 59 years, 5-year risk was 2.4% (95% CI, 2.0% to 2.8%) for non-HT users, 3.0% (95% CI, 2.6% to 3.5%) for estrogen users, and 4.2% (95% CI, 3.7% to 4.6%) for estrogen plus progestin users. Advanced-stage breast cancer risk was increased 1.7-fold for postmenopausal HT users who had very high density (BIRADS-4) compared to those with average density (BIRADS-2). Conclusion Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT, especially estrogen plus progestin.

Abstract Background: There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study of CLL identified seven genetic variants that increased the risk of CLL within a European population. Methods: We evaluated the association of these variants, or variants in linkage disequilibrium with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls. Results: Of these seven single nucleotide polymorphisms (SNP), six had P trend < 0.05 and had estimated odds ratios (OR) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 [OR, 1.47; 95% confidence intervals (CI), 1.19-1.80; P trend = 0.0003] near IRF4 and rs735665 near GRAMD1B (OR, 1.47; 95% CI, 1.14-1.89; P trend = 0.003). However, no associations (P > 0.05) were found for rs11083846, nor were any found for any SNP in linkage disequilibrium with rs11083846. Conclusions: Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis. Cancer Epidemiol Biomarkers Prev; 19(4); 1098–102. ©2010 AACR.

Purpose Mammographic density and lobular involution are both significant risk factors for breast cancer, but whether these reflect the same biology is unknown. We examined the involution and density association in a large benign breast disease (BBD) cohort. Patients and Methods Women in the Mayo Clinic BBD cohort who had a mammogram within 6 months of BBD diagnosis were eligible. The proportion of normal lobules that were involuted was categorized by an expert pathologist as no (0%), partial (1% to 74%), or complete involution (≥ 75%). Mammographic density was estimated as the four-category parenchymal pattern. Statistical analyses adjusted for potential confounders and evaluated modification by parity and age. We corroborated findings in a sample of women with BBD from the Mayo Mammography Health Study (MMHS) with quantitative percent density (PD) and absolute dense and nondense area estimates. Results Women in the Mayo BBD cohort (n = 2,667) with no (odds ratio, 1.7; 95% CI, 1.2 to 2.3) or partial (odds ratio, 1.3; 95% CI, 1.0 to 1.6) involution had greater odds of high density (DY pattern) than those with complete involution (P trend < .01). There was no evidence for effect modification by age or parity. Among 317 women with BBD in the MMHS study, there was an inverse association between involution and PD (mean PD, 22.4%, 21.6%, 17.2%, for no, partial, and complete, respectively; P trend = .04) and a strong positive association of involution with nondense area (P trend < .01). No association was seen between involution and dense area (P trend = .56). Conclusion We present evidence of an inverse association between involution and mammographic density.

Purpose Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women. Methods We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women. Results There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic. Conclusion Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.

AbstractMammographic percent density (PD) is a strong risk factor for breast cancer, but there has been relatively little systematic evaluation of other features in mammographic images that might additionally predict breast cancer risk. We evaluated the association of a large number of image texture features with risk of breast cancer using a clinic-based case-control study of digitized film mammograms, all with screening mammograms before breast cancer diagnosis. The sample was split into training (123 cases and 258 controls) and validation (123 cases and 264 controls) data sets. Age-adjusted and body mass index (BMI)–adjusted odds ratios (OR) per SD change in the feature, 95% confidence intervals, and the area under the receiver operator characteristic curve (AUC) were obtained using logistic regression. A bootstrap approach was used to identify the strongest features in the training data set, and results for features that validated in the second half of the sample were reported using the full data set. The mean age at mammography was 64.0 ± 10.2 years, and the mean time from mammography to breast cancer was 3.7 ± 1.0 (range, 2.0-5.9 years). PD was associated with breast cancer risk (OR, 1.49; 95% confidence interval, 1.25-1.78). The strongest features that validated from each of several classes (Markovian, run length, Laws, wavelet, and Fourier) showed similar ORs as PD and predicted breast cancer at a similar magnitude (AUC = 0.58-0.60) as PD (AUC = 0.58). All of these features were automatically calculated (unlike PD) and measure texture at a coarse scale. These features were moderately correlated with PD (r = 0.39-0.76), and after adjustment for PD, each of the features attenuated only slightly and retained statistical significance. However, simultaneous inclusion of these features in a model with PD did not significantly improve the ability to predict breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(3):837–45)

Abstract Purpose: Immunotherapeutic modalities are commonly used for treatment of patients with melanoma. The therapeutic success in preclinical models has not yielded the expected clinical results. To understand this discrepancy, we attempted to define immune homeostasis of 209 patients with melanoma across stages of disease relative to normal controls. Experimental Design: Peripheral blood mononuclear cells (PBMC) and plasma were collected from patients and healthy donors. PBMC were analyzed for frequencies of natural killer, dendritic, and T cells and their functional status. Matched plasma samples were analyzed for the concentrations of 27 cytokines, chemokines, and growth factors. RNA was isolated from 24 metastatic melanoma tumor biopsies and profiled by microarray analysis. Results: The frequency of natural killer, T, and dendritic cells in patients does not significantly change across stages of melanoma. However, plasma concentrations of Th2 cytokines [interleukin (IL)-4, IL-5, IL-10, and IL-13] in tumor-bearing patients were significantly higher than those with resected melanoma. Expression array analysis of metastatic melanoma revealed that the malignant melanocytes were not the source of the Th2 cytokines but did highly up-regulate vascular endothelial growth factor (VEGF) transcripts, consistent with plasma VEGF concentrations. In vitro VEGF exposure of normal PBMC lead to repolarization from Th1 to Th2 emulating the state of metastatic melanoma. Conclusions: Patients with metastatic melanoma exist in a state of Th2-mediated “chronic inflammation” as a result of at least VEGF overproduction by malignant tumors. These data support prior observations regarding the effect of VEGF on immune cell function and suggests consideration of VEGF inhibitors in future cancer immunotherapy clinical studies in metastatic melanoma.

Abstract We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, ≥ 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

Background High-intensity repetitive athletic activities may predispose the brachial plexus to repetitive stretch, compression, and subsequent injury, although painless shoulder weakness is a rare event. Purpose The physical examination and electrodiagnostic findings in a series of United States Navy special warfare trainees who presented with acute painless shoulder weakness are presented, along with subsequent treatment and return-to-duty timeline. Study Design Case series; Level of evidence, 4. Methods From August 2005 to August 2006, a total of 11 of 212 (5%) Navy Basic Underwater Demolition School trainees were identified with acute onset (<3 weeks) painless shoulder weakness without any prior shoulder injury. In all shoulders, symptoms began during a telephone pole lift-carry drill. All trainees underwent serial examinations, electrodiagnostic testing, and a comprehensive rehabilitation program. Results Physical examination revealed universal weakness in flexion and abduction and electrodiagnostic studies confirmed injury to the C5-6 area of the brachial plexus (axillary, suprascapular, and musculocutaneous). All 11 patients were removed from training and started on a physical therapy program until functional recovery at a mean of 21 weeks after onset of symptoms (range, 12-24). All 11 resumed military activities; however, only 6 completed the Navy Basic Underwater Demolition School program. Conclusion In physically intense training or athletic environments, injuries to the upper brachial plexus may present with various forms of upper extremity dysfunction, including painless shoulder weakness. This information provides insight into a potentially debilitating shoulder problem and offers guidance on future training principles.

Abstract Breast density is a strong risk factor for breast cancer; however, no standard assessment method exists. An automated breast density method was modified and compared with a semi-automated, user-assisted thresholding method (Cumulus method) and the Breast Imaging Reporting and Data System four-category tissue composition measure for their ability to predict future breast cancer risk. The three estimation methods were evaluated in a matched breast cancer case-control (n = 372 and n = 713, respectively) study at the Mayo Clinic using digitized film mammograms. Mammograms from the craniocaudal view of the noncancerous breast were acquired on average 7 years before diagnosis. Two controls with no previous history of breast cancer from the screening practice were matched to each case on age, number of previous screening mammograms, final screening exam date, menopausal status at this date, interval between earliest and latest available mammograms, and residence. Both Pearson linear correlation (R) and Spearman rank correlation (r) coefficients were used for comparing the three methods as appropriate. Conditional logistic regression was used to estimate the risk for breast cancer (odds ratios and 95% confidence intervals) associated with the quartiles of percent breast density (automated breast density method, Cumulus method) or Breast Imaging Reporting and Data System categories. The area under the receiver operator characteristic curve was estimated and used to compare the discriminatory capabilities of each approach. The continuous measures (automated breast density method and Cumulus method) were highly correlated with each other (R = 0.70) but less with Breast Imaging Reporting and Data System (r = 0.49 for automated breast density method and r = 0.57 for Cumulus method). Risk estimates associated with the lowest to highest quartiles of automated breast density method were greater in magnitude [odds ratios: 1.0 (reference), 2.3, 3.0, 5.2; P trend &lt; 0.001] than the corresponding quartiles for the Cumulus method [odds ratios: 1.0 (reference), 1.7, 2.1, and 3.8; P trend &lt; 0.001] and Breast Imaging Reporting and Data System [odds ratios: 1.0 (reference), 1.6, 1.5, 2.6; P trend &lt; 0.001] method. However, all methods similarly discriminated between case and control status; areas under the receiver operator characteristic curve were 0.64, 0.63, and 0.61 for automated breast density method, Cumulus method, and Breast Imaging Reporting and Data System, respectively. The automated breast density method is a viable option for quantitatively assessing breast density from digitized film mammograms. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3090–7)