Citations

Purpose Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur. Patients and Methods All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer-specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site-specific manner (eg, death resulting from breast cancer in a patient with breast cancer). Results Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre-existing CLL after adjusting for age, sex, race, and disease stage. Conclusion Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed.

Abstract Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3′ untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 × 10−6). This SNP was not associated with the other NHL subtypes (all P &gt; 0.05). Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. Impact: These data provide support that a functional variant within the 3′UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk. Cancer Epidemiol Biomarkers Prev; 22(3); 461–6. ©2013 AACR.

Summary A recent meta‐analysis of three genome‐wide association studies of chronic lymphocytic leukaemia ( CLL ) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non‐ H odgkin lymphoma ( NHL ) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0·01; rs210142: P = 6·8 × 10 −3 ). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.

Abstract B24 Purpose Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States for which no recommended screening guidelines are available. An estimated 34,290 deaths related to PC is expected to occur in 2008 and the 5-year relative survival rate for this cancer is 5% for all stages combined. A person's chance of developing this cancer increases three-fold if a first-degree relative has pancreatic cancer. The purpose of this study was to assess attitudes of unaffected family members in the Mayo Clinic Pancreas Cancer Family study toward PC cancer risk and future screening options. This is the first study to report such attitudes of PC family members. Subjects and Methods At-risk family members with two or more relatives affected with pancreas cancer in the kindred and primary care controls completed a survey asking about: perceived PC risk, degree of PC worry/concern, attitude toward cancer screening in general, and intentions regarding PC screening if it were a blood test or endoscopic ultrasound. Results 386 family members in 109 PC kindreds and 1058 controls completed surveys. Forty-six percent of PC family members reported that it was likely they would develop PC during their lifetime compared to 6% of controls. Forty-one percent of family members reported having thoughts regarding the possibility of getting pancreatic cancer during the past month versus 4.6% of controls. Similarly, 74% of family members reported concern about getting PC as compared to 40.6% of controls. 94% of family members reported they would be likely to undergo a blood-based PC screening test compared to 89.7% of controls. For endoscopic ultrasound, 71% of family members would be likely to undergo screening as compared to 55% of controls. All comparisons were statistically significant. Conclusion Compared to controls, PC family members perceive their personal PC risk to be high and report a higher rate of PC-related cancer worry/concern. A high percentage of family members and controls indicate receptivity to PC screening, especially if it were a blood test. If the screening is more invasive (i.e. EUS), interest declines, particularly among controls. This information can help investigators to understand and address potential motivators and barriers to recruitment for future PC studies and indicates that there is a need to develop educational interventions among these families to reduce their actual and perceived pancreatic cancer risk. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B24.

AbstractFree light chains (FLCs) are the most commonly detected paraproteins in chronic lymphocytic leukemia (CLL). We examined the types of FLC abnormalities and prognostic utility of the FLC assay compared with standard prognostic biomarkers in a prospective cohort of 339 patients with newly diagnosed CLL. Three types of FLC abnormalities were identified: monoclonal elevated FLC (elevated κ and/or λ with abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or λ with normal FLC ratio), and ratio-only FLC abnormality (normal range κ and λ with abnormal FLC ratio). One hundred sixty-five patients (49%) had a FLC abnormality with approximately equal distribution among monoclonal elevation, polyclonal elevation, and ratio-only abnormality. All FLC abnormalities were associated with poor time to first treatment: monoclonal FLC (hazard ratio [HR], 4.99; 95% confidence interval [CI], 2.94-8.48), polyclonal FLC (HR, 2.40; 95% CI, 1.24-4.64), ratio-only FLC (HR, 2.57; 95% CI, 1.40-4.69). Monoclonal FLC and polyclonal FLC were associated with poor overall survival compared with patients with normal FLC. Results remained significant after adjusting for Rai stage. The FLC assay is a simple, widely available clinical test with similar prognostic utility as routinely used prognostic biomarkers for CLL. Among persons with FLC abnormalities, the type of abnormality affects prognostic significance.

Abstract Background. MBL is defined as a monoclonal expansion of B lymphocytes (&lt; 5 × 109/L) in the blood without associated lymphadenopathy or organomegaly; MBLs with a chronic lymphocytic leukemia (CLL) immunophenotype have been termed as CLL-like MBL. The prevalence of CLL-like MBL in the general population is 3.5-12% but increases with age; however, the frequency is even higher (∼13-18%) among unaffected relatives from CLL families (i.e., families with two or more CLL members). We and others have found that a small proportion of individuals with CLL-like MBL individuals and lymphocytosis will progress to CLL requiring treatment (∼1.1% per year). Because CLL and NHL have been shown to aggregate together within families, suggesting a shared pathogenesis, we evaluated the frequency of MBL in NHL families. Methods. Individuals were obtained from an ongoing study of NHL families (i.e., families with 2 or more NHL members). However, we limited to NHL families with at most 1 individual with CLL due to the known increased frequency of MBL in CLL families. Multi-color flow cytometry was performed on fresh peripheral blood samples. A CBC and differential count was simultaneously obtained using an automated blood cell counter. Five possible flow diagnoses were defined as: CLL-like MBL (CD5+CD20dim), atypical MBL (CD5+CD20bright), non-CLL like MBL (CD5−), and normal immunophenotype (NIPT). Medical records of NHL cases were reviewed to confirm disease. Results. A total of 30 individuals from 16 NHL families had available flow cytometry results. The mean age at flow analysis was 56 years (range 37− 83 years). We identified 5 individuals with MBL from 4 families: 3 of the 6 had CLL-like MBL, 1 had atypical MBL, and 1 had non-CLL like MBL. The remaining 25 individuals had a NIPT. Thus, the MBL rate in NHL families is 17% (5/30). Among the CD5+ MBL (both CLL-like and atypical MBL) individuals, all were female and the mean absolute lymphocyte count was 1.4 × 109/L. Of interest, 1 of the CLL-like MBL individuals is from a family where two members had monoclonal gammopathy of uncertain significance (MGUS). Conclusion: Our data show that MBLs of various phenotypes can be found at a higher prevalence in NHL families than that of the general population. Further, the frequency of MBL in NHL families is comparable to that of CLL families. Although more work is needed, our results suggest that MBL may be clustering within NHL families, and thus support a possible common inherited predisposition of NHL and CLL, with MBL signifying a shared early pathogenetic step. 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 1853.

Abstract Pancreatic cancer is a devastating disease for which the role of dietary risk factors remains inconclusive. We evaluated fruit, vegetable, fiber, and grain consumption with pancreatic cancer risk using a clinic-based case-control design, excluding participants who reported changing their diet within 5 years prior to entering the study. Our study included 384 rapidly ascertained cases and 983 non-cases (frequency matched on age at time of recruitment (± 5 years), race, sex, and region of residence) who completed epidemiologic surveys and a 144-item food frequency questionnaire developed by the National Cancer Institute. Logistic regression was used to calculate odds ratios (OR) and 95% CIs, adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. Comparing highest to lowest quintiles, we observed significant (OR &lt; 0.01) inverse associations with significant trends (ptrend &lt; 0.01) for citrus, melon, and berries, other fruit, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, and whole grains. Adjusting for diabetes or total sugar intake in the multivariate logistic regression model did not significantly affect results. Consuming a diet high in fruits, vegetables, fiber, and whole grains may reduce the risk of developing pancreatic cancer. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A85.

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.

Abstract Vitamin D insufficiency is common globally and low levels are linked to higher cancer incidence. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated the relationship of 25(OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, TTT (hazard ratio[HR] = 1.66; P = .005) and OS (HR = 2.39; P = .01) were shorter for 25(OH)D-insufficient patients. In the validation cohort, 61 of 153 patients (39.9%) were 25(OH)D insufficient. After a median follow-up of 9.9 years, TTT (HR = 1.59; P = .05) and OS (HR 1.63; P = .06) were again shorter for 25(OH)D-insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, Rai stage, CD38 status, ZAP-70 status, immunoglobulin heavy chain variable (IGHV) gene mutation status, CD49d status, and cytogenetic abnormalities assessed by interphase fluorescent in situ hybridization testing, 25(OH)D insufficiency remained an independent predictor of TTT (HR = 1.47; P = .008), although the association with OS was not significant (HR = 1.47; P = .07). Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing.