Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase‐Control (MCC‐Spain) study were recruited (2008‐2013). The consumption of AS, from table‐top sweeteners and artificially sweetened beverages, was assessed through a self‐administered and validated food frequency questionnaire (FFQ). Sex‐specific quartiles among controls were determined to compare moderate consumers (<third quartile) and high consumers (≥ third quartile) vs non consumers (reference category), distinguishing aspartame‐containing products and other AS. Unconditional logistic regression models were used to estimate adjusted OR and 95%CI, and results were stratified by diabetes status. Overall, we found no associations between the consumption of aspartame or other AS and cancer. Among participants with diabetes, high consumption of other AS was associated with colorectal cancer (OR = 1.58, 95% CI 1.05‐2.41, P trend = .03) and stomach cancer (OR = 2.27 [0.99‐5.44], P trend = .06). High consumption of aspartame, was associated with stomach cancer (OR = 2.04 [0.7‐5.4], P trend = .05), while a lower risk was observed for breast cancer (OR = 0.28 [0.08‐0.83], P trend = .03). In some cancers, the number of cases in participants with diabetes were small and results should be interpreted cautiously. We did not find associations between use of AS and cancer, but found associations between high consumption of aspartame and other AS and different cancer types among participants with diabetes.

Risk factors associated with monoclonal B-cell lymphocytosis (MBL), a potential precursor of chronic lymphocytic leukaemia (CLL), remain unknown. Using a cross-sectional study design, we investigated demographic, medical and behavioural risk factors associated with MBL. “Low-count” MBL (cases) were defined as individuals with very low median absolute count of clonal B-cells, identified from screening of healthy individuals and the remainder classified as controls. 452 individuals completed a questionnaire with their general practitioner, both blind to the MBL status of the subject. Odds ratios (OR) and 95% confidence interval (CI) for MBL were estimated by means of unconditional logistic regression adjusted for confounding factors. MBL were detected in 72/452 subjects (16%). Increasing age was strongly associated with MBL (P-trend<0.001). MBL was significantly less common among individuals vaccinated against pneumococcal or influenza (OR 0.49, 95% confidence interval (CI): 0.25 to 0.95; P-value = 0.03 and OR: 0.52, 95% CI: 0.29 to 0.93, P-value = 0.03, respectively). Albeit based on small numbers, cases were more likely to report infectious diseases among their children, respiratory disease among their siblings and personal history of pneumonia and meningitis. No other distinguishing epidemiological features were identified except for family history of cancer and an inverse relationship with diabetes treatment. All associations described above were retained after restricting the analysis to CLL-like MBL. Overall, these findings suggest that exposure to infectious agents leading to serious clinical manifestations in the patient or its surroundings may trigger immune events leading to MBL. This exploratory study provides initial insights and directions for future research related to MBL, a potential precursor of chronic lymphocytic leukaemia. Further work is warranted to confirm these findings.

Alkylphenolic compounds are chemicals with endocrine disrupting properties that have been widely used in industry with important changes in their usage over time. Few epidemiologic studies have evaluated the effect of alkylphenolic compounds on human health. We investigated whether occupational exposure to alkylphenolic compounds is associated with breast and prostate cancer. We carried out a population-based case-control study including 1513 incident cases of breast cancer, 1095 of prostate cancer, and 3055 controls, frequency matched by sex, age and region. Occupational exposure to alkylphenolic compounds was estimated using a recently developed job-exposure matrix, which considered different scenarios of exposure and different subtypes of alkylphenolic compounds. History of occupational exposure to alkylphenolic compounds was modestly associated with breast cancer (OR = 1.23; 95% CI = 1.01-1.48). Within the different scenarios, the occupational use of domestic tensioactives was positively associated with breast cancer (OR = 1.28; 95% CI = 1.02-1.60), while occupational exposure in other scenarios showed mostly a suggestion of a similar positive associations. Exposure to nonylphenol ethoxylates was positively associated with breast cancer (OR = 1.21; 95% CI = 1.00-1.47), while exposure to other compounds was uncommon. In general, we did not observe associations between alkylphenolic compounds and prostate cancer, except for a positive association among men occupationally exposed to cosmetic, hair and personal hygiene products. Our findings suggest a modest association between breast cancer risk and occupational exposure to alkylphenolic compounds, and no associations between these compounds and prostate cancer risk. These findings warrant further corroboration in other studies.

Diet is a modifiable risk factor for several neoplasms but evidence for chronic lymphocytic leukemia is sparse. Previous studies examining the association between single-food items and chronic lymphocytic leukemia risk have yielded mixed results, while few studies have been conducted on overall diet, reporting inconclusive findings. This study aimed to evaluate the association between adherence to three dietary patterns and chronic lymphocytic leukemia in the MCC-Spain case-control study. Anthropometric, sociodemographic, medical and dietary information was collected for 369 chronic lymphocytic leukemia cases and 1,605 controls. Three validated dietary patterns - Western, Prudent and Mediterranean - were reconstructed in the MCC-Spain data. The association between adherence to each dietary pattern and chronic lymphocytic leukemia was assessed, overall and by Rai stage, using mixed logistic regression models adjusted for potential confounders. High adherence to a Western dietary pattern (i.e high intakes of high-fat dairy products, processed meat, refined grains, sweets, caloric drinks, and convenience food) was associated with chronic lymphocytic leukemia (ORQ4vs.Q1=1.63 (95%CI 1.11; 2.39); p-trend=0.02; OR 1-SD increase=1.19 (95%CI 1.03; 1.37)), independently of Rai stages. No differences in the association were observed by sex, body mass index, energy intake, tobacco, physical activity, working on a farm and family history of hematologic malignancies. No associations were observed for Mediterranean and Prudent dietary patterns and chronic lymphocytic leukemia. This study provides the first evidence for an association between a Western dietary pattern and chronic lymphocytic leukemia, suggesting that a proportion of chronic lymphocytic leukemia cases could be prevented by modifying dietary habits. Further research, especially with a prospective design, is warranted to confirm these findings.