Publications by authors named "Alain Monnereau"

72 Publications

Occupational Insecticide Exposure and Risk of Non-Hodgkin Lymphoma: A Pooled Case-Control Study from the InterLymph Consortium.

Int J Cancer 2021 Jul 16. Epub 2021 Jul 16.

Centre for Occupational and Environmental Health, Division of Population Health, University of Manchester, Manchester, UK.

Evidence for the human health effects of pesticides is needed to inform risk assessment. We studied the relationship between occupational insecticide use and risk of non-Hodgkin lymphoma (NHL) by pooling data from nine case-control studies participating in the InterLymph Consortium, including 7909 cases and 8644 controls from North America, the European Union, and Australia. Insecticide use was coded using self-report or expert assessment, for insecticide groups (e.g., organophosphates, pyrethroids) and active ingredients (e.g., malathion, permethrin). Associations with insecticides were estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CI) for all NHL and NHL subtypes, with adjustment for study site, demographic factors, and use of other pesticides. Occupational insecticide use, overall, was not associated with risk of NHL. Use of organophosphate insecticides was associated with increased risk of all NHL and the subtype follicular lymphoma, and an association was found with diazinon, in particular (ever use: OR=2.05, 95% CI: 1.24-3.37). The carbamate insecticide, carbaryl, was associated with risk of all NHL, and the strongest associations were found with T-cell NHL for ever-use (OR=2.44, 95% CI: 1.13-5.28) and longer duration (>8 years vs. never: OR=2.90, 95% CI: 1.02-8.25). There was no association of NHL with other broad groups of insecticides, including organochlorine and pyrethroids, and some inverse associations were estimated in relation to historical DDT use. Our findings contribute to the totality of evidence available to help inform risk decisions by public health and regulatory agencies - of importance given continued, widespread use of organophosphate and carbamate insecticides. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33740DOI Listing
July 2021

Passive environmental residential exposure to agricultural pesticides and hematological malignancies in the general population: a systematic review.

Environ Sci Pollut Res Int 2021 Jun 24. Epub 2021 Jun 24.

Gironde Register of Hematologic Malignancies, Institut Bergonié, 229 cours de l'Argonne, 33000, Bordeaux, France.

Incidence rates of hematological malignancies have been constantly increasing over the past 40 years. In parallel, an expanding use of agricultural pesticides has been observed. Only a limited number of studies investigated the link between hematological malignancies risk and passive environmental residential exposure to agricultural pesticides in the general population. The purpose of our review was to summarize the current state of knowledge on that question. A systematic literature search was conducted using PubMed and Scopus databases. We built a scoring scale to appraise relevance of each selected articles. We included 23 publications: 13 ecological studies, 9 case-control studies and a cohort study. Positive associations were reported between hematological malignancies and individual pesticides, pesticide groups, all pesticides without distinction, or some crop types. Relevance score was highly various across studies regardless of their design. Children studies were the majority and had overall higher relevance scores. The effect of passive environmental residential exposure to agricultural pesticides on hematological malignancies risk is suggested by the literature. The main limitation of the literature available is the high heterogeneity across studies, especially in terms of exposure assessment approach. Further studies with high methodological relevance should be conducted.
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http://dx.doi.org/10.1007/s11356-021-14789-3DOI Listing
June 2021

Chronic viral hepatitis, HIV infection and Non-Hodgkin lymphomas in West Africa, a case-control study.

Int J Cancer 2021 Jun 14. Epub 2021 Jun 14.

Service d'hématologie, Centre Hospitalier Universitaire de Yopougon, Abidjan, Côte d'Ivoire.

Non-Hodgkin lymphomas (NHL) are underestimated causes of cancer in West Africa where chronic viral hepatitis and HIV are endemic. While the association with HIV infection has already been characterized, limited information is available on the association between chronic viral hepatitis and NHL in sub-Saharan Africa. A case-control study was conducted in referral hospitals of Abidjan (Cote d'Ivoire) and Dakar (Senegal). Cases of NHL were matched with controls on age, gender and participating site. The diagnosis of NHL relied on local pathological examination completed with immunohistochemistry. HIV, HBV and HCV serology tests were systematically performed. A conditional logistic regression model estimated the associations by the Odds Ratio (OR) with their 95% confidence interval (CI). A total of 117 NHL cases (Abidjan n = 97, Dakar n = 20) and their 234 matched controls were enrolled. Cases were predominantly men (68.4%) and had a median age of 50 years (IQR 37-57). While Diffuse Large B-cell lymphoma were the most reported morphological type (n = 35) among mature B-cell NHL, the proportion mature T-cell NHL (30%) was high. The prevalence figures of HBV, HCV and HIV infection were 12.8%, 7.7% and 14.5%, respectively among cases of NHL. In multivariate analysis, HBV, HCV and HIV were independently associated with NHL with OR of 2.23 (CI 1.05-4.75), 4.82 (CI 1.52-15.29) and 3.32 (CI 1.54-7.16), respectively. Chronic viral hepatitis B and C were significantly associated with NHL in West Africa. Timely preventive measures against HBV infection and access to curative anti-HCV treatment might prevent a significant number of NHL.
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http://dx.doi.org/10.1002/ijc.33709DOI Listing
June 2021

Palliative care referral in cancer patients with regard to initial cancer prognosis: a population-based study.

Public Health 2021 Jun 24;195:24-31. Epub 2021 May 24.

Epicene team, University of Bordeaux, Inserm, Bordeaux Population Health Research Centre, Epicene Team, UMR 1219, 33000, Bordeaux, France; Unité d'épidémiologie et de recherche cliniques, Institut Bergonié, 33000, Bordeaux, France.

Objectives: More than half of cancer patients require palliative care; however, inequality in access and late referral in the illness trajectory are major issues. This study assessed the cumulative incidence of first hospital-based palliative care (HPC) referral, as well as the influence of patient-, tumor-, and care-related factors.

Study Design: This is a retrospective population-based study.

Methods: The study included patients from the 2014 population-based cancer registry of Gironde, France. International Classification of Diseases, Tenth Revision, coding for palliative care identified HPC referrals from 2014 to 2018. The study included 8424 patients. Analyses considered the competing risk of death and were stratified by initial cancer prognosis (favorable vs unfavorable [if metastatic or progressive cancer]).

Results: The 4-year incidence of HPC was 16.7% (95% confidence interval, 16.6-16.8). Lung cancer led to more referrals, whereas breast, colorectal, and prostatic locations were associated to less frequent HPC compared with other solid tumors. Favorable prognosis central nervous system tumors and unfavorable prognosis hematological malignancies also showed less HPC. The incidence of HPC was higher in tertiary centers, particularly for older patients. In the favorable prognosis subgroup, older and non-deprived patients received more HPC. In the unfavorable prognosis subgroup, the incidence of HPC was lower in patients who lived in rural areas than those who lived in urban areas.

Conclusions: One-sixth of cancer patients require HPC. Some factors influencing referral depend on the initial cancer prognosis. Our findings support actions to improve accessibility, especially for deprived patients, people living in rural areas, those with hematological malignancies, and those treated outside tertiary centers. In addition, consideration of age as factor of HPC may allow for improved design of the referral system.
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http://dx.doi.org/10.1016/j.puhe.2021.03.020DOI Listing
June 2021

A French multicentric prospective prognostic cohort with epidemiological, clinical, biological and treatment information to improve knowledge on lymphoma patients: study protocol of the "REal world dAta in LYmphoma and survival in adults" (REALYSA) cohort.

BMC Public Health 2021 03 2;21(1):432. Epub 2021 Mar 2.

Inserm U1219 - EPICENE team, Université de Bordeaux, Bordeaux, France.

Background: Age-adjusted lymphoma incidence rates continue to rise in France since the early 80's, although rates have slowed since 2010 and vary across subtypes. Recent improvements in patient survival in major lymphoma subtypes at population level raise new questions about patient outcomes (i.e. quality of life, long-term sequelae). Epidemiological studies have investigated factors related to lymphoma risk, but few have addressed the extent to which socioeconomic status, social institutional context (i.e. healthcare system), social relationships, environmental context (exposures), individual behaviours (lifestyle) or genetic determinants influence lymphoma outcomes, especially in the general population. Moreover, the knowledge of the disease behaviour mainly obtained from clinical trials data is partly biased because of patient selection.

Methods: The REALYSA ("REal world dAta in LYmphoma and Survival in Adults") study is a real-life multicentric cohort set up in French areas covered by population-based cancer registries to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up. We aim to include 6000 patients over 4 to 5 years. Adult patients without lymphoma history and newly diagnosed with one of the following 7 lymphoma subtypes (diffuse large B-cell, follicular, marginal zone, mantle cell, Burkitt, Hodgkin, mature T-cell) are invited to participate during a medical consultation with their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a documented HIV infection. Patients are treated according to the standard practice in their center. Clinical data, including treatment received, are extracted from patients' medical records. Patients' risk factors exposures and other epidemiological data are obtained at baseline by filling out a questionnaire during an interview led by a clinical research assistant. Biological samples are collected at baseline and during treatment. A virtual tumor biobank is constituted for baseline tumor samples. Follow-up data, both clinical and epidemiological, are collected every 6 months in the first 3 years and every year thereafter.

Discussion: This cohort constitutes an innovative platform for clinical, biological, epidemiological and socio-economic research projects and provides an opportunity to improve knowledge on factors associated to outcome of lymphoma patients in real life.

Trial Registration: 2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619 .
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http://dx.doi.org/10.1186/s12889-021-10433-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927409PMC
March 2021

Multidimensional penalized splines for incidence and mortality-trend analyses and validation of national cancer-incidence estimates.

Int J Epidemiol 2020 08;49(4):1294-1306

Service de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France.

Background: Cancer-incidence and mortality-trend analyses require appropriate statistical modelling. In countries without a nationwide cancer registry, an additional issue is estimating national incidence from local-registry data. The objectives of this study were to (i) promote the use of multidimensional penalized splines (MPS) for trend analyses; (ii) estimate the national cancer-incidence trends, using MPS, from only local-registry data; and (iii) propose a validation process of these estimates.

Methods: We used an MPS model of age and year for trend analyses in France over 1990-2015 with a projection up to 2018. Validation was performed for 22 cancer sites and relied essentially on comparison with reference estimates that used the incidence/health-care ratio over the period 2011-2015. Alternative estimates that used the incidence/mortality ratio were also used to validate the trends.

Results: In the validation assessment, the relative differences of the incidence estimates (2011-2015) with the reference estimates were <5% except for testis cancer in men and < 7% except for larynx cancer in women. Trends could be correctly derived since 1990 despite incomplete histories in some registries. The proposed method was applied to estimate the incidence and mortality trends of female lung cancer and prostate cancer in France.

Conclusions: The validation process confirmed the validity of the national French estimates; it may be applied in other countries to help in choosing the most appropriate national estimation method according to country-specific contexts. MPS form a powerful statistical tool for trend analyses; they allow trends to vary smoothly with age and are suitable for modelling simple as well as complex trends thanks to penalization. Detailed trend analyses of lung and prostate cancers illustrated the suitability of MPS and the epidemiological interest of such analyses.
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http://dx.doi.org/10.1093/ije/dyaa078DOI Listing
August 2020

Effectiveness of first-line cetuximab in wild-type RAS metastatic colorectal cancer according to tumour BRAF mutation status from the EREBUS cohort.

Br J Clin Pharmacol 2021 Mar 15;87(3):1120-1128. Epub 2020 Sep 15.

Hepato-Gastro-Enterology and Digestive Oncology Department, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France.

Aims: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC).

Methods: EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression.

Results: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients.

Conclusions: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.
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http://dx.doi.org/10.1111/bcp.14472DOI Listing
March 2021

Cancer Among Adolescents and Young Adults Between 2000 and 2016 in France: Incidence and Improved Survival.

J Adolesc Young Adult Oncol 2021 02 15;10(1):29-45. Epub 2020 May 15.

Registre National des Cancers de l'Enfant, Registre National des Tumeurs Solides de l'Enfant, CHRU Nancy, Vandœuvre-lès-Nancy, France.

This study was undertaken to determine cancer survival and describe the spectrum of cancers diagnosed among French adolescent and young adult (AYA) population. All cases of cancer diagnosed in 15-24 years, recorded by all French population-based registries (18% of the French population), over the 2000-2016 period, were included. Age-standardized incidence rates, conventional annual percentage change (cAPC) of incidence over time, and 5-year overall survival (5yOS) were calculated. We analyzed 2734 cancer diagnoses in adolescents and 4199 in young adults. Overall incidence rates were 231.9/10 in 15-19 year olds and 354.0/10 in 20-24 year olds. The most frequently diagnosed cancers in male AYA were malignant gonadal germ-cell tumors (GCT), Hodgkin lymphoma (HL), and malignant melanoma and were HL, thyroid carcinoma, and malignant melanoma in females. Cancer incidence was stable over time with a cAPC of 0.8% ( = 0.72). For all cancers combined, 5yOS was 86.6% (95% CI: 85.8-87.4), >85% for HL, non-Hodgkin lymphomas (NHL), GCT, thyroid carcinomas, and malignant melanomas, and around 60% and lower for osteosarcomas, Ewing tumors, hepatic carcinomas, and rhabdomyosarcomas. The 5yOS has significantly improved from 2000-2007 to 2008-2015 for all cancers pooled, with a substantial gain of 4% for 15-19 year olds and 3% for 20-24 year olds. Notwithstanding the encouraging results for some cancers, and overall, persistent poorer survivals in AYA were shown compared to children for acute lymphoblastic leukemia, osteosarcoma, Ewing tumor, rhabdomyosarcoma, and malignant hepatic tumors. These disparities require further investigation to identify and address the causes of these inferior outcomes.
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http://dx.doi.org/10.1089/jayao.2020.0017DOI Listing
February 2021

Incidence and time trends of sarcoma (2000-2013): results from the French network of cancer registries (FRANCIM).

BMC Cancer 2020 Mar 6;20(1):190. Epub 2020 Mar 6.

French Network of Cancer Registries, F-31000, Toulouse, France.

Background: The exhaustive collection of new sarcoma cases and their second histologic review offer a unique opportunity to study their incidence and time trends in France according to the major subtypes.

Methods: Data were collected from population-based cancer registries covering 22% of the French population. Crude and world age-standardized incidence rates (ASR) were estimated according to anatomic, histological and genetic groups, age and sex over the 2010-2013 period.

Results: Time trends in incidence were calculated by the annual percent change over the 2000-2013 period. During the most recent period (2010-2013), 3942 patients with sarcoma were included. The ASR of soft-tissue and bone sarcomas, and gastro-intestinal stromal tumors (GIST) were 2.1, 1.0 and 0.6, respectively. For the four most frequent histological subtypes (unclassified, leiomyosarcoma, GIST and liposarcoma), the ASR ranged from 0.4 to 0.7. ASRs were 1.9 for complex genomic and 1.3 for recurrent translocation sarcomas. The time-trend analysis showed a significant increase of sarcoma incidence rate between 2000 and 2005, which stabilized thereafter. Incidence rates increased for four histological subtypes (GIST, chondrosarcoma, myxofibrosarcoma, solitary fibrous tumors) and decreased for three (leiomyosarcomas, Kaposi sarcoma and fibrosarcoma).

Conclusion: To our knowledge, this study is the first to investigate sarcoma incidence based on a systematic pathological review of these cancers and on the updated sarcoma classifications. Due to the paucity of literature on sarcomas, future studies using data from population-based cancer registries should consider a standardized inclusion criterion presented in our study to better describe and compare data between countries.
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http://dx.doi.org/10.1186/s12885-020-6683-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059296PMC
March 2020

Lipid Trait Variants and the Risk of Non-Hodgkin Lymphoma Subtypes: A Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2020 05 27;29(5):1074-1078. Epub 2020 Feb 27.

Emory University, Atlanta, Georgia.

Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis.

Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated ( < 5 × 10) with high-density lipoprotein (HDL, = 164), low-density lipoprotein (LDL, = 137), total cholesterol (TC, = 161), and triglycerides (TG, = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI).

Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00-1.30) and MZL (OR = 1.09; 95% CI, 1.01-1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83-0.99), all at nominal significance ( < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99-1.19; = 0.087). No associations were noteworthy after adjusting for multiple testing.

Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes.

Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196490PMC
May 2020

Genetically Determined Height and Risk of Non-hodgkin Lymphoma.

Front Oncol 2019 28;9:1539. Epub 2020 Jan 28.

Interdisciplinary Department of Medicine, University of Bari, Bari, Italy.

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00-1.17, = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01-1.31, = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
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http://dx.doi.org/10.3389/fonc.2019.01539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999122PMC
January 2020

Incidence, prognostic impact and clinical outcomes of renal impairment in patients with multiple myeloma: a population-based registry.

Nephrol Dial Transplant 2021 02;36(3):482-490

CHU de Bordeaux, Service de Néphrologie-Transplantation-Dialyse-Aphérèses, Hôpital Pellegrin, Bordeaux, France.

Background: Renal impairment (RI), a severe complication in multiple myeloma (MM), is considered as a poor prognostic factor. Patient survival has increased with the use of novel drugs and autologous stem-cell transplantation (ASCT). However, specific evolution of the incidence of RI in MM and its impact on prognosis remain unclear.

Methods: Using a population-based registry of 1038 newly diagnosed MM in Gironde, France, we evaluated the incidence trends of RI in MM patients and assessed net survival according to factors of interest using Pohar-Perme indicator and excess mortality rate regression. We also reviewed 114 cases of MM with RI to describe their clinical outcomes.

Results: In our population-based study, 24.6% of MM patients presented with RI (12.9% required haemodialysis). Median survival time was 21 months in patients with RI versus not reached at 3 years for other patients (P < 0.01). Age >73 years, RI, comorbidities and non-use of drugs or ASCT were associated with excess mortality risk. The effect of RI on excess mortality rates was maximum in the first 6 months after diagnosis. In the observational study, median follow-up time was 22.5 months; factors associated with renal response were haematologic response [odds ratio (OR) 6.81; P < 0.01] and previous chronic kidney disease (OR 0.26; P = 0.04). Factors associated with 1-year overall survival were haematological [hazard ratio (HR) 0.13; P < 0.01] and renal response (HR 0.27; P = 0.03).

Conclusions: RI represents an independent negative prognostic factor in MM in the first 6 months after diagnosis. Renal recovery and haematologic response are the strongest markers associated with patient survival.
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http://dx.doi.org/10.1093/ndt/gfz211DOI Listing
February 2021

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways.

Hum Mol Genet 2020 01;29(1):70-79

Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
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http://dx.doi.org/10.1093/hmg/ddz228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001601PMC
January 2020

Occupational exposure to pesticides and multiple myeloma in the AGRICAN cohort.

Cancer Causes Control 2019 Nov 18;30(11):1243-1250. Epub 2019 Sep 18.

Institut National de la santé Et de la Recherche médicale (INSERM), Unité Mixte de Recherche (UMR) 1086 ANTICIPE, Caen, France.

Purpose: Epidemiological studies have found an increased risk of multiple myeloma (MM) in farmers. Few studies have investigated the detailed circumstances of occupational pesticide exposure which could explain these increased risks (pesticide use on crops, seeds or on animals, contact with treated crops) and the role of other exposures. In the Agriculture and Cancer cohort (AGRICAN), we assessed the associations between MM and crop- or animal-related activities, with specific attention to pesticide exposure via use on animals and crops or contact with treated crops and to disinfectant exposure.

Methods: Analyses concerned 155,192 participants, including 269 incident MM identified by cancer registries from enrolment (2005-2007) to 2013. Cox models using attained age as time scale were run to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results: MM risk was increased in farmers (i) who started using pesticides on crops in the 1960s, especially among those applying pesticides on corn (≥ 20 years: HR 1.73, 95% CI 1.08, 2.78, p for trend < 0.01) and (ii) using insecticides on animals (HR 1.48, 95% CI 1.11, 1.98), especially among horse farmers (≥ 10 years: HR 2.77, 95% CI 1.22-6.27, p for trend = 0.01). We also observed significant elevated risks with disinfectant use in animal barns.

Conclusions: Findings support the role of pesticide use on crops and animals in the occurrence of MM risk in farmers.
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http://dx.doi.org/10.1007/s10552-019-01230-xDOI Listing
November 2019

Novel analytical methods to interpret large sequencing data from small sample sizes.

Hum Genomics 2019 08 30;13(1):41. Epub 2019 Aug 30.

Laboratory of Mammary and Leukaemic Oncogenesis, Inserm U1218 ACTION, Bergonié Cancer Institute, University of Bordeaux, 146 rue Léo Saignat, bâtiment TP 4ème étage, case 50, 33076, Bordeaux, France.

Background: Targeted therapies have greatly improved cancer patient prognosis. For instance, chronic myeloid leukemia is now well treated with imatinib, a tyrosine kinase inhibitor. Around 80% of the patients reach complete remission. However, despite its great efficiency, some patients are resistant to the drug. This heterogeneity in the response might be associated with pharmacokinetic parameters, varying between individuals because of genetic variants. To assess this issue, next-generation sequencing of large panels of genes can be performed from patient samples. However, the common problem in pharmacogenetic studies is the availability of samples, often limited. In the end, large sequencing data are obtained from small sample sizes; therefore, classical statistical analyses cannot be applied to identify interesting targets. To overcome this concern, here, we described original and underused statistical methods to analyze large sequencing data from a restricted number of samples.

Results: To evaluate the relevance of our method, 48 genes involved in pharmacokinetics were sequenced by next-generation sequencing from 24 chronic myeloid leukemia patients, either sensitive or resistant to imatinib treatment. Using a graphical representation, from 708 identified polymorphisms, a reduced list of 115 candidates was obtained. Then, by analyzing each gene and the distribution of variant alleles, several candidates were highlighted such as UGT1A9, PTPN22, and ERCC5. These genes were already associated with the transport, the metabolism, and even the sensitivity to imatinib in previous studies.

Conclusions: These relevant tests are great alternatives to inferential statistics not applicable to next-generation sequencing experiments performed on small sample sizes. These approaches permit to reduce the number of targets and find good candidates for further treatment sensitivity studies.
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http://dx.doi.org/10.1186/s40246-019-0235-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717342PMC
August 2019

Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.

Genet Epidemiol 2019 10 13;43(7):844-863. Epub 2019 Aug 13.

Medicina Traslazionale, Università del Piemonte Orientale, Vercelli, Italy.

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.
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http://dx.doi.org/10.1002/gepi.22242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763347PMC
October 2019

Gastric MALT lymphoma in a population-based study in France: clinical features, treatments and survival.

Aliment Pharmacol Ther 2019 09 26;50(6):654-663. Epub 2019 Jul 26.

Strasbourg, France.

Background: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease, and most available data on gastric MALT lymphoma (GML) come from clinical studies of selected patients treated in centres of excellence.

Aims: To analyse the clinical features, management and survival of GML patients in a population-based study in France METHODS: All new cases of GML diagnosed between 2002 and 2010 in 11 French areas covered by cancer registries were included. Pathology reports were verified and, if necessary, reviewed by an expert pathologist. All clinical data were retrospectively collected from medical files and analysed using stata V. 14 software.

Results: Four hundred and sixteen patients with confirmed GML (50% male, median age 67 years) were identified. Among them, 44 showed an early transformation into diffuse large B cell lymphoma and were considered to have had an initially missed high-grade lymphoma. At diagnosis, 76% of patients were at stage IE/II, and 24% at stage III/IV of the disease. Helicobacter pylori infection was found in 57% of the patients. Eradication treatment was administered to 76% of patients and complete remission (CR) was obtained in 39%. One hundred and ninety patients received at least one other treatment, including 10 already in CR after eradication. Altogether, CR was obtained in 70% of patients and the 5-year overall survival was 79% (95% CI [75-83]).

Conclusions: In comparison to clinical series, in the general population, GMLs are more frequently diagnosed at an advanced stage, their clinical management is heterogeneous, and there is a risk of misdiagnosis and overtreatment. These results highlight the necessity of following currently available guidelines in this field.
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http://dx.doi.org/10.1111/apt.15409DOI Listing
September 2019

Animal farming and the risk of lymphohaematopoietic cancers: a meta-analysis of three cohort studies within the AGRICOH consortium.

Occup Environ Med 2019 11 13;76(11):827-837. Epub 2019 Jul 13.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Bethesda, Maryland, USA.

Objective: Animal farming entails a variety of potential exposures, including infectious agents, endotoxins and pesticides, which may play a role in the aetiology of lymphohaematopoietic cancers (LHCs). The aim of this study was to assess whether farming specific animal species is associated with the risk of overall LHC or its subtypes.

Methods: Data from three prospective cohort studies in the USA, France and Norway which are part of the Agricultural Cohort consortium and which collected information about animal farming and cancer were used. Analyses included 316 270 farmers and farm workers. Adjusted Cox models were used to investigate the associations of 13 histological subtypes of LHC (n=3282) with self-reported livestock (cattle, pigs and sheep/goats) and poultry (ever/never and numbers raised) farming. Cohort-specific HRs were combined using random-effects meta-analysis.

Results: Ever animal farming in general or farming specific animal species was not meta-associated with overall LHC. The risk of myeloid malignancies decreased with increasing number of livestock (p trend=0.01). Increased risk of myeloproliferative neoplasms was seen with increasing number of sheep/goats (p trend <0.01), while a decreased risk was seen with increasing number of livestock (p trend=0.02). Between cohorts, we observed heterogeneity in the association of type of animal farmed and various LHC subtypes.

Conclusions: This large-scale study of three prospective agricultural cohorts showed no association between animal farming and LHC risk, but few associations between specific animal species and LHC subtypes were observed. The observed differences in associations by countries warrant further investigations.
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http://dx.doi.org/10.1136/oemed-2018-105655DOI Listing
November 2019

ETIOSARC study : environmental aetiology of sarcomas from a French prospective multicentric population-based case-control study-study protocol.

BMJ Open 2019 06 18;9(6):e030013. Epub 2019 Jun 18.

Inserm U1219 - EPICENE team, Université de Bordeaux, BordeauxCedex, Aquitaine, France.

Introduction: Sarcomas are rare tumours of connective tissue. The exact overall incidence of sarcomas is unknown due to diagnostic difficulties and the various histological subtypes (over 80 subtypes). However, the apparent increasing incidence of sarcomas suggests environmental causes such as pesticides. Except for some specific factors (ie, ionising radiation, vinyl chloride, dioxin and genetic predispositions) the scientific knowledge on the aetiology of sarcomas is sparse and inconsistent. France is a particularly appropriate country to set up a study investigating the causes of sarcoma occurrence due to the French organisation in treatment and care of sarcoma patients, which is highly structured and revolved around national expert networks. The main objective of the ETIOlogy of SARcomas (ETIOSARC) project is to study the role of lifestyle, environmental and occupational factors in the occurrence of sarcomas among adults from a multicentric population-based case-control study.

Methods And Analysis: Cases will be all incident patients (older than 18 years) prospectively identified in 15 districts of France covered by a general population-based cancer registry and/or a reference centre in sarcoma's patient care over a 3-year period with an inclusion start date ranging from February 2019 to January 2020 and histologically confirmed by a second review of the diagnosis. Two controls will be individually matched by sex, age (5 years group) and districts of residence and randomly selected from electoral rolls. A standardised questionnaire will be administered by a trained interviewer in order to gather information about occupational and residential history, demographic and socioeconomic characteristics and lifestyle factors. At the end of the interview, a saliva sample will be systematically proposed. This study will permit to validate or identify already suspected risk factors for sarcomas such as phenoxyherbicides, chlorophenol and to generate new hypothesis to increase our understanding about the genetic and environmental contributions in the carcinogenicity process.

Ethics And Dissemination: The present study is promoted by the French National Institute of Health and Medical Research (identification number C17-03). This study received National French Ethic committee (CPP Sud Méditerrannée I) approval (identification number 18-31) and French Data Protection Authority (CNIL) approval (identification number 918171). Results of this study will be published in international peer-reviewed journals. Technical appendix, statistical code and dataset will be available in the Dryad repository when collection data are completed.

Trial Registration Number: NCT03670927.
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http://dx.doi.org/10.1136/bmjopen-2019-030013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588955PMC
June 2019

Blood transfusion history and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.

Cancer Causes Control 2019 Aug 4;30(8):889-900. Epub 2019 Jun 4.

Dept of Epidemiology and Biostatistics, University of California San Francisco, 3333 California Street, Suite 280, San Francisco, CA, 94118, USA.

Purpose: To conduct a pooled analysis assessing the association of blood transfusion with risk of non-Hodgkin lymphoma (NHL).

Methods: We used harmonized data from 13 case-control studies (10,805 cases, 14,026 controls) in the InterLymph Consortium. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusted for study design variables.

Results: Among non-Hispanic whites (NHW), history of any transfusion was inversely associated with NHL risk for men (OR 0.74; 95% CI 0.65-0.83) but not women (OR 0.92; 95% CI 0.83-1.03), p = 0.014. Transfusion history was not associated with risk in other racial/ethnic groups. There was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion, and further adjustment for socioeconomic status, body mass index, smoking, alcohol use, and HCV seropositivity did not alter the results. Associations for NHW men were stronger in hospital-based (OR 0.56; 95% CI 0.45-0.70) but still apparent in population-based (OR 0.84; 95% CI 0.72-0.98) studies.

Conclusions: In the setting of a literature reporting mainly null and some positive associations, and the lack of a clear methodologic explanation for our inverse association restricted to NHW men, the current body of evidence suggests that there is no association of blood transfusion with risk of NHL.
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http://dx.doi.org/10.1007/s10552-019-01188-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613988PMC
August 2019

Using healthcare claims data to analyze the prevalence of BCR-ABL-positive chronic myeloid leukemia in France: A nationwide population-based study.

Cancer Med 2019 06 30;8(6):3296-3304. Epub 2019 Apr 30.

B2PHI Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases, Inserm U1181, UVSQ, Paris Saclay Univ, Villejuif, France.

Background: Data on Chronic Myeloid Leukemia (CML) prevalence are scarce. Here we provide an estimation of the prevalence of CML in France for the year 2014 using French national health insurance data.

Methods: We selected patients claiming reimbursement for tyrosine kinase inhibitors (TKI) or with hospital discharge diagnoses for CML, BCR/ABL-positive or with full reimbursement of health care expenses for myeloid leukemia. We built an algorithm which we validated on a random sample of 100 potential CML patients by comparing the results obtained using the algorithm and the opinion of two hematologists who reviewed the patient demographics and sequence of care abstracted from claims data (internal validity). For external validity, we compared the number of incident CML patients identified using the algorithm with those recorded in French population-based cancer registries in departments covered by such a registry.

Results: We identified 10 789 prevalent CML patients in 2014, corresponding to a crude prevalence rate of 16.3 per 100 000 inhabitants [95% confidence interval (CI) 16.0-16.6]: 18.5 in men [18.0-19.0] and 14.2 in women [13.8-14.6]. The crude CML prevalence was less than 1.6 per 100 000 [1.2-2.0] under age 20, increasing to a maximum of 48.2 [45.4-51.2) at ages 75-79. It varied from 10.2 to 23.8 per 100 000 across French departments. The algorithm showed high internal and external validity. Concordance rate between the algorithm and the hematologists was 96%, and the numbers of incident CML patients identified using the algorithm and the registries were 162 and 150, respectively.

Conclusion: We built and validated an algorithm to identify CML patients in administrative healthcare databases. In addition to prevalence estimation, the algorithm could be used for future economic evaluations or pharmaco-epidemiological studies in this population.
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http://dx.doi.org/10.1002/cam4.2200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558491PMC
June 2019

Pesticide use and risk of non-Hodgkin lymphoid malignancies in agricultural cohorts from France, Norway and the USA: a pooled analysis from the AGRICOH consortium.

Int J Epidemiol 2019 10;48(5):1519-1535

Section of Environment and Radiation, International Agency for Research on Cancer (IARC), Lyon, France.

Background: Pesticides are commonly used in agriculture, and previous studies endorsed the need to further investigate the possible association between their use and risk of lymphoid malignancies in agricultural workers.

Methods: We investigated the relationship of ever use of 14 selected pesticide chemical groups and 33 individual active chemical ingredients with non-Hodgkin lymphoid malignancies (NHL) overall or major subtypes, in a pooled analysis of three large agricultural worker cohorts. Pesticide use was derived from self-reported history of crops cultivated combined with crop-exposure matrices (France and Norway) or self-reported lifetime use of active ingredients (USA). Cox regression models were used to estimate cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs), which were combined using random effects meta-analysis to calculate meta-HRs.

Results: During follow-up, 2430 NHL cases were diagnosed in 316 270 farmers accruing 3 574 815 person-years under risk. Most meta-HRs suggested no association. Moderately elevated meta-HRs were seen for: NHL and ever use of terbufos (meta-HR = 1.18, 95% CI: 1.00-1.39); chronic lymphocytic leukaemia/small lymphocytic lymphoma and deltamethrin (1.48, 1.06-2.07); and diffuse large B-cell lymphoma and glyphosate (1.36, 1.00-1.85); as well as inverse associations of NHL with the broader groups of organochlorine insecticides (0.86, 0.74-0.99) and phenoxy herbicides (0.81, 0.67-0.98), but not with active ingredients within these groups, after adjusting for exposure to other pesticides.

Conclusions: Associations of pesticides with NHL appear to be subtype- and chemical-specific. Non-differential exposure misclassification was an important limitation, showing the need for refinement of exposure estimates and exposure-response analyses.
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http://dx.doi.org/10.1093/ije/dyz017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857760PMC
October 2019

[Descriptive epidemiology of cancer in metropolitan France: Incidence, survival and prevalence].

Bull Cancer 2019 Jul - Aug;106(7-8):617-634. Epub 2019 Mar 2.

Université Paul-Sabatier, faculté de médecine, réseau des registres de cancers Francim, 37, allée Jules-Guesde, 31073 Toulouse cedex, France.

Introduction: Incidence, mortality, survival and prevalence are key indicators to assess public health policies and estimate the needs of the population for cancer management. The aim of this article is to provide the more current estimates of these indicators, in line with the fifteenth operational objective of the 2014-2019 Cancer Plan "Collect data/Support Public Health".

Methods: Incidence and survival data came from cancer registries. Mortality data came from the French epidemiology center on medical causes of death. Prevalence was estimated by using incidence and survival estimates.

Results: In metropolitan France in 2017, the estimated number of new cancer cases and cancer deaths was respectively 399,500 and 150,000. The most frequent cancers (breast, prostate) had highest net survivals: 78 and 84% at 10 years. Several cancers (including lung, liver and pancreatic cancers) had worse prognosis (5-year survival≤33%). In 2017, 1,396,000 men and 1,359,000 women had cancer in the previous 15 years, representing respectively 5.4% and 4.8% of the population aged 15 and over.

Discussion: Despite the decrease of cancer mortality, the prognosis of some cancers remains poor and the cancer prevalence is high. These results highlight the need for intensifying the efforts already made in cancer prevention, diagnosis, and treatment and justify the interest in the post-cancer period.
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http://dx.doi.org/10.1016/j.bulcan.2018.11.016DOI Listing
August 2019

Socioeconomic environment and disparities in cancer survival for 19 solid tumor sites: An analysis of the French Network of Cancer Registries (FRANCIM) data.

Int J Cancer 2019 03 3;144(6):1262-1274. Epub 2018 Dec 3.

University Hospital of Caen, Caen cedex, France; 'ANTICIPE' U1086 INSERM-UCN, Team labeled 'Ligue Contre le Cancer', Centre François Baclesse, Caen, France.

Social inequalities are concerning along the cancer continuum. In France, social gradient in health is particularly marked but little is known about social gradient in cancer survival. We aimed to investigate the influence of socioeconomic environment on cancer survival, for all cancers reported in the French Network of Cancer Registries. We analyzed 189,657 solid tumors diagnosed between 2006 and 2009, recorded in 18 registries. The European Deprivation Index (EDI), an ecological index measuring relative poverty in small geographic areas, assessed social environment. The EDI was categorized into quintiles of the national distribution. One- and five-year age-standardized net survival (ASNS) were estimated for each solid tumor site and deprivation quintile, among men and among women. We found that 5-year ASNS was lower among patients living in the most deprived areas compared to those living in the least deprived ones for 14/16 cancers among men and 16/18 cancers among women. The extent of cancer survival disparities according to deprivation varied substantially across the cancer sites. The reduction in ASNS between the least and the most deprived quintile reached 34% for liver cancer among men and 59% for bile duct cancer among women. For pancreas, stomach and esophagus cancer (among men), and ovary and stomach cancer (among women), deprivation gaps were larger at 1-year than 5-year survival. In conclusion, survival was worse in the most deprived areas for almost all cancers. Our results from population-based cancer registries data highlight the need for implementing actions to reduce social inequalities in cancer survival in France.
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http://dx.doi.org/10.1002/ijc.31951DOI Listing
March 2019

Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

Nat Commun 2018 10 10;9(1):4182. Epub 2018 Oct 10.

Epidemiology Research Program, American Cancer Society, Atlanta, 30303, GA, USA.

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.
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http://dx.doi.org/10.1038/s41467-018-06541-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180091PMC
October 2018

Pooled study of occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma.

Occup Environ Med 2018 11 18;75(11):798-806. Epub 2018 Aug 18.

Department of Public Health and Clinical Molecular Medicine, University of Cagliari, Cagliari, Italy.

Objectives: To investigate the association between occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma (MM) in a large, consortium-based study.

Methods: We pooled data on 2854 cases and 10 743 controls from nine studies participating in the InterLymph consortium. Occupational exposures to benzene, toluene and xylene were assigned by a job-exposure matrix, coupled with 'correction' of exposure probability by self-reported or expert-assessed exposure from the individual studies. Cumulative intensity was calculated as the job-specific exposure intensity multiplied by job duration, summed across jobs. Associations were estimated using logistic regression, with inclusion of covariates for study matching factors and other potential confounders. We repeated our main analysis using random-effects meta-analysis to evaluate heterogeneity of effect.

Results: Benzene, toluene and xylene were each associated with MM. For the three solvents, the highest quartile of high-probability cumulative intensity exposure (vs unexposed) was associated with 42% to 63% increased risks of MM. Associations with toluene and xylene exposures were fairly consistent and robust to sensitivity analyses. The estimated effect for benzene was moderately heterogeneous between the studies. Each solvent's association with MM was stronger for exposure occurring within 20 years of diagnosis than with exposure lagged by more than 20 years.

Conclusions: Our study adds important evidence for a role of aromatic hydrocarbon solvents in causation of MM. The difficulty in disentangling individual compounds in this group and a lack of data on potential carcinogenicity of toluene and xylene, in widespread current use, underscore a need for further epidemiological evaluation.
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http://dx.doi.org/10.1136/oemed-2018-105154DOI Listing
November 2018

Adolescent and young adult oncology patients in France: Heterogeneity in pathways of care.

Pediatr Blood Cancer 2018 09 17;65(9):e27235. Epub 2018 May 17.

CHRU Nancy, Registre National des cancers de l'Enfant, Registre National des Tumeurs Solides de l'Enfant, Vandœuvre-lès-Nancy, France.

Background: In order to evaluate at the population level the impact of the actions developed in France since 2004 to organize the care of adolescents and young adults (AYAs) with cancer, we conducted the present study to provide an unbiased view of the pathway of care of these patients.

Methods: Using a population-based registry, we conducted a review of all cases of cancer diagnosed during 2012 and 2013 in 15- to 24-year-old patients living in nineteen French administrative areas.

Results: The median times for diagnosis and treatment of the 993 included AYAs were 9 weeks (3-22) and 1 day (0-20), respectively. Delays in diagnosis were significantly longer in young adults than in adolescents, especially for soft-tissue sarcomas (48.7 weeks vs. 15.4 weeks, P = 0.04) and bone tumors (21.4 weeks vs. 10.1 weeks, P = 0.04). The first physicians seen by patients were mostly general practitioners (67.4%). Most patients (77.5%) were treated in adult units. Management decisions were taken within the context of a multidisciplinary team (MDT) in 85.3% of cases. MDT meetings that involved both pediatric and adult oncologists were uncommon (15.7% of patients). Twenty-six percent of patients were included in randomized or nonrandomized clinical studies. The proportion of inclusion was significantly higher in adolescents (39.5%) than in young adults (16.8%).

Conclusion: In France, pathways of care for AYAs are heterogeneous. It is necessary to organize a national network of expert centers with adequate medical skills and specific psychosocial support and facilities to provide the best possible care for these patients.
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http://dx.doi.org/10.1002/pbc.27235DOI Listing
September 2018

Determinants of cancer treatment and mortality in older cancer patients using a multi-state model: Results from a population-based study (the INCAPAC study).

Cancer Epidemiol 2018 08 25;55:39-44. Epub 2018 May 25.

Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, Epicene team, UMR 1219, F-33000 Bordeaux, France; Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonié, Comprehensive Cancer Center, F-33000 Bordeaux, France.

Introduction: Several studies have reported disparities in the care management and survival of older cancer patients. The aim of our study was to identify determinants of treatment administration in this population of cancer patients aged over 65 years taking into account competing risks of death.

Methods: The INCAPAC study is a population-based study. Four cancer registries and three prospective cohort studies on older subjects (age ≥65 years) from Gironde, a French department, were merged to identify older cancer patients. We used a non-parametric multi-state model including three states (cancer, treatment and all-cause death). This model allowed studying determinants of treatment administration (all treatments including curative, symptomatic and palliative treatments) and mortality considering that patients can move from cancer state to death state, either directly or through the treatment phase. Studied variables were demographic and socioeconomic-, cancer-, health-, and geriatric-related.

Results: A total of 450 patients were included in the analyses. They were mainly aged 85 and over, men and educated. Among included patients, 372 (83%) received cancer treatment. In the final multivariate model, dementia was associated with a lower likelihood of receiving cancer treatment (HR = 0.68, 95% CI = 0.47-0.99). In treated patients, age, sex, comorbidities, dependency and stage at diagnosis were associated to all-cause mortality, and in untreated patients, diagnosis of dementia and stage at diagnosis were associated to mortality.

Conclusion: Further studies are necessary to understand the impact of geriatric impairments on treatment administration and to develop clinical practice guidelines.
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http://dx.doi.org/10.1016/j.canep.2018.04.013DOI Listing
August 2018

HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

Cancer Res 2018 07 7;78(14):4086-4096. Epub 2018 May 7.

Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci ( trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. HLA gene diversity reduces risk for non-Hodgkin lymphoma. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065509PMC
July 2018

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

Blood 2018 06 19;131(23):2541-2551. Epub 2018 Apr 19.

Huntsman Cancer Institute and Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; = 4.4 × 10). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; = 7.8 × 10) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; = 9.8 × 10). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.
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http://dx.doi.org/10.1182/blood-2017-11-814608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992865PMC
June 2018