Family history, genes and gene-environment interaction in risk and prognosis of non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignant diseases arising from lymphocytes. There are about 40 subtypes according to the World Health Organizations classification system, differing in morphology, immunophenotype, genetic and/or clinical features. Immunodeficiency, family history, autoimmune disease and some infectious agents are established risk factors for NHL. For most incident NHL patients, however, the reason is not known. One of the most common NHL subtypes, follicular lymphoma (FL), has been associated with smoking in most but not all studies. FL risk is strongly associated with germline genetic variation in the human leukocyte antigen (HLA) DRB1 gene, and aminoacid variation in certain positions of the HLA-DRB1 molecule. In Study I, we used a casecontrol study design to test the hypothesis that smoking is a risk factor for FL among individuals with certain amino-acid combinations in HLA-DRB1, including in positions 70-74 (known as the shared epitope (SE) in rheumatoid arthritis). We found that individuals that carried two SE alleles and were former or current smokers had approximately 2 and 3,5 times increased risk of FL, respectively, as compared to individuals that carried zero SE alleles and never smoked. The interaction was significant when assessed by estimating the attributable proportions of interaction (0.15≤ APoverall≤1.0; 0.005≤ APwomen≤1.0). This finding provides further evidence for a role of smoking in follicular lymphomagenesis, and offers a new model to explore FL etiology. The prognosis of NHL not only varies by subtype, but also within subtypes for reasons that we do not fully understand. Prognostic indices are commonly used in NHL to guide choice of treatment and predict disease course. These include the host factors age and performance status along with indicators of tumor burden, and provide a rough estimation of outcome. Other host factors such as lifestyle factors and medical history as well as host genetic variation are being explored for their potential contribution to better prognostic prediction. This was the focus of Study II-IV. In Study II, we tested the hypothesis that smoking status, attained education (proxy for socioeconomic status), body mass index, ultraviolet radiation exposure, autoimmune disease or family history of hematopoietic malignancy influenced overall and lymphomarelated survival among NHL patients overall and major subtypes. We found evidence that current smoking, few years of attained education and history of autoimmune disease increased the risk of all-cause death among NHL patients overall. Smoking also increased the risk of death among patients with diffuse large B-cell lymphoma. Attained education was also associated with lymphoma-related death. Further studies are needed to understand mechanisms for these associations and how they should be accounted for in the clinical setting. In Study III, we tested the hypothesis that single nucleotide polymorphisms (SNPs) have an impact on FL survival or progression by 1) conducting a meta-analysis of two GWAS, and 2) exploring 22 SNPs previously reported to be associated with FL outcome. In the metaanalysis, no SNP was associated with FL survival at genome-wide significance, although one SNP in the ABCA10 gene on chromosome 17 was borderline associated (rs10491178: Prandom= 5.24 x10-8). In line with previous studies, two linked SNPs in IL8 and one in CD46 were negatively associated with FL progression. Our results mainly provide further evidence of an impact of SNPs involved in immune functions on follicular lymphoma outcome. In Study IV, we further investigated the hypothesis that inherited factors influence survival among patients with a lymphoid malignancy by testing concordance in survival between two first-degree relatives with lymphoid malignancies. We found that individuals with a firstdegree relative with good prognosis had a better survival than individuals with a first-degree relative with expected or poor survival among individuals with the same broad type of lymphoid malignancy, especially indolent lymphomas. Our results support a role of heritability in the outcome primarily of indolent lymphomas

A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival

Abstract Background: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. Methods: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. Results: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×1

The annual proportions (%) of childhood cancer survivors and matched references who each of the years 2009–2018 had specialized outpatient care, inpatient care, sickness absence (SA), disability pension (DP), and sickness absence and/or disability pension (SA/DP), respectively.

The annual proportions (%) of childhood cancer survivors and matched references who each of the years 2009–2018 had specialized outpatient care, inpatient care, sickness absence (SA), disability pension (DP), and sickness absence and/or disability pension (SA/DP), respectively.</p

The annual mean number of sickness absence (SA) and disability pension (DP) net days in general and by type of SA and DP diagnoses in 2009 through 2018 among young adult childhood cancer survivors and their matched references (A); stratified by sex (B); and by sex and main types of childhood cancer (C).

The annual mean number of sickness absence (SA) and disability pension (DP) net days in general and by type of SA and DP diagnoses in 2009 through 2018 among young adult childhood cancer survivors and their matched references (A); stratified by sex (B); and by sex and main types of childhood cancer (C).</p

Crude and adjusted odds ratio (OR) and 95% confidence intervals (CI) for sickness absence and/or disability pension >90 days in 2018 among childhood cancer survivors and among references, respectively.

Crude and adjusted odds ratio (OR) and 95% confidence intervals (CI) for sickness absence and/or disability pension >90 days in 2018 among childhood cancer survivors and among references, respectively.</p

Distribution of sociodemographic characteristics at baseline (2008) among childhood cancer survivors and matched references, and childhood cancer characteristics among childhood cancer survivors; among all and stratified by sex.

Distribution of sociodemographic characteristics at baseline (2008) among childhood cancer survivors and matched references, and childhood cancer characteristics among childhood cancer survivors; among all and stratified by sex.</p

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A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival

Background: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. Methods: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999–2002 and in the United States 2001–2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. Results: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10−8). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24 ×10−8). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival. Conclusions: The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS. Electronic supplementary material The online version of this article (doi:10.1186/s12881-014-0113-6) contains supplementary material, which is available to authorized users

European standard clinical practice recommendations for children and adolescents with primary and recurrent osteosarcoma

Osteosarcoma is a challenging disease requiring multidisciplinary management in expert centers for optimal outcome. There are no current international protocols or guidelines specific for pediatric and adolescent osteosarcoma. The European Standard Clinical Practice (ESCP) project is a collaboration between ERN PaedCan and SIOP Europe’s Clinical Trial Groups to develop approved clinical recommendations reflecting current best practice. This manuscript is a summary of the full ESCP guideline for patients with osteosarcoma. The manuscript provides evidence graded recommendations for diagnosis, staging, management, response evaluation and follow-up. The methodology as defined in the standard operating procedures of the European Society for Medical Oncology (ESMO) was applied. Experts of the Fight OsteoSarcoma Through European Research (FOSTER) consortium contributed. In summary, the ESCP provides guidance on low-grade, but has a focus on high-grade osteosarcoma. In high-grade osteosarcoma the outcomes of most recent trials for clinical subgroups (e.g., metastatic vs. non-metastatic, resectable vs. non-resectable) are discussed, for treatment-naïve as well as for recurrent/refractory disease. An overview of current evidence also highlights the need for further therapeutic development as patients with primary metastatic or recurrent/refractory high-grade osteosarcoma still have a poor prognosis. Intensified collaborative research is identified as a prerequisite to increase survival and to limit long-term toxicities

Biological sample collection to advance research and treatment: a Fight Osteosarcoma Through European Research (FOSTER) and Euro Ewing Consortium (EEC) statement

Osteosarcoma and Ewing sarcoma are bone tumours mostly diagnosed in children, adolescents and young adults. Despite multi-modal therapy combining multi-agent chemotherapy with local therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been ground-breaking. A greater understanding of biological subgroups, the role of the tumour immune microenvironment, factors that promote metastasis and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic and clinically linked biological analysis of patient samples but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage and analysis of patient samples. Two international panels of scientists, clinicians and patient and parent advocates have formed the Fight Osteosarcoma Through European Research (FOSTER) consortium and the Euro Ewing Consortium (EEC). The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (e.g. time points, diagnostic samples, liquid biopsy tubes), handling and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonisation with practical, legal and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration and improve outcomes