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- Chattopadhyay, Subhayan, et al.
(author)
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Risk of second primary cancer following myeloid neoplasia and risk of myeloid neoplasia as second primary cancer : a nationwide, observational follow up study in Sweden
- 2018
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In: The Lancet Haematology. - 2352-3026. ; 5:8, s. 368-377
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Journal article (peer-reviewed)abstract
- Background: Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers—ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer—to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. Methods: Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. Findings: Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1·29, 95% CI 1·17–1·41), chronic myeloid leukaemia (1·52, 1·35–1·69), myelodysplastic syndrome (1·42, 1·26–1·59), and all myeloproliferative neoplasms (1·37, 1·30–1·43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1·57, 1·48–1·65), chronic myeloid leukaemia (1·26, 1·13–1·40), and myelodysplastic syndrome (1·54, 1·42–1·67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5·08 and 10·04). Interpretation: The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. Funding: Deutsche Krebshilfe, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation, Finnish Cancer Organizations, Swedish Research Council, ALF from Region Skåne, and Bloodwise.
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- Chattopadhyay, Subhayan, et al.
(author)
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Second primary cancers in non-Hodgkin lymphoma : Bidirectional analyses suggesting role for immune dysfunction
- 2018
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 143:10, s. 2449-2457
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Journal article (peer-reviewed)abstract
- Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients.
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- Went, Molly, et al.
(author)
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Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes
- 2019
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In: Human Genomics. - : Springer Science and Business Media LLC. - 1479-7364. ; 13:1
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Journal article (peer-reviewed)abstract
- BackgroundWhile genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS).ResultsGWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80–491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus.ConclusionsOur findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.
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| 5. |
- Zheng, Guoqiao, et al.
(author)
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Second primary cancers in patients with acute lymphoblastic, chronic lymphocytic and hairy cell leukaemia
- 2019
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 185:2, s. 232-239
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Journal article (peer-reviewed)abstract
- Improvement of survival in lymphocytic leukaemia has been accompanied by the occurrence of second primary cancer (SPCs). Based on Swedish Family Cancer Database, we applied bi-directional analyses in which relative risks (RRs) were calculated for any SPCs in patients with chronic lymphocytic leukaemia (CLL), acute lymphoblastic leukaemia (ALL) and hairy cell leukaemia (HCL) and the risks of these leukaemias as SPCs. After CLL, RRs were significant for 20 SPCs, and high for skin squamous cell cancer (24·58 for in situ and 7·63 for invasive), Merkel cell carcinoma (14·36), Hodgkin lymphoma (7·16) and Kaposi sarcoma (6·76). Conversely, 15 CLL cancer pairs were reciprocally increased. The increased risks were reciprocal for ALL and four cancers. RR for ALL was 15·35 after myeloid neoplasia. HCL showed reciprocally increased RRs with non-Hodgkin lymphoma and melanoma. The concordance between RRs for bi-directional associations between CLL and different cancers, and HCL and different cancers was highly significant. For CLL (also for HCL), the bi-directional risks with skin cancers and other immune-related cancers suggest the probable involvement of immune dysfunction. For ALL, treatment may contribute to risks of multiple SPCs. Increased risk of ALL after haematological neoplasms may indicate bone marrow dysfunction. These findings may help guide treatment decisions and prognostic assessment.
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- Law, Philip J., et al.
(author)
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Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.
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| 8. |
- Li, Ni L., et al.
(author)
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Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism
- 2017
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:11, s. 2556-2564
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Journal article (peer-reviewed)abstract
- Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.
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| 9. |
- Schmidt, Amand F., et al.
(author)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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In: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Journal article (peer-reviewed)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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| 10. |
- Sud, Amit, et al.
(author)
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Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk
- 2019
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 134:12, s. 960-969
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Journal article (peer-reviewed)abstract
- Estimating familial cancer risks is clinically important in being able to discriminate between individuals in the population at differing risk for malignancy. To gain insight into the familial risk for the different hematological malignancies and their possible inter-relationship, we analyzed data on more than 16 million individuals from the Swedish Family-Cancer Database. After identifying 153 115 patients diagnosed with a primary hematological malignancy, we quantified familial relative risks (FRRs) by calculating standardized incident ratios (SIRs) in 391 131 of their first-degree relatives. The majority of hematological malignancies showed increased FRRs for the same tumor type, with the highest FRRs being observed for mixed cellularity Hodgkin lymphoma (SIR, 16.7), lymphoplasmacytic lymphoma (SIR, 15.8), and mantle cell lymphoma (SIR, 13.3). There was evidence for pleiotropic relationships; notably, chronic lymphocytic leukemia was associated with an elevated familial risk for other B-cell tumors and myeloproliferative neoplasms. Collectively, these data provide evidence for shared etiological factors for many hematological malignancies and provide information for identifying individuals at increased risk, as well as informing future gene discovery initiatives.
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