| 1. |
- Andersson, Natalie, et al.
(författare)
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DEVOLUTION—A method for phylogenetic reconstruction of aneuploid cancers based on multiregional genotyping data
- 2021
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Phylogenetic reconstruction of cancer cell populations remains challenging. There is a particular lack of tools that deconvolve clones based on copy number aberration analyses of multiple tumor biopsies separated in time and space from the same patient. This has hampered investigations of tumors rich in aneuploidy but few point mutations, as in many childhood cancers and high-risk adult cancer. Here, we present DEVOLUTION, an algorithm for subclonal deconvolution followed by phylogenetic reconstruction from bulk genotyping data. It integrates copy number and sequencing information across multiple tumor regions throughout the inference process, provided that the mutated clone fraction for each mutation is known. We validate DEVOLUTION on data from 56 pediatric tumors comprising 253 tumor biopsies and show a robust performance on simulations of bulk genotyping data. We also benchmark DEVOLUTION to similar bioinformatic tools using an external dataset. DEVOLUTION holds the potential to facilitate insights into the development, progression, and response to treatment, particularly in tumors with high burden of chromosomal copy number alterations.
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| 2. |
- Baranasic, Jurica, et al.
(författare)
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Germline variants of the genes involved in NF-kB activation are associated with the risk of COPD and lung cancer development
- 2023
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Ingår i: Acta Pharmaceutica. - 1330-0075. ; 73:2, s. 243-256
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are closely related diseases associated with smoking history and dysregulated immune response. However, not all smokers develop the disease, indicating that genetic susceptibility could be important. Therefore, the aim of this study was to search for the potential overlapping genetic biomarkers, with a focus on single nucleotide polymorphisms (SNPs) located in the regulatory regions of immune-related genes. Additionally, the aim was to see if an identified SNP has potentially an effect on proinflamma-tory cytokine concentration in the serum of COPD patients. We extracted summary data of variants in 1511 immune-related genes from COPD and LC genome-wide association studies (GWAS) from the UK Biobank. The LC data had 203 cases, patients diagnosed with LC, and 360 938 controls, while COPD data had 1 897 cases and 359 297 controls. Assuming 1 association/gene, SNPs with a p-value < 3.3 × 10-5 were considered statistically significantly associated with the disease. We identified seven SNPs located in different genes (BAG6, BTNL2, TNF, HCP5, MICB, NCR3, ABCF1, TCF7L1) to be associated with the COPD risk and two with the LC risk (HLA-C, HLA-B), with statistical significance. We also identified two SNPs located in the IL2RA gene associated with LC (rs2386841; p = 1.86 × 10-4) and COPD (rs11256442; p = 9.79 × 10-3) but with lower significance. Functional studies conducted on COPD patients showed that RNA expression of IL2RA, IFNγand related proinflammatory cytokines in blood serum did not correlate with a specific genotype. Although results presented in this study do not fully support our hypothesis, it is worth to mention that the identified genes/SNPs that were associated with either COPD or LC risk, all were involved in the activation of the NF-κB transcription factor which is closely related to the regulation of the inflammatory response, a condition associated with both pathologies.
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| 3. |
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| 4. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance : a genome-wide genetic interaction study
- 2018
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci.RESULTS: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P < 5.3 × 10- 3) downstream to allograft rejection pathway (P < 5.6 × 10- 4) and autoimmune thyroid disease pathway (P < 9.3 × 10- 4) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10- 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS.CONCLUSIONS: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses.
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| 5. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
- 2019
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, TH17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.
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| 6. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Impact of family history of cancer on risk and mortality of second cancers in patients with prostate cancer
- 2019
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1365-7852 .- 1476-5608. ; 22:1, s. 143-149
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survival rates are increasing in patients with prostate cancer, and second primary cancers (SPCs) are becoming more common in these patients. However, the etiology and clinical consequences of SPCs are not well-known. We define the impact of family history on SPC and causes of mortality in these patients. Patients and methods: A nation-wide cohort study based on the Swedish Family-Cancer Database covering 4.4 million men and 80,449 prostate cancers diagnosed between 1990 and 2015. Relative risks (RRs) and cumulative incidence for SPCs and for familial SPC were calculated for prostate cancer patients. Results: SPC was diagnosed in 6,396 men and more than a third of these patients had a first-degree family history of any cancer; the familial risk was 1.37 (95% CI: 1.27–1.40), compared to 1.10 (1.08–1.16), without a family history. Cumulative incidence by the age of 83 years reached 21% for prostate cancer alone, 28% in those with SPC, and 35% in patients with SPC and family history. Family history was associated with the risk of seven specific SPCs, including colorectal, lung, kidney, bladder and skin (both melanoma and squamous cell) cancers, and leukemia. Colorectal and lung cancers were common SPCs, and family history doubled the risk of these SPCs. In patients with SPC, half of all causes of death were due to SPC and only 12.77% were due to prostate cancer. Most deaths in SPC were caused by lung and colorectal cancers. Conclusions: SPCs were an important cause of death in patients with prostate cancer and family history was an important risk factor for SPCs. Prevention of SPC should be essential when prostate cancer survival rates are being improved and this could start by conducting a thorough assessment of family history at the time of prostate cancer diagnosis.
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| 7. |
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| 8. |
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| 9. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Prostate cancer survivors : Risk and mortality in second primary cancers
- 2018
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 7:11, s. 5752-5759
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Tidskriftsartikel (refereegranskat)abstract
- To assess etiological and clinical consequences of second primary cancers (SPCs) in prostate cancer (PC) patients, we followed newly diagnosed patients to identify men who were diagnosed with a SPC and recorded their causes of death. We used the Swedish Family-Cancer Database to assess relative risks (RRs) and causes of death in SPCs until the year 2015 in patients with a PC diagnosis between 2001 and 2010. Among a total of 4.26 million men, 76 614 were diagnosed with PC at the median age of 71 years. Among them, 8659 (11.3%) received a subsequent diagnosis of SPC after a median follow-up of 4 years. The most common SPCs were colorectal, skin, bladder, and lung cancers, melanoma, and non-Hodgkin lymphoma. The ranking was almost identical with first cancers among elderly men in Sweden. The RR for SPCs in prostate-specific antigen—detected PC was approximately equal to RR in other PC. Mortality patterns of PC patients were distinct depending on the presence or absence of SPC. Among patients with SPC, 47.8% died as a result of the corresponding SPC, followed by other causes (22.2%) and PC (18.1%). For patients without SPC, PC and non-neoplastic causes almost matched each other as the main causes of death (48.5% and 47.8%). The results suggest that SPCs appear autonomous from primary PC and reflect incidence and mortality of first cancers in general. SPC was the most common cause of death in patients with SPC; close to half of the patients died due to SPC. For improved survival in PC patients, prevention and early detection of SPCs would be important, and the present results suggest that risk factors for SPC in PC are the same as those for first cancer in general.
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| 10. |
- Chattopadhyay, Subhayan, et al.
(författare)
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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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Ingår i: The Lancet Haematology. - 2352-3026. ; 5:8, s. 368-377
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Tidskriftsartikel (refereegranskat)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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