| 11. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Second primary cancers in non-Hodgkin lymphoma : Bidirectional analyses suggesting role for immune dysfunction
- 2018
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 143:10, s. 2449-2457
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Tidskriftsartikel (refereegranskat)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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| 12. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Second primary cancers in non-Hodgkin lymphoma : Family history and survival
- 2020
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 146:4, s. 970-976
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Tidskriftsartikel (refereegranskat)abstract
- Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses and family history of cancer may be a risk factor for SPCs. Using the Swedish Family-Cancer Database on non-Hodgkin lymphoma (NHL), we assessed the influence of family history on risk of SPCs and of SPCs on survival. NHL patients were identified from the years 1958 to 2015 and generalized Poisson models were used to calculate relative risks (RRs) for SPCs and familial SPCs. Among 14,393 NHL patients, a total of 1,866 (13.0%) were diagnosed with SPC. Familial risk of nine particular cancers was associated with risks of these cancers as SPCs, with twofold to fivefold increase in RRs. At the end of a 25-year follow-up period, the survival probability for persons with SPC was only 20% of that for patients without SPC; the hazard ratio for SPC was 1.59 (95% CI: 1.46–1.72). Survival could be predicted by the prognostic groups based on first cancers and HRs increase systematically with worse prognosis yielding a trend of p = 4.6 × 10 −5 . SPCs had deleterious consequences for survival in NHL patients. Family history was associated with increasing numbers of SPCs. Prevention of SPCs and their early detection is an important target in the overall strategy to improve survival in NHL patients. Counseling for avoidance of risk factors and targeted screening based on family history are feasible steps in risk reduction.
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| 13. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Second Primary Cancers in Patients with Invasive and In Situ Squamous Cell Skin Carcinoma, Kaposi Sarcoma, and Merkel Cell Carcinoma : Role for Immune Mechanisms?
- 2020
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X. ; 140:1, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- Second primary cancers (SPCs) are becoming a common cancer entity, which may interfere with survival in relatively benign first primary cancers. We examined the hypothesis that immune dysfunction may contribute to SPCs by assessing SPCs associated with known immune responsive skin cancers, invasive and in situ squamous cell carcinoma, Kaposi sarcoma, and Merkel cell carcinoma. Cancers were identified from the Swedish Cancer Registry from the year 1958 to 2015. Standardized relative risks were calculated bidirectionally for any SPC after skin cancer and for skin cancer as SPC. Over 80,000 first primary cancers were identified for each invasive and in situ squamous cell carcinoma of the skin. Bidirectional increased risks were observed for 26 cancers associated with invasive skin cancer; the Spearman rank correlation was 0.72 (P = 4.6 × 10–5). The highest bidirectional relative risks were for invasive and in situ skin cancer as SPCs (14.59 and 16.71, respectively). Remarkably high risks for second in situ squamous cell carcinoma of the skin were found after Kaposi sarcoma (685.68) and Merkel cell carcinoma (117.23). The high systematic bidirectional risks between immune responsive skin cancers and most other cancers suggest that immune suppression is a key mechanism contributing to an increased risk of SPCs.
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| 14. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST
- 2021
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Ingår i: Briefings in Bioinformatics. - : Oxford University Press (OUP). - 1477-4054 .- 1467-5463. ; 22:6
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Tidskriftsartikel (refereegranskat)abstract
- Clonal deconvolution of mutational landscapes is crucial to understand the evolutionary dynamics of cancer. Two limiting factors for clonal deconvolution that have remained unresolved are variation in purity and chromosomal copy number across different samples of the same tumor. We developed a semi-supervised algorithm that tracks variant calls through multi-sample spatiotemporal tumor data. While normalizing allele frequencies based on purity, it also adjusts for copy number changes at clonal deconvolution. Absent à priori copy number data, it renders in silico copy number estimations from bulk sequences. Using published and simulated tumor sequences, we reliably segregated clonal/subclonal variants even at a low sequencing depth (~50×). Given at least one pure tumor sample (>70% purity), we could normalize and deconvolve paired samples down to a purity of 40%. This renders a reliable clonal reconstruction well adapted to multi-regionally sampled solid tumors, which are often aneuploid and contaminated by non-cancer cells.
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| 15. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Weaponized genomics : potential threats to international and human security
- 2024
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Ingår i: Nature reviews genetics. - 1471-0056 .- 1471-0064. ; 25:1-2
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Tidskriftsartikel (refereegranskat)abstract
- Genetic technologies are revolutionizing human health. In parallel, geopolitical instability has prompted renewed discussions on the risks of DNA technology being weaponized in international conflict. With today’s changing security environment, we argue that risk assessments must be broadened from genetically targeted weapons to a series of new domains.
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| 16. |
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| 17. |
- Petersson, Alexandra, et al.
(författare)
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Branching copy number evolution and parallel immune profiles across the regional tumor space of resected pancreatic cancer
- 2022
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Ingår i: Molecular Cancer Research. - 1557-3125. ; 20:5, s. 749-761
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution and phylogenetic analysis. A mathematical complexity score was developed to calculate the network extent of each phylogeny. Spatial variation in abundancy and tumor nest infiltration of immune cells was analyzed by double immunohistochemical staining. Copy number heterogeneity was denoted as the major contributing factor to the branching architectures of the produced phylogenetic trees. Increased tree complexity was significantly inversely associated with OS, and larger regional maximum aberrations (higher treetops) were associated with increased PD-L1 expression on tumor cells. Contrastingly, a FREM1 gene amplification, found in one patient, coincided with a particularly vigorous immune response. Findings from this limited case series suggest that complex evolutionary patterns may be associated with a shorter survival in surgically treated PDAC patients. Some hypothesis-generating associations with the surrounding immune microenvironment were also detected.Implications: Evolutionary copy number patterns may be associated with survival in patients with resected PDAC.
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| 18. |
- Rastegar, Bahar, et al.
(författare)
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Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution
- 2023
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 29:14, s. 2668-2677
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
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| 19. |
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| 20. |
- Saunders, Charlie N., et al.
(författare)
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Search for AL amyloidosis risk factors using Mendelian randomization
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:13, s. 2725-2731
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Tidskriftsartikel (refereegranskat)abstract
- In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencingALamyloidosis risk.Weperformed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.
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