1,196 results on '"Kari Hemminki"'
Search Results
2. Survival in hematological malignancies in the Nordic countries through a half century with correlation to treatment
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Kari Hemminki, Janne Hemminki, Asta Försti, and Amit Sud
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Cancer Research ,Oncology ,Hematology - Abstract
Studies of survival in hematological malignancies (HMs) have generally shown an improvement over time, although most of these studies are limited by a short follow-up period. Using the NORDCAN database with data from Denmark, Finland, Norway and Sweden, we follow periodic increases in relative survival in seven HMs through half a century up to 2015–2019. Five-year survival improved in all seven HMs, reaching 90% for Hodgkin lymphoma (HL), myeloproliferative neoplasias and chronic lymphocytic leukemia (CLL), 60% for multiple myeloma (MM) and chronic myeloid leukemias (CMLs), 50% for the myelodysplastic syndromes and 30% for acute myeloid leukemia (AML). Improvements in survival over 50 years ranged from 20% to more than 50% units across the different HMs. The likely reasons for such progress include earlier diagnoses, improved risk stratification and advances in treatment. We observed differing temporal trends in improvements in survival. The gradual increases observed in HL, CLL and AML highlight the impact of optimization of existing therapies and improvements in diagnostics and risk stratification, whereas the rapid increases observed in the CMLs and MM highlight the impact of novel therapies. Recent therapeutic advances may further improve survival in HMs where survival remains low such as in AML.
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- 2023
3. Autoimmune diseases as comorbidities for liver, gallbladder, and biliary duct cancers in Sweden
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Kari Hemminki, Kristina Sundquist, Jan Sundquist, Asta Försti, Vaclav Liska, Akseli Hemminki, and Xinjun Li
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Cancer Research ,Oncology - Published
- 2023
4. Re: Mark N. Brook, Holly Ní Raghallaigh, Koveela Govindasami, et al. Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study. Eur Urol 2023;83:257–66
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Kari Hemminki, Jianguang Ji, and Jan Sundquist
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Urology - Published
- 2023
5. Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?
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Angelica Macauda, Alyssa Clay-Gilmour, Thomas Hielscher, Michelle A.T. Hildebrandt, Marcin Kruszewski, Robert Z. Orlowski, Shaji K. Kumar, Elad Ziv, Enrico Orciuolo, Elizabeth E. Brown, Asta Försti, Rosalie G. Waller, Mitchell J. Machiela, Stephen J. Chanock, Nicola J. Camp, Marcin Rymko, Małgorzata Raźny, Wendy Cozen, Judit Várkonyi, Chiara Piredda, Matteo Pelosini, Alem A. Belachew, Edyta Subocz, Kari Hemminki, Malwina Rybicka-Ramos, Graham G. Giles, Roger L. Milne, Jonathan N. Hofmann, Jan Maciej Zaucha, Annette Juul Vangsted, Hartmut Goldschmidt, S. Vincent Rajkumar, Waldemar Tomczak, Juan Sainz, Aleksandra Butrym, Marzena Watek, Elżbieta Iskierka-Jazdzewska, Gabriele Buda, Dennis P. Robinson, Artur Jurczyszyn, Marek Dudziński, Joaquin Martinez-Lopez, Jason P. Sinnwell, Susan L. Slager, Krzysztof Jamroziak, Rui Manuel Vieira Reis, Niels Weinhold, Parveen Bhatti, Luis G. Carvajal-Carmona, Daria Zawirska, Aaron D. Norman, Grzegorz Mazur, Sonja I. Berndt, Daniele Campa, Celine M. Vachon, and Federico Canzian
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Oncology ,Risk Factors ,Epidemiology ,Humans ,Genetic Predisposition to Disease ,Multiple Myeloma ,Polymorphism, Single Nucleotide ,Genome-Wide Association Study - Abstract
Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.
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- 2022
6. Supplementary Tables S1-S3 from A Comprehensive Meta-analysis of Case–Control Association Studies to Evaluate Polymorphisms Associated with the Risk of Differentiated Thyroid Carcinoma
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Stefano Landi, Asta Försti, Federica Gemignani, Kari Hemminki, Alfonso Cristaudo, Aleksandra Köhler, Bowang Chen, Franco Bambi, Monica Cipollini, Ombretta Melaiu, Cristina Romei, Rossella Elisei, and Gisella Figlioli
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Table S1. Comparison between results from literature and results from the present GWAS for all the SNPs extracted from literature. Table S2. Data published in literature where only one genetic model (either dominant or recessive) was reported in the manuscript. No allelic OR or additive model could be evaluated according to the data reported in the manuscript. Table S3. Meta-analyses of the literature data for the SNPs evaluated in two or more than one study.
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- 2023
7. Data from A Comprehensive Meta-analysis of Case–Control Association Studies to Evaluate Polymorphisms Associated with the Risk of Differentiated Thyroid Carcinoma
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Stefano Landi, Asta Försti, Federica Gemignani, Kari Hemminki, Alfonso Cristaudo, Aleksandra Köhler, Bowang Chen, Franco Bambi, Monica Cipollini, Ombretta Melaiu, Cristina Romei, Rossella Elisei, and Gisella Figlioli
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Background: Linkage analyses and association studies suggested that inherited genetic variations play a role in the development of differentiated thyroid carcinoma (DTC).Methods: We combined the results from a genome-wide association study (GWAS) performed by our group and from published studies on DTC. With a first approach, we evaluated whether a SNP published as associated with the risk of DTC could replicate in our GWAS (using FDR as adjustment for multiple comparisons). With the second approach, meta-analyses were performed between literature and GWAS when both sources suggested an association, increasing the statistical power of the analysis.Results: rs1799814 (CYP1A1), rs1121980 (FTO), and 3 SNPs within 9q22 (rs965513, rs7048394, and rs894673) replicated the associations described in the literature. In addition, the meta-analyses between literature and GWAS revealed 10 more SNPs within 9q22, six within FTO, two within SOD1, and single variations within HUS1, WDR3, UGT2B7, ALOX12, TICAM1, ATG16L1, HDAC4, PIK3CA, SULF1, IL11RA, VEGFA, and 1p31.3, 2q35, 8p12, and 14q13.Conclusion: This analysis confirmed several published risk loci that could be involved in DTC predisposition.Impact: These findings provide evidence for the role of germline variants in DTC etiology and are consistent with a polygenic model of the disease. Cancer Epidemiol Biomarkers Prev; 25(4); 700–13. ©2016 AACR.
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- 2023
8. Supplementary Figure 2 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 734K, TLR5 structure is not perturbed by SNP-related amino acid exchanges.
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- 2023
9. Supplementary Table 2 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 28K, Characteristics of the 613 CRC patients at the time of diagnosis.
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- 2023
10. Supplementary Table 6 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 24K, Reported disease associations of TLR5 rs5744174 according to http://geneticassociationdb.nih.gov.
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- 2023
11. Supplementary Methods from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 182K
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- 2023
12. Supplementary Figure Legend from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 107K
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- 2023
13. Supplementary Figure 3 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 143K, Work flow for analyses in whole blood.
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- 2023
14. Supplementary Figure 1 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 23K, SNP rs4988453 does not alter the promoter activity of MyD88 or ACAA1 during starvation or the influence of PPAR inhibitors.
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- 2023
15. Supplementary Table 5 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 32K, Multivariate analysis of CRC survival and the polymorphisms TLR5 rs5744174, TIRAP rs611953 and rs625413 and MyD88 rs4988453.
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- 2023
16. Supplementary Table 4 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 42K, Association of polymorphisms with survival.
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- 2023
17. Supplementary Figure 4 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 24K, TLR4 function is not affected by TLR5 F616L in primary immune cells.
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- 2023
18. Supplementary Table 3 from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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PDF file - 32K, Association of selected polymorphisms with CRC clinical characteristics.
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- 2023
19. Data from Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
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Alexander N.R. Weber, Clemens Schafmayer, Kari Hemminki, Julia-Stefanie Frick, Dominik Hartl, Jochen Hampe, Jesus Lascorz, Sebastian Hinz, Jessica Walter, Nils Heits, Witigo von Schönfels, Melanie Bevier, Jelena Knežević, Jana Eckert, Asta Försti, and Sascha N. Klimosch
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Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1β mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. Cancer Res; 73(24); 7232–42. ©2013 AACR.
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- 2023
20. Are population level familial risks and germline genetics meeting each other?
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Kari Hemminki, Xinjun Li, Asta Försti, and Charis Eng
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Oncology ,Genetics (clinical) - Abstract
Large amounts of germline sequencing data have recently become available and we sought to compare these results with population-based family history data. Family studies are able to describe aggregation of any defined cancers in families. The Swedish Family-Cancer Database is the largest of its kind in the world, covering the Swedish families through nearly a century with all cancers in family members since the start of national cancer registration in 1958. The database allows estimation of familial risks, ages of cancer onset and the proportion of familial cancer in different family constellations. Here, we review the proportion of familial cancer for all common cancers and specify them based on the number of affected individuals. With the exception of a few cancers, age of onset of familial cancer is not different from all cancers combined. The highest proportions of familial cancer were found for prostate (26.4%), breast (17.5%) and colorectal (15.7%) cancers, but the proportions of high-risk families with multiple affected individuals were only 2.8%, 1% and 0.9%, respectively. A large sequencing study on female breast cancer found that BRCA1 and BRCA2 mutations could account for 2% of the cases (subtracting the proportions in healthy individuals) and that all germline mutations accounted for 5.6% of the cases. Early age of onset was a distinct feature of only BRCA mutations. In heritable colorectal cancer, Lynch syndrome genes dominate. Large studies on penetrance in Lynch syndrome have shown an approximately linear increase in risk from 40–50 years up to age 80 years. Interesting novel data revealed a strong modification of familial risk by unknown factors. High-risk germline genetics of prostate cancer is characterized by BRCA and other DNA repair genes. HOXB13 encodes a transcription factor which contributes to germline risk of prostate cancer. A strong interaction was shown with a polymorphism in the CIP2A gene. The emerging germline landscape of common cancers can be reasonably accommodated by family data on these cancers as to high-risk proportions and age of onset.
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- 2023
21. GWAS-Identified Variants for Obesity Do Not Influence the Risk of Developing Multiple Myeloma: A Population-Based Study and Meta-Analysis
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José Manuel Sánchez-Maldonado, Antonio José Cabrera-Serrano, Subhayan Chattopadhyay, Daniele Campa, María del Pilar Garrido, Angelica Macauda, Rob Ter Horst, Andrés Jerez, Mihai G. Netea, Yang Li, Kari Hemminki, Federico Canzian, Asta Försti, Juan Sainz, Institut Català de la Salut, [Sánchez-Maldonado JM, Cabrera-Serrano AJ] Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, Granada, Spain. [Chattopadhyay S] Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany. [Campa D] Department of Biology, University of Pisa, Pisa, Italy. [Garrido MDP] Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain. [Macauda A] Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Jerez A] Experimental Hematology Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Genetic variants ,Organic Chemistry ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES] ,Mieloma múltiple - Aspectes genètics ,Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight::Overweight::Obesity [DISEASES] ,Obesitat - Complicacions ,Hemic and Lymphatic Diseases::Hematologic Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Hemorrhagic Disorders::Hemostatic Disorders::Multiple Myeloma [DISEASES] ,General Medicine ,Catalysis ,Computer Science Applications ,enfermedades hematológicas y linfáticas::enfermedades hematológicas::enfermedades hematológicas y linfáticas::enfermedades hematológicas::trastornos hemorrágicos::trastornos hemostáticos::mieloma múltiple [ENFERMEDADES] ,Inorganic Chemistry ,All institutes and research themes of the Radboud University Medical Center ,Multiple myeloma ,Susceptibility ,afecciones patológicas, signos y síntomas::signos y síntomas::peso corporal::sobrepeso::obesidad [ENFERMEDADES] ,Obesity ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS] - Abstract
Multiple myeloma (MM) is an incurable disease characterized by the presence of malignant plasma cells in the bone marrow that secrete specific monoclonal immunoglobulins into the blood. Obesity has been associated with the risk of developing solid and hematological cancers, but its role as a risk factor for MM needs to be further explored. Here, we evaluated whether 32 genome-wide association study (GWAS)-identified variants for obesity were associated with the risk of MM in 4189 German subjects from the German Multiple Myeloma Group (GMMG) cohort (2121 MM cases and 2068 controls) and 1293 Spanish subjects (206 MM cases and 1087 controls). Results were then validated through meta-analysis with data from the UKBiobank (554 MM cases and 402,714 controls) and FinnGen cohorts (914 MM cases and 248,695 controls). Finally, we evaluated the correlation of these single nucleotide polymorphisms (SNPs) with cQTL data, serum inflammatory proteins, steroid hormones, and absolute numbers of blood-derived cell populations (n = 520). The meta-analysis of the four European cohorts showed no effect of obesity-related variants on the risk of developing MM. We only found a very modest association of the POC5rs2112347G and ADCY3rs11676272G alleles with MM risk that did not remain significant after correction for multiple testing (per-allele OR = 1.08, p = 0.0083 and per-allele OR = 1.06, p = 0.046). No correlation between these SNPs and functional data was found, which confirms that obesity-related variants do not influence MM risk., Instituto de Salud Carlos III (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Salud y Familia de la Junta de Andalucía (PY20/01282), Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS (01ZX1309)
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- 2023
22. Do GWAS-Identified Risk Variants for Chronic Lymphocytic Leukemia Influence Overall Patient Survival and Disease Progression?
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Antonio José Cabrera-Serrano, José Manuel Sánchez-Maldonado, Rob ter Horst, Angelica Macauda, Paloma García-Martín, Yolanda Benavente, Stefano Landi, Alyssa Clay-Gilmour, Yasmeen Niazi, Blanca Espinet, Juan José Rodríguez-Sevilla, Eva María Pérez, Rossana Maffei, Gonzalo Blanco, Matteo Giaccherini, James R. Cerhan, Roberto Marasca, Miguel Ángel López-Nevot, Tzu Chen-Liang, Hauke Thomsen, Irene Gámez, Daniele Campa, Víctor Moreno, Silvia de Sanjosé, Rafael Marcos-Gragera, María García-Álvarez, Trinidad Dierssen-Sotos, Andrés Jerez, Aleksandra Butrym, Aaron D. Norman, Mario Luppi, Susan L. Slager, Kari Hemminki, Yang Li, Sonja I. Berndt, Delphine Casabonne, Miguel Alcoceba, Anna Puiggros, Mihai G. Netea, Asta Försti, Federico Canzian, and Juan Sainz
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Genetic variants ,Organic Chemistry ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,All institutes and research themes of the Radboud University Medical Center ,Susceptibility ,Polygenic risk scoring ,Chronic lymphocytic leukemia ,Overall survival ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients, Horizon 2020 856620, Instituto de Salud Carlos III Spanish Government, Marie Curie Actions PI17/02256 PI20/01845, Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades y FEDER PY20/01282, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P50 CA97274 R01 CA92153
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- 2023
23. Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization
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Esther Clavero, José Manuel Sanchez-Maldonado, Angelica Macauda, Rob Ter Horst, Belém Sampaio-Marques, Artur Jurczyszyn, Alyssa Clay-Gilmour, Angelika Stein, Michelle A. T. Hildebrandt, Niels Weinhold, Gabriele Buda, Ramón García-Sanz, Waldemar Tomczak, Ulla Vogel, Andrés Jerez, Daria Zawirska, Marzena Wątek, Jonathan N. Hofmann, Stefano Landi, John J. Spinelli, Aleksandra Butrym, Abhishek Kumar, Joaquín Martínez-López, Sara Galimberti, María Eugenia Sarasquete, Edyta Subocz, Elzbieta Iskierka-Jażdżewska, Graham G. Giles, Malwina Rybicka-Ramos, Marcin Kruszewski, Niels Abildgaard, Francisco García Verdejo, Pedro Sánchez Rovira, Miguel Inacio da Silva Filho, Katalin Kadar, Małgorzata Razny, Wendy Cozen, Matteo Pelosini, Manuel Jurado, Parveen Bhatti, Marek Dudzinski, Agnieszka Druzd-Sitek, Enrico Orciuolo, Yang Li, Aaron D. Norman, Jan Maciej Zaucha, Rui Manuel Reis, Miroslaw Markiewicz, Juan José Rodríguez Sevilla, Vibeke Andersen, Krzysztof Jamroziak, Kari Hemminki, Sonja I. Berndt, Vicent Rajkumar, Grzegorz Mazur, Shaji K. Kumar, Paula Ludovico, Arnon Nagler, Stephen J. Chanock, Charles Dumontet, Mitchell J. Machiela, Judit Varkonyi, Nicola J. Camp, Elad Ziv, Annette Juul Vangsted, Elizabeth E. Brown, Daniele Campa, Celine M. Vachon, Mihai G. Netea, Federico Canzian, Asta Försti, Juan Sainz, Institut Català de la Salut, [Clavero E] Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain. [Sanchez-Maldonado JM] Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, Granada, Spain. Instituto de Investigación Biosanataria IBs, Granada, Granada, Spain. [Macauda A] Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Ter Horst R] Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, GA Nijmegen, The Netherlands. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [Sampaio-Marques B] Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal. [Jurczyszyn A] Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, Kraków, Poland. [Jerez A] Experimental Hematology Unit, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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fenómenos fisiológicos celulares::muerte celular::autofagia [FENÓMENOS Y PROCESOS] ,Cell Physiological Phenomena::Cell Death::Autophagy [PHENOMENA AND PROCESSES] ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,Organic Chemistry ,Hemic and Lymphatic Diseases::Hematologic Diseases::Blood Protein Disorders::Paraproteinemias::Hemic and Lymphatic Diseases::Hematologic Diseases::Multiple Myeloma [DISEASES] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Mieloma múltiple - Aspectes genètics ,General Medicine ,Biological Factors::Biomarkers [CHEMICALS AND DRUGS] ,Catalysis ,factores biológicos::biomarcadores [COMPUESTOS QUÍMICOS Y DROGAS] ,Computer Science Applications ,multiple myeloma ,autophagy ,genetic variants ,genetic susceptibility ,Inorganic Chemistry ,All institutes and research themes of the Radboud University Medical Center ,Autofàgia ,Marcadors bioquímics ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Physical and Theoretical Chemistry ,enfermedades hematológicas y linfáticas::enfermedades hematológicas::trastornos de las proteínas sanguíneas::paraproteinemias::enfermedades hematológicas y linfáticas::enfermedades hematológicas::mieloma múltiple [ENFERMEDADES] ,Molecular Biology ,Spectroscopy - Abstract
Autophagy; Genetic variants; Multiple myeloma Autofagia; Variantes genéticas; Mieloma múltiple Autofàgia; Variants genètiques; Mieloma múltiple Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10−9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways. This work was supported by the European Union’s Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB). This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).
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- 2023
24. Author Correction: Functional dissection of inherited non-coding variation influencing multiple myeloma risk
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Ram Ajore, Abhishek Niroula, Maroulio Pertesi, Caterina Cafaro, Malte Thodberg, Molly Went, Erik L. Bao, Laura Duran-Lozano, Aitzkoa Lopez de Lapuente Portilla, Thorunn Olafsdottir, Nerea Ugidos-Damboriena, Olafur Magnusson, Mehmet Samur, Caleb A. Lareau, Gisli H. Halldorsson, Gudmar Thorleifsson, Gudmundur L. Norddahl, Kristbjorg Gunnarsdottir, Asta Försti, Hartmut Goldschmidt, Kari Hemminki, Frits van Rhee, Scott Kimber, Adam S. Sperling, Martin Kaiser, Kenneth Anderson, Ingileif Jonsdottir, Nikhil Munshi, Thorunn Rafnar, Anders Waage, Niels Weinhold, Unnur Thorsteinsdottir, Vijay G. Sankaran, Kari Stefansson, Richard Houlston, and Björn Nilsson
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
25. LONG-TERM SURVIVAL TRENDS IN SOLID CANCERS IN THE NORDIC COUNTRIES MARKING TIMING OF IMPROVEMENTS
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Kari Hemminki, Asta Försti, Vaclav Liska, Anna Kanerva, Otto Hemminki, Akseli Hemminki, Research Programs Unit, HUS Gynecology and Obstetrics, Akseli Eetu Hemminki / Principal Investigator, Clinicum, University of Helsinki, TRIMM - Translational Immunology Research Program, Department of Obstetrics and Gynecology, HUS Abdominal Center, Urologian yksikkö, Department of Oncology, and HUS Comprehensive Cancer Center
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Treatment ,Cancer Research ,periodic survival ,treatment ,Oncology ,3122 Cancers ,Periodic survival ,relative survival ,prognosis ,Early diagnosis ,Prognosis ,Relative survival ,early diagnosis - Abstract
Survival studies are an important indicator of the success of cancer control. We analyzed the 5-year relative survival in 23 solid cancers in Denmark, Finland, Norway and Sweden over a 50-year period (1970-2019) at the NORDCAN database accessed from the International Agency for Research on Cancer website. We plotted survival curves in 5-year periods and showed 5-year periodic survival. The survival results were summarized in 4 groups: 1) cancers with historically good survival (50% in 1970-74) which include melanoma and breast, endometrial and thyroid cancers; 2) cancers which constantly improved survival at least 20 % units over the 50 year period, including cancers of the stomach, colon, rectum, kidney, brain and ovary; 3) cancer with increase in survival20 % units with changes taking place in a narrow time window, including oral, oropharyngeal, testicular and prostate cancers; 4) the remaining cancers with20 % unit improvement in survival including lung, esophageal, liver, pancreatic, bladder, soft tissue, penile, cervical and vulvar cancers. For cancers in groups 1 and 2, the constant development implied multiple improvements in therapy, diagnosis and patient care. Cancers in group 3 included testicular cancers with known therapeutic improvements but for the others large incidence changes probably implied that cancer stage (prostate) or etiology (oropharynx) changed into a more tractable form. Group 4 cancers included those with dismal survival 50 years ago but a clear tendency upwards. In 17 cancers 5-year survival reached between 50 and 100 % while in only 6 cancers it remained at below 50%. This article is protected by copyright. All rights reserved.
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- 2022
26. Personal comorbidities and their subsequent risks for liver, gallbladder and bile duct cancers
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Kari Hemminki, Kristina Sundquist, Jan Sundquist, Asta Försti, Vaclav Liska, Akseli Hemminki, Xinjun Li, Department of Oncology, HUS Comprehensive Cancer Center, University of Helsinki, and TRIMM - Translational Immunology Research Program
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Cancer Research ,alcohol ,3122 Cancers ,VIRUS-INFECTION ,hepatocellular carcinoma ,TRENDS ,DISEASE ,smoking ,comorbidity ,INFLAMMATION ,Oncology ,risk factor ,HEPATOCELLULAR-CARCINOMA ,familial risk - Abstract
Many environmental risk factors for hepatobiliary cancers are known but whether they are associated with specific cancer types is unclear. We present here a novel approach of assessing standardized incidence ratios (SIRs) of previously diagnosed comorbidities for hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cholangiocarcinoma (CCA) and ampullary cancer. The 13 comorbidities included alcohol and nonalcohol related liver disease, chronic obstructive pulmonary disease, gallstone disease, viral and other kinds of hepatitis, infection of bile ducts, hepatic and other autoimmune diseases, obesity and diabetes. Patients were identified from the Swedish Inpatient Register from 1987 to 2018, and their cancers were followed from 1997 onwards. SIRs for HCC were 80 to 100 in men and women diagnosed with hepatitis C virus and they were also >10 in patients diagnosed with hepatitis B virus, other kind of hepatitis, hepatic autoimmune disease and nonalcohol related liver disease. Many of these risks, as well as alcohol related liver disease, were either specific to HCC or were shared with intrahepatic CCA. For GBC, CCA and ampullary cancer infection of bile ducts was the main risk factor. Gallstone disease, nonhepatic autoimmune diseases and diabetes were associated with all hepatobiliary cancers. The limitations of the study include inability to cover some rare risk factors and limited follow-up time. Many of the considered comorbidities are characterized by chronic inflammation and/or overt immune disturbance in autoimmune diseases. The results suggest that local chronic inflammation and a related immune disturbance is the carcinogenic trigger for all these cancers.
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- 2022
27. Overview on population screening for carriers with germline BRCA mutation in China
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Huijun Lei, Min Zhang, Luyao Zhang, Kari Hemminki, Xiao-jia Wang, and Tianhui Chen
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Cancer Research ,Oncology - Abstract
Carriers with BRCA1/2 germline pathogenic variants are associated with a high risk of breast and ovarian cancers (also pancreatic and prostate cancers). While the spectrum on germline BRCA mutations among the Chinese population shows ethnic specificity, the identification of carriers with germline BRCA mutation before cancer onset is the most effective approach to protect them. This review focused on the current status of BRCA1/2 screening, the surveillance and prevention measures, and discussed the issues and potential impact of BRCA1/2 population screening in China. We conducted literature research on databases PubMed and Google Scholar, as well as Chinese databases CNKI and Wangfang Med Online database (up to 31 March 2022). Latest publications on germline BRCA1/2 prevalence, spectrum, genetic screening as well as carrier counseling, surveillance and prevention were captured where available. While overall 15,256 records were retrieved, 72 publications using germline BRCA1/2 testing were finally retained for further analyses. Germline BRCA1/2 mutations are common in Chinese patients with hereditary breast, ovarian, prostate and pancreatic cancers. Within previous studies, a unique BRCA mutation spectrum in China was revealed. Next-generation sequencing panel was considered as the most common method for BRCA1/2 screening. Regular surveillance and preventive surgeries were tailored to carriers with mutated-BRCA1/2. We recommend that all Chinese diagnosed with breast, ovarian, pancreatic or prostate cancers and also healthy family members, shall undergo BRCA1/2 gene test to provide risk assessment. Subsequently, timely preventive measures for mutation carriers are recommended after authentic genetic counseling.
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- 2022
28. Theranostics Nanomedicine Applications for Colorectal Cancer and Metastasis: Recent Advances
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Phanindra Babu Kasi, Venkata Ramana Mallela, Filip Ambrozkiewicz, Andriy Trailin, Václav Liška, and Kari Hemminki
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Inorganic Chemistry ,theranostics ,clinical status ,Organic Chemistry ,cancer therapy ,colorectal cancer ,General Medicine ,Physical and Theoretical Chemistry ,nanomedicine ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, and metastatic CRC is a fatal disease. The CRC-affected tissues show several molecular markers that could be used as a fresh strategy to create newer methods of treating the condition. The liver and the peritoneum are where metastasis occurs most frequently. Once the tumor has metastasized to the liver, peritoneal carcinomatosis is frequently regarded as the disease’s final stage. However, nearly 50% of CRC patients with peritoneal carcinomatosis do not have liver metastases. New diagnostic and therapeutic approaches must be developed due to the disease’s poor response to present treatment choices in advanced stages and the necessity of an accurate diagnosis in the early stages. Many unique and amazing nanomaterials with promise for both diagnosis and treatment may be found in nanotechnology. Numerous nanomaterials and nanoformulations, including carbon nanotubes, dendrimers, liposomes, silica nanoparticles, gold nanoparticles, metal-organic frameworks, core-shell polymeric nano-formulations, and nano-emulsion systems, among others, can be used for targeted anticancer drug delivery and diagnostic purposes in CRC. Theranostic approaches combined with nanomedicine have been proposed as a revolutionary approach to improve CRC detection and treatment. This review highlights recent studies, potential, and challenges for the development of nanoplatforms for the detection and treatment of CRC.
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- 2023
29. Response to letter entitled: Re: Survival trends in solid cancers in the Nordic countries through 50 years
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Kari Hemminki
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Cancer Research ,Oncology - Published
- 2023
30. Genome-wide meta-analysis of monoclonal gammopathy of undetermined significance (MGUS) identifies risk loci impacting IRF-6
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Alyssa Clay-Gilmour, Subhayan Chattopadhyay, Michelle A. T. Hildebrandt, Hauke Thomsen, Niels Weinhold, Pavel Vodicka, Ludmila Vodickova, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Börge Schmidt, Christian Langer, Roman Hajek, Göran Hallmans, Ulrika Pettersson-Kymmer, Claes Ohlsson, Florentin Späth, Richard Houlston, Hartmut Goldschmidt, Elisabet E. Manasanch, Aaron Norman, Shaji Kumar, S. Vincent Rajkumar, Susan Slager, Asta Försti, Celine M. Vachon, and Kari Hemminki
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Oncology ,Medizin ,Paraproteinemias ,Humans ,Hematologi ,Hematology ,Monoclonal Gammopathy of Undetermined Significance - Abstract
CA extern
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- 2022
31. Second Primary Cancers After Kidney Cancers, and Kidney Cancers as Second Primary Cancers
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Asta Försti, Otto Hemminki, Kristina Sundquist, Kari Hemminki, Jan Sundquist, Guoqiao Zheng, Tianhui Chen, Research Programs Unit, Clinicum, TRIMM - Translational Immunology Research Program, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, and Helsinki University Hospital Area
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Oncology ,medicine.medical_specialty ,STRATEGIES ,Urology ,lcsh:RC870-923 ,lcsh:RC254-282 ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,RENAL-CELL CARCINOMA ,Renal cell carcinoma ,Internal medicine ,Medicine ,Family history ,Lung cancer ,030304 developmental biology ,RISK ,0303 health sciences ,business.industry ,Cancer ,Cancer etiology ,Kidney Cancer ,3126 Surgery, anesthesiology, intensive care, radiology ,Sex difference ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,UPPER URINARY-TRACT ,3. Good health ,Cancer registry ,Relative risk ,UROTHELIAL CARCINOMA ,030220 oncology & carcinogenesis ,business ,Second primary cancer ,Kidney cancer ,Cancer incidence ,Cancer Etiology ,NEOPLASMS - Abstract
Background Second primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce. Objective In this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks. Design, setting, and participants Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register. Outcome measurements and statistical analysis We employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC. Results and limitations We identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC. Conclusions The bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits. Patient summary Close to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer., Take Home Message The study results recommend considering strategies for early detection and prevention of second primary cancer. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits.
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- 2021
32. An investigation of DNA damage and DNA repair in chemical carcinogenesis triggered by small-molecule xenobiotics and in cancer: Thirty years with the comet assay
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Pavel Vodicka, Sona Vodenkova, Josef Horak, Alena Opattova, Kristyna Tomasova, Veronika Vymetalkova, Rudolf Stetina, Kari Hemminki, and Ludmila Vodickova
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Health, Toxicology and Mutagenesis ,Genetics - Published
- 2023
33. Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients
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Ludmila Vodickova, Andrea Cumova, Sivaramakrishna Rachakonda, Pavel Soucek, Rajesh Kumar, Sona Vodenkova, Michal Kroupa, Andrea Rossnerova, Kari Hemminki, Vaclav Liska, Veronika Vymetalkova, Kristyna Tomasova, and Pavel Vodicka
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Adult ,lymphocytes ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genotype ,Health, Toxicology and Mutagenesis ,Breast Neoplasms ,Genome-wide association study ,Single-nucleotide polymorphism ,telomerase ,Toxicology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Genetic model ,Biomarkers, Tumor ,Leukocytes ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Alleles ,Genetics (clinical) ,Aged ,Neoplasm Staging ,Genetic association ,Cancer staging ,Aged, 80 and over ,business.industry ,Telomere Homeostasis ,Middle Aged ,peripheral blood ,medicine.disease ,3. Good health ,030104 developmental biology ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,genetic variation ,Leukocytes, Mononuclear ,RNA ,Female ,business ,Genome-Wide Association Study - Abstract
Disruption of telomere length (TL) homeostasis in peripheral blood lymphocytes has been previously assessed as a potential biomarker of breast cancer (BC) risk. The present study addressed the relationship between lymphocyte TL (LTL), prognosis and clinicopathological features in the BC patients since these associations are insufficiently explored at present. LTL was measured in 611 BC patients and 154 healthy controls using the monochrome multiplex quantitative Polymerase Chain Reaction assay. In addition, we genotyped nine TL-associated single-nucleotide polymorphisms that had been identified through genome-wide association studies. Our results showed that the patients had significantly (P = 0.001, Mann–Whitney U-test) longer LTL [median (interquartile range); 1.48 (1.22–1.78)] than the healthy controls [1.27 (0.97–1.82)]. Patients homozygous (CC) for the common allele of hTERT rs2736108 or the variant allele (CC) of hTERC rs16847897 had longer LTL. The latter association remained statistically significant in the recessive genetic model after the Bonferroni correction (P = 0.004, Wilcoxon two-sample test). We observed no association between LTL and overall survival or relapse-free survival of the patients. LTL did not correlate with cancer staging based on Union for International Cancer Control (UICC), The tumor node metastasis (TNM) staging system classification, tumour grade or molecular BC subtypes. Overall, we observed an association between long LTL and BC disease and an association of the hTERC rs16847897 CC genotype with increased LTL. However, no association between LTL, clinicopathological features and survival of the patients was found.
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- 2020
34. Overview on health research ethics in North Africa
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Meriem Khyatti, Amina Gihbid, Diaa Marzouk, Wafaa Abd El Aal, Azza Saleh, Hany Sleem, My Driss El Messaoudi, Kari Hemminki, and Wagida A Anwar
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The purpose of this article is to overview the status of health research ethics in Morocco and NA countries, with reference to other Middle Eastern countries. The EU and NA Migrants: Health and Health Systems project (EUNAM) has supported the revision of the status of health research ethics in NA countries, by holding meetings and discussions to collect information about research ethics committees in Egypt, and revising the structure and guidelines of the committees, as well as reviewing the literature concerning ethics activities in the concerned countries. This overview has revealed that although efforts regarding health research ethics in NA countries need to be enhanced, in the form of establishment of more institutional ethics committees, noticeable efforts have been made to regulate research ethics in certain countries in the Middle East, This can be seen in the new regulations, which contain the majority of protections mentioned in the international guidelines related to research ethics. For most of the internationally registered research ethics committees in NA countries, the composition and functionality reflect the international guidelines. National Research Ethics laws and increased collaborative activities between these countries are crucial requirements. Furthermore, although there is growing awareness of research ethics in these countries, which extends to teaching efforts to undergraduate and postgraduate medical students, National guidelines for strengthening ethical review systems, as well as enhanced educational training of research ethics for investigators, are needed in this region.Keywords: health research, ethics, North Africa
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- 2022
35. Incidence Differences Between First Primary Cancers and Second Primary Cancers Following Skin Squamous Cell Carcinoma as Etiological Clues
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Akseli Hemminki, Kristina Sundquist, Jan Sundquist, Guoqiao Zheng, Asta Försti, and Kari Hemminki
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Oncology ,medicine.medical_specialty ,Epidemiology ,business.industry ,Melanoma ,Incidence (epidemiology) ,Cancer ,030204 cardiovascular system & hematology ,medicine.disease ,3. Good health ,Cancer registry ,03 medical and health sciences ,0302 clinical medicine ,Relative risk ,Internal medicine ,medicine ,Etiology ,Skin Squamous Cell Carcinoma ,030212 general & internal medicine ,Skin cancer ,business - Abstract
Background: Most literature on second primary cancers (SPCs) focuses on possible factors, which may increase the risk of these cancers, and little attention has been paid for the overall incidence differences between first primary cancers (FPCs) and same SPCs. We wanted to compare the incidence rates for all common cancers when these were diagnosed as FPCs and SPCs after invasive and in situ squamous cell carcinoma (SCC) of the skin, which are usually treated by surgery only. Methods: Cancers were identified from the Swedish Cancer Registry from the years 1990 through to 2015, and they included, in addition to skin cancers, 20 male cancers totaling 484,850 patients and 22 female cancers totaling 452,909 patients. Standardized incidence rates and relative risks (RRs) were calculated for sex-specific common cancers as FPC and as SPC after skin SCC. Spearman rank correlations were used in the analysis of incidence ranking of FPC and SPC. Results: Of total, 29,061 men and 23,533 women developed invasive SCC and 27,842 men and 36,383 women in situ SCC. The total number of 20 other male cancers was 484,850 and of 22 female cancers it was 452,909. Rank correlations ranged from 0.90 to 0.96 (P~5×10−6), indicating that overall skin SCC did not interfere with SPC formation. The exceptions were increased SPC risks for melanoma, sharing risk factors with skin SCC, and non-Hodgkin and Hodgkin lymphoma, and cancers of the upper aerodigestive tract, connective tissue, and male and female genitals suggesting contribution by skin cancer initiated immune dysfunction. Conclusion: The incidence ranking of SPCs after skin cancers largely follows the incidence ranking of FPCs indicating that overall skin SCC does not greatly interfere with the intrinsic carcinogenic process. The main deviations in incidence between FPC and SPC appeared to be due to shared risk factors or immunological processes promoting immune responsive cancer types. (Less)
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- 2020
36. Genetic predisposition for multiple myeloma
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Maroulio Pertesi, Richard S. Houlston, Björn Nilsson, Kari Hemminki, Markus Hansson, and Molly Went
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0301 basic medicine ,Genetics ,Cancer Research ,medicine.medical_specialty ,Candidate gene ,Family aggregation ,Genome-wide association study ,Hematology ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Genetic variation ,Genetic predisposition ,medicine ,Medical genetics ,Allele ,Genetic association - Abstract
Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct evidence for genetic predisposition to MM. Genome-wide association studies have identified common risk alleles at 24 independent loci. Sequencing studies of familial cases and kindreds have begun to identify promising candidate genes where variants with strong effects on MM risk might reside. Finally, functional studies are starting to give insight into how identified risk alleles promote the development of MM. Here, we review recent findings in MM predisposition field, and highlight open questions and future directions.
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- 2020
37. Second Primary Cancers in Melanoma Patients Critically Shorten Survival
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Subhayan Chattopadhyay, Akseli Hemminki, Guoqiao Zheng, Jan Sundquist, Asta Försti, Kristina Sundquist, and Kari Hemminki
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Oncology ,medicine.medical_specialty ,Relative survival ,Epidemiology ,Proportional hazards model ,business.industry ,Melanoma ,Hazard ratio ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,3. Good health ,Metastasis ,Cancer registry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,business ,Survival analysis - Abstract
Background: Survival in malignant cutaneous melanoma has improved but increasing survival will result in an increased likelihood of the occurrence of second primary cancers (SPCs). SPCs may adversely interfere with survival. We quantified survival in patients with different types of SPCs, in comparison to known poor prognostic indicators of metastatic disease. Methods: Data for melanoma and any SPCs were obtained from the Swedish Cancer Registry for years 2003 through 2015, including clinical TNM classification. SPCs were grouped into three ‘prognostic groups’ based on 5-year relative survival of these cancers as first primary cancer. Kaplan-Meier survival curves were generated and hazard ratios were estimated using Cox regression, adjusted for a number of variables and treating diagnosis of SPC as a time-dependent variable. Results: The total number of first melanoma patients was 28,716 followed by 3,202 (11.1%) SPCs, 1/3 of which had a second melanoma while 2/3 had other SPCs. Among men diagnosed at age over 70 years, who survived at least 10 years, 31.4% had SPC. HRs (95% CI) for survival increased systematically from the reference rate of 1.00 (no SPC) to 1.59 (1.35–1.87) with SPC of good prognosis (78.6% of SPCs) to 3.49 (2.58–4.72) of moderate prognosis (12.0%) and to 7.93 (5.50–11.44) of poor prognosis (9.4%). In patients without SPC, the HRs increased to 2.62 (2.02–3.39) with any nodal metastases and to 5.88 (4.57–7.57) with any distant metastases compared to patients without local or distant metastases. Conclusion: The data showed that SPCs are an increasingly common negative prognostic factor for melanoma. Future attempts to improve melanoma survival need to target SPCs. (Less)
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- 2020
38. Germline Variants of
- Author
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Lizhen, Zhu, Beiping, Miao, Dagmara, Dymerska, Magdalena, Kuswik, Elena, Bueno-Martínez, Lara, Sanoguera-Miralles, Eladio A, Velasco, Nagarajan, Paramasivam, Matthias, Schlesner, Abhishek, Kumar, Ying, Yuan, Jan, Lubinski, Obul Reddy, Bandapalli, Kari, Hemminki, and Asta, Försti
- Abstract
Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the
- Published
- 2021
39. Whole-Exome Sequencing Identifies a Novel Germline Variant in
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Beiping, Miao, Diamanto, Skopelitou, Aayushi, Srivastava, Sara, Giangiobbe, Dagmara, Dymerska, Nagarajan, Paramasivam, Abhishek, Kumar, Magdalena, Kuświk, Wojciech, Kluźniak, Katarzyna, Paszkowska-Szczur, Matthias, Schlesner, Jan, Lubinski, Kari, Hemminki, Asta, Försti, and Obul Reddy, Bandapalli
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Male ,Receptor Protein-Tyrosine Kinases ,Oncogenes ,Middle Aged ,Pedigree ,Cell Movement ,Exome Sequencing ,Humans ,Family ,Female ,Genetic Predisposition to Disease ,Neoplasm Invasiveness ,Tumor Suppressor Protein p53 ,Colorectal Neoplasms ,Cyclic AMP Response Element-Binding Protein ,Cell Adhesion Molecules ,Proto-Oncogene Proteins c-akt ,Germ-Line Mutation ,Aged ,Cell Proliferation - Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (
- Published
- 2021
40. Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
- Author
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Yasmeen Niazi, Nagarajan Paramasivam, Joanna Blocka, Abhishek Kumar, Stefanie Huhn, Matthias Schlesner, Niels Weinhold, Rolf Sijmons, Mirjam De Jong, Brian Durie, Hartmut Goldschmidt, Kari Hemminki, and Asta Försti
- Subjects
non-coding genome ,familial multiple myeloma ,MAPK pathway ,whole-genome sequencing ,General Medicine - Abstract
Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5′ untranslated region (UTR) and 3′ UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways.
- Published
- 2022
41. Genetic epidemiology of colorectal cancer and associated cancers
- Author
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Kari Hemminki and Hong-Yao Yu
- Subjects
Adult ,Male ,Oncology ,Proband ,medicine.medical_specialty ,Databases, Factual ,Colorectal cancer ,Health, Toxicology and Mutagenesis ,Genetic counseling ,Toxicology ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Databases, Genetic ,Genetics ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Lung cancer ,Melanoma ,Genetics (clinical) ,030304 developmental biology ,Sweden ,0303 health sciences ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,Adenomatous Polyposis Coli ,Genetic epidemiology ,030220 oncology & carcinogenesis ,Relative risk ,Female ,Colorectal Neoplasms ,business - Abstract
We review here data on familial risk in colorectal cancer (CRC) generated from the Swedish Family-Cancer Database, the largest resource of its kind in the world. Although the concordant familial risk for CRC (i.e. CRC risk in families of CRC patients) has been reasonably well established, the studies on discordant familial risks (i.e. CRC risk in families with any other cancers) are rare. Because different cancers could be caused by shared genetic susceptibility or shared environment, data of associations of discordant cancers may provide useful information for identifying common risk factors. In analyses between any of 33 discordant cancers relative risks (RRs) for discordant cancers were estimated in families with increasing numbers of probands with CRC; in the reverse analyses, RRs for CRC were estimated in families with increasing numbers of probands with discordant cancers. In separate analyses, hereditary non-polyposis colorectal cancer (HNPCC) families were excluded from the study, based on HNPCC related double primary cancers, to assess the residual familial RRs. We further reviewed familial risks of colon and rectal cancers separately in search for distinct discordant associations. The reviewed data suggested that colon cancer was associated with a higher familial risk for CRC compared to rectal cancer. The previous data had reported associations of CRC with melanoma, thyroid and eye cancers. Nervous system cancer was only associated with colon cancer, and lung cancer only associated with rectal cancer. The reviewed data on discordant association may provide guidance to gene identification and may help genetic counseling.
- Published
- 2019
42. Second primary cancers in non‐Hodgkin lymphoma: Family history and survival
- Author
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Richard S. Houlston, Amit Sud, Subhayan Chattopadhyay, Jan Sundquist, Kari Hemminki, Guoqiao Zheng, Kristina Sundquist, Akseli Hemminki, Asta Försti, Department of Oncology, HUS Comprehensive Cancer Center, University of Helsinki, and Faculty of Medicine
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Databases, Factual ,3122 Cancers ,Kaplan-Meier Estimate ,survival ,Second Primary Cancers ,MALIGNANCIES ,03 medical and health sciences ,prognostic grouping ,AGE ,0302 clinical medicine ,prevention ,EUROPE 1999-2007 ,Internal medicine ,SWEDEN ,Humans ,HISTOLOGY ,Medicine ,familial risk ,Family history ,Risk factor ,Family Health ,RISK ,business.industry ,Lymphoma, Non-Hodgkin ,Hazard ratio ,DEATH ,Cancer ,Neoplasms, Second Primary ,Middle Aged ,Familial risk ,second cancers ,medicine.disease ,TUMORS ,TIME ,3. Good health ,Lymphoma ,REGISTRY ,030220 oncology & carcinogenesis ,Relative risk ,Female ,business - 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 were associated with risks of these cancers as SPCs, with 2 to 5-fold increases 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 = 4.6x10-5. 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. This article is protected by copyright. All rights reserved.
- Published
- 2019
43. Update on genetic predisposition to colorectal cancer and polyposis
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Sergi Castellví-Bel, Maren Fridtjofsen Olsen, Trinidad Caldés, Richarda M. de Voer, Kari Hemminki, Laura Valle, Clara Ruiz-Ponte, Yael Goldberg, Pilar Garre, Margareta Nordling, Wenche Sjursen, and Asta Försti
- Subjects
0301 basic medicine ,Candidate gene ,Cancer-Predisposing Gene ,Colorectal cancer ,Clinical Biochemistry ,Biochemistry ,Germline ,03 medical and health sciences ,0302 clinical medicine ,Càncer colorectal ,medicine ,Genetic predisposition ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Malalties hereditàries ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Alleles ,Germ-Line Mutation ,Genetic testing ,Genetics ,medicine.diagnostic_test ,business.industry ,Genetic Variation ,General Medicine ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,030104 developmental biology ,Adenomatous Polyposis Coli ,MSH3 ,030220 oncology & carcinogenesis ,Molecular Medicine ,DNA mismatch repair ,Colorectal Neoplasms ,business ,Genetic disorders ,Biomarkers - Abstract
The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition. © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). DOI: 10.1016/j.mam.2019.03.001
- Published
- 2019
44. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults
- Author
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Ruth M. Pfeiffer, Emma E. McGee, Jill Koshiol, Katherine A. McGlynn, Kari Hemminki, Felipe A. Castro, Neal D. Freedman, Rachael Z. Stolzenberg-Solomon, Eric A. Engels, and Leticia Nogueira
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Case-control study ,Cancer ,Odds ratio ,medicine.disease ,Primary sclerosing cholangitis ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,Epidemiology ,medicine ,Gallbladder cancer ,business ,Liver cancer ,Intrahepatic Cholangiocarcinoma - Abstract
Growing evidence suggests that people with autoimmune conditions may be at increased risk of hepatobiliary tumors. In the present study, we evaluated associations between autoimmune conditions and hepatobiliary cancers among adults aged ≥66 in the United States. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data (1992–2013) to conduct a population-based, case–control study. Cases (n = 32,443) had primary hepatobiliary cancer. Controls (n = 200,000) were randomly selected, cancer-free adults frequency-matched to cases by sex, age and year of selection. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations with 39 autoimmune conditions identified via Medicare claims. We also conducted separate analyses for diagnoses obtained via inpatient versus outpatient claims. Sixteen conditions were associated with at least one hepatobiliary cancer. The strongest risk estimates were for primary biliary cholangitis with hepatocellular carcinoma (OR: 31.33 [95% CI: 23.63–41.56]) and primary sclerosing cholangitis with intrahepatic cholangiocarcinoma (7.53 [5.73–10.57]), extrahepatic cholangiocarcinoma (5.59 [4.03–7.75]), gallbladder cancer (2.06 [1.27–3.33]) and ampulla of Vater cancer (6.29 [4.29–9.22]). Associations with hepatobiliary-related conditions as a group were observed across nearly all cancer sites (ORs ranging from 4.53 [95% CI: 3.30–6.21] for extrahepatic cholangiocarcinoma to 7.18 [5.94–8.67] for hepatocellular carcinoma). Restricting to autoimmune conditions diagnosed via inpatient claims, 6 conditions remained associated with at least one hepatobiliary cancer, and several risk estimates increased. In the outpatient restricted analysis, 12 conditions remained associated. Multiple autoimmune conditions are associated with hepatobiliary cancer risk in the US Medicare population, supporting a shared immuno-inflammatory etiology to these cancers.
- Published
- 2018
45. Borderline Ovarian Tumors Share Familial Risks with Themselves and Invasive Cancers
- Author
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Hongyao Yu, Guoqiao Zheng, Anna Kanerva, Kristina Sundquist, Kari Hemminki, and Asta Försti
- Subjects
Oncology ,medicine.medical_specialty ,Epidemiology ,Offspring ,Genetic counseling ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Family history ,Ovarian Neoplasms ,030219 obstetrics & reproductive medicine ,Preventive strategy ,business.industry ,Thyroid ,Anus ,medicine.disease ,3. Good health ,Leukemia ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Borderline ovarian tumors ,business - Abstract
Background: Borderline ovarian tumors (BOTs) are a subgroup of ovarian malignancies with low malignant potential. Very limited earlier data are available on familial clustering of BOTs with other cancers. We aim to explore histology-specific familial associations among BOTs and associations between BOTs and any invasive cancers. Methods: On the basis of 16.1 million individuals in the Swedish Family-Cancer Database, we estimated familial risks for overall or histology-specific patients with BOT considering both BOT and any invasive cancers in first-degree relatives (parents or siblings), as well as familial risks for invasive cancers considering family history of BOTs. Results: A total of 4,199 BOT cases were found in the offspring generation; among them, 34 (0.8%) cases had first-degree relatives diagnosed with any BOT, and 2,489 (59.3%) cases with any invasive cancers. A family history of BOT was associated with risks for all BOTs (RR = 2.20, P < 0.001). Papillary BOT in first-degree relatives was associated with the increased risk of having the same type of BOT (RR = 10.10, P < 0.001). BOTs showed familial associations with some invasive cancers, most consistently with colorectal, ovarian, pancreatic, lung, and bone cancers, and with leukemia. In histologic analyses, associations of BOT with even rare cancers of the anus, thyroid, and endocrine glands were noted. Conclusions: BOTs may share susceptibility with themselves and a number of invasive cancers. Impact: These results provide insight into familial associations of BOT for the first time, which may help with the etiologic mechanism and preventive strategy of BOTs, as well as the genetic counseling for patients with BOT. Cancer Epidemiol Biomarkers Prev; 27(11); 1358–63. ©2018 AACR.
- Published
- 2018
46. Genetic variation associated with chromosomal aberration frequency: A genome‐wide association study
- Author
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Alena Kazimirova, Magdalena Barancokova, Sona Vodenkova, Marta Staruchova, Markus M. Nöthen, Maria Dusinska, Asta Försti, Ludovit Musak, Ludmila Vodickova, Per Hoffmann, Yasmeen Niazi, Kari Hemminki, Katarina Volkovova, Pavel Vodicka, Hauke Thomsen, Michal Kroupa, Bozena Smolkova, and Veronika Vymetalkova
- Subjects
Adult ,Male ,Slovakia ,medicine.medical_specialty ,DNA Repair ,Epidemiology ,Health, Toxicology and Mutagenesis ,Single-nucleotide polymorphism ,Genome-wide association study ,010501 environmental sciences ,Biology ,Polymorphism, Single Nucleotide ,01 natural sciences ,03 medical and health sciences ,Neoplasms ,Genetic variation ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Autistic Disorder ,Promoter Regions, Genetic ,Gene ,Genetics (clinical) ,Czech Republic ,030304 developmental biology ,0105 earth and related environmental sciences ,Chromosome Aberrations ,Genetics ,0303 health sciences ,Chromosome ,Cancer ,Middle Aged ,medicine.disease ,Cytogenetic Analysis ,Medical genetics ,Female ,Down Syndrome ,DNA Damage ,Genome-Wide Association Study - Abstract
Chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBL) measured with the conventional cytogenetic assay have been used for human biomonitoring of genotoxic exposure for decades. CA frequency in peripheral blood is a marker of cancer susceptibility. Previous studies have shown associations between genetic variants in metabolic pathway, DNA repair and major mitotic checkpoint genes and CAs. We conducted a genome-wide association study on 576 individuals from the Czech Republic and Slovakia followed by a replication in two different sample sets of 482 (replication 1) and 1288 (replication 2) samples. To have a broad look at the genetic susceptibility associated with CA frequency, the sample sets composed of individuals either differentially exposed to smoking, occupational/environmental hazards, or they were untreated cancer patients. Phenotypes were divided into chromosome- and chromatid-type aberrations (CSAs and CTAs, respectively) and total chromosomal aberrations (CAtot). The arbitrary cutoff point between individuals with high and low CA frequency was 2% for CAtot and 1% for CSA and CTA. The data were analyzed using age, sex, occupation/cancer and smoking history as covariates. Altogether 11 loci reached the P-value of 10−5 in the GWAS. Replication 1 supported the association of rs1383997 (8q13.3) and rs2824215 (21q21.1) in CAtot and rs983889 (5p15.1) in CTA analysis. These loci were found to be associated with genes involved in mitosis, response to environmental and chemical factors and genes involved in syndromes linked to chromosomal abnormalities. Identification of new genetic variants for the frequency of CAs offers prediction tools for cancer risk in future. 2018 Wiley Periodicals, Inc. (Less)
- Published
- 2018
47. Familial risks of second primary cancers and mortality in ovarian cancer patients
- Author
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Asta Försti, Subhayan Chattopadhyay, Guoqiao Zheng, Kristina Sundquist, and Kari Hemminki
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Epidemiology ,familial cancer ,Second Primary Cancers ,lcsh:Infectious and parasitic diseases ,cause of death ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,second primary cancer ,cumulative incidence ,medicine ,lcsh:RC109-216 ,Clinical Epidemiology ,Cumulative incidence ,Family history ,Original Research ,Cause of death ,business.industry ,Cancer ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Relative risk ,Etiology ,Ovarian cancer ,business - Abstract
Guoqiao Zheng,1,2 Subhayan Chattopadhyay,1,2 Asta Försti,1,3 Kristina Sundquist,3–6 Kari Hemminki1,3 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany; 2Faculty of Medicine, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany; 3Center for Primary Health Care Research, Lund University, 205 02 Malmö, Skåne County, Sweden; 4Department of Family Medicine and Community Health, 5Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Izumo, Japan Background: With improving survival in ovarian cancer, second primary cancers (SPCs) and their etiological foundations are becoming an issue. The ways in which family history may influence the occurrence of SPCs and the related mortality are not well known. Methods: Based on the Swedish Family-Cancer Database, we identified 11,300 ovarian cancer patients and followed them for diagnoses of SPCs until the end of 2015. Relative risks (RRs) of SPC in patients who had parents or siblings diagnosed with the same cancer (positive family history) were compared to those in patients without a family history (negative family history). Causes of death were compared between patients with and without SPC. Results: A total of 1,111 (9.8%) ovarian cancer patients developed SPC with a median follow-up of 8 years. The impact of a family history of cancer on the risk of the same cancer as SPC was significant for colon (RRpositive family history [95% CI] vs RRnegative family history [95% CI]: 4.95 [3.03–8.09] vs 2.00 [1.63–2.47]), lung (3.32 [1.88–5.84] vs 1.45 [1.16–1.83]), and breast (2.08 [1.58–2.73] vs 1.01 [0.88–1.15]) cancers. With a family history of any cancer, the RR for non-ovarian SPCs was 1.66 (1.54–1.74), in contrast to 1.38 (1.24–1.54) for SPCs without any family history (P-trend
- Published
- 2018
48. Whole Genome Sequencing Prioritizes CHEK2, EWSR1, and TIAM1 as Possible Predisposition Genes for Familial Non-Medullary Thyroid Cancer
- Author
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Aayushi Srivastava, Sara Giangiobbe, Diamanto Skopelitou, Beiping Miao, Nagarajan Paramasivam, Chiara Diquigiovanni, Elena Bonora, Kari Hemminki, Asta Försti, Obul Reddy Bandapalli, Srivastava, Aayushi, Giangiobbe, Sara, Skopelitou, Diamanto, Miao, Beiping, Paramasivam, Nagarajan, Diquigiovanni, Chiara, Bonora, Elena, Hemminki, Kari, Försti, Asta, and Bandapalli, Obul Reddy
- Subjects
0301 basic medicine ,Tumor suppressor gene ,Endocrinology, Diabetes and Metabolism ,EWING SARCOMA BREAKPOINT REGION 1 ,Quantitative trait locus ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,germline variant ,03 medical and health sciences ,0302 clinical medicine ,familial non-medullary thyroid cancer ,non-syndromic ,CHEK2 ,Gene ,Genetics ,Whole genome sequencing ,whole genome sequencing ,lcsh:RC648-665 ,biology ,business.industry ,3. Good health ,Minor allele frequency ,familial thyroid cancer ,030104 developmental biology ,whole-genome sequencing ,EWSR1 ,030220 oncology & carcinogenesis ,TIAM1 ,Personalized medicine ,biology.gene ,business - Abstract
Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.
- Published
- 2021
49. Second Primary Cancers After Gastric Cancer, and Gastric Cancer as Second Primary Cancer
- Author
-
Tianhui Chen, Jan Sundquist, Asta Försti, Kristina Sundquist, Akseli Hemminki, Guoqiao Zheng, Kari Hemminki, Department of Oncology, HUS Comprehensive Cancer Center, Research Programs Unit, TRIMM - Translational Immunology Research Program, and University of Helsinki
- Subjects
Oncology ,medicine.medical_specialty ,cancer incidence ,GENETICS ,Epidemiology ,3122 Cancers ,UNITED-STATES ,Infectious and parasitic diseases ,RC109-216 ,Malignancy ,stomach cancer ,Breast cancer ,Internal medicine ,medicine ,Clinical Epidemiology ,Stomach cancer ,MUTATION ,Original Research ,RISK ,MALIGNANCY ,RENAL-TRANSPLANTATION ,business.industry ,MORTALITY ,Cancer ,medicine.disease ,TRENDS ,Lynch syndrome ,3. Good health ,Cancer registry ,relative risk ,cancer etiology ,second primary cancer ,Skin cancer ,business ,Cancer Etiology - Abstract
Guoqiao Zheng,1â 3 Kristina Sundquist,3â 5 Jan Sundquist,3â 6 Tianhui Chen,7 Asta Försti,1,3,8,9 Akseli Hemminki,10,11 Kari Hemminki1â 3,12 1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 3Center for Primary Health Care Research, Lund University, Malmö, Sweden; 4Department of Family Medicine and Community Health; 5Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Center for Community-Based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Shimane, Japan; 7Department of Cancer Prevention, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310022, Peopleâs Republic of China; 8Hopp Childrenâs Cancer Center (KiTZ), Heidelberg, Germany; 9Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; 10Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; 11Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 12Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, 30605, Czech RepublicCorrespondence: Kari HemminkiBiomedical Center, Charles University Medical Faculty in Pilsen, Pilsen, 30605, Czech RepublicEmail K.Hemminki@dkfz.deBackground: Second primary cancers (SPCs) are increasing, which may negatively influence patient survival. Gastric cancer (GC) has poor survival and when it is diagnosed as SPC it is often the cause of death. We wanted to analyze the risk of SPCs after GC and the risk of GC as SPC after any cancer. Such bidirectional analysis is important in relation to fatal cancers because SPCs may be under-reported in the short-term survival period.Methods: Cancers were obtained from the Swedish Cancer Registry from years 1990 through 2015. Standardized incidence ratios (SIRs) were used to estimate bidirectional relative.Results: We identified 23,137 GC patients who developed 1042 SPCs (4.5%); 2158 patients had GC as SPC. While the risk for three SPCs was increased after GC, seven first primary cancers were followed by an increased risk of GC as SPC, including esophageal, colorectal, bladder, squamous cell skin and breast cancers and non-Hodgkin lymphoma. Breast cancer, which was followed by a diagnosis of second GC, showed an excess of lobular histology.Conclusion: Multiple primary cancers in the same individuals may signal genetic predisposition. Accordingly, the association of GC with breast cancer may be related to mutations in the CDH1 gene, and clustering of colorectal, small intestinal and bladder cancers could be related to Lynch syndrome. The third line of findings supports a contribution of immune dysfunction on the increased risk of GC as SPC after skin cancer and non-Hodgkin lymphoma. Early detection of GC in the risk groups could save lives.Keywords: cancer incidence, relative risk, second primary cancer, cancer etiology, stomach cancer
- Published
- 2021
50. Family history of any cancer for childhood leukemia patients in Sweden
- Author
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Xinjun Li, Kristina Sundquist, Asta Försti, Jan Sundquist, and Kari Hemminki
- Subjects
Oncology ,medicine.medical_specialty ,Childhood leukemia ,business.industry ,Internal medicine ,medicine ,Cancer ,Family history ,medicine.disease ,business - Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood leukemia, while the other types, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) are much rarer. While data on familial risks for childhood ALL have been emerging, such data for the other childhood leukemias are hardly available. We aim to fill in the gap of knowledge by assessing familial clustering of each childhood leukemia with childhood and adult leukemia and with any cancer. We identified 4461 childhood leukemias from the Swedish Cancer Registry and obtained their family members from the Multigeneration Register. Standardized incidence ratios (SIRs) were 3.34 for singleton siblings both diagnosed with ALL before age 20 years and 1.64 for those who had a family member diagnosed with ALL in adult age. Other childhood leukemias showed no familial risk, but childhood ALL risk was increased to 1.40 when adult family members were diagnosed with CLL. Childhood ALL was associated with endometrial cancer, and female ALL patients showed increased risk when family members were diagnosed with testicular cancer, melanoma, and skin squamous cell carcinoma. Childhood CLL was associated with rectal cancer, and childhood AML was associated with pancreatic and bladder cancers. As most of these associations are reported for the first time, there is a need to replicate the findings from independent sources.
- Published
- 2021
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