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  • Went, Molly, et al. (författare)
  • Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
  • 2018
  • Ingår i: Blood Cancer Journal. - Nature Publishing Group. - 2044-5385. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
  • Went, Molly, et al. (författare)
  • Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
  • 2018
  • Ingår i: Nature communications. - 2041-1723. ; 9:1, s. 3707
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM. © 2018, The Author(s).
  • Went, Molly, et al. (författare)
  • Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes
  • 2019
  • Ingår i: Human Genomics. - BioMed Central (BMC). - 1479-7364. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundWhile genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS).ResultsGWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80–491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus.ConclusionsOur findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.
  • Yu, Hongyao, et al. (författare)
  • Common cancers share familial susceptibility : Implications for cancer genetics and counselling
  • 2017
  • Ingår i: Journal of Medical Genetics. - BMJ Publishing Group. - 0022-2593. ; 54, s. 248-253
  • Tidskriftsartikel (refereegranskat)abstract
    • Background It has been proposed that cancer is more common in some families than in others, but the hypothesis lacks population level support. We use a novel approach by studying any cancers in large threegeneration families and thus are able to find risks even though penetrance is low. Methods Individuals in the nation-wide Swedish Family- Cancer Database were organised in three generations and the relative risk (RR) of cancer was calculated to the persons in the third generation by the numbers of patients with cancer in generations 1, 2 and 3. Results The RRs for any cancer in generation 3 increased by the numbers of affected relatives, reaching 1.61 when at least seven relatives were diagnosed. The median patient had two affected relatives, and 7.0% had five or more affected relatives with an RR of 1.46, which translated to an absolute risk of 21.5% compared with 14.7% in population by age 65 years. For prostate cancer, the RR was 2.85 with four or more affected family members with any cancer, and it increased to 14.42 with four or more concordant cancers in family members. RRs for prostate cancer were approximately equal (2.70 vs 2.85) if a man had one relative with prostate cancer or four or more relatives diagnosed with any cancer. Conclusions A strong family history of cancer, regardless of tumour type, increases cancer risk of family members and calls for mechanistic explanations. Our data provide tools for counselling of patients with cancer with both low and high familiar risks.
  • Yu, Hongyao, et al. (författare)
  • Familial Associations of Colon and Rectal Cancers With Other Cancers
  • 2019
  • Ingår i: Diseases of the Colon and Rectum. - Springer. - 0012-3706. ; 62:2, s. 189-195
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Many studies have indicated that colon and rectal cancers differ in etiology and histology. OBJECTIVE: The aim of this study was to investigate whether the associations of colon and rectal cancers with any other (discordant) cancer were site specific. DESIGN: A novel approach was implemented in which cancer risks were analyzed in families with increasing numbers of family members diagnosed with defined cancers. The novel assumption was that, for a true familial association, the risk should increase by the number of affected family members. In separate analyses, familial risks were calculated after the exclusion of putative families with hereditary nonpolyposis colorectal cancer. SETTINGS: The study was conducted using the Swedish Family-Cancer Database. MAIN OUTCOME MEASURES: The outcome measure was relative risk. RESULTS: Relative risks of colorectal cancer and colon cancer were higher when family members were diagnosed with colon cancer than when family members were diagnosed with rectal cancer (incidence rate ratio for colorectal: 1.82 (95% CI, 1.74-1.90) vs 1.61 (95% CI, 1.51-1.71); incidence rate ratio for colon: 1.92 (95% CI, 1.83-2.02) vs 1.56 (95% CI, 1.45-1.69)). Relative risks for 10 discordant cancers were increased in colon or rectal cancer families, whereas none of the relative risks differed significantly between colon and rectal cancers. After deleting hereditary nonpolyposis colorectal cancer families, the relative risks of endometrial and ovarian cancers were no longer significant. LIMITATIONS: Genetic data are unavailable in the database. CONCLUSIONS: Our results suggested that familial risks for colon cancer were higher than risks for rectal cancer in families of patients with colorectal cancer and colon cancer. The relationships of lung cancer and nervous system cancer with colorectal cancer were site specific. The associations of colon and rectal cancers with lung cancer, myeloma, and cancer of unknown primary appeared not to point out known syndromes and may suggest involvement of a novel predisposition. See Video Abstract at http://links.lww.com/DCR/A791.
  • Yu, Hongyao, et al. (författare)
  • Familial associations of colorectal cancer with other cancers
  • 2017
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) has a strong familial component which extends to discordant cancers (ie non-CRC tumors). This is best seen in cancer syndromes such as hereditary non-polyposis colorectal cancer (HNPCC) which predisposes to several tumor types. Population-based family studies have also found discordant associations for CRC but they have included cancers which manifest in HNPCC, and there is no convincing evidence of discordant associations beyond the known syndromes. We address familial associations of non-CRC tumors with CRC using the resources of the Swedish Family-Cancer Database and applying a powerful approach of assessing familial relative risks in families of increasing numbers of patients with discordant cancers. Among 1.8 million cancer patients and over 200,000 CRC cases consistent familial associations of CRC was observed for several HNPCC related cancers. However, for small intestinal, pancreatic and nervous system cancers RRs remained essentially unchanged when potential HNPCC families were excluded, suggesting involvement of genes not related to HNPCC. Two independent associations of CRC were found for melanoma, thyroid and eye cancers and these appeared not to be related to known syndromes. A number of other cancers associated with CRC in single analyses and independent studies are required to assess the relevance of such findings.
  • Yu, Hongyao, et al. (författare)
  • Familial Urinary Bladder Cancer with Other Cancers
  • 2018
  • Ingår i: European urology oncology. - Elsevier. - 2588-9311. ; 1:6, s. 461-466
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Family risks for urinary tract cancers (excluding kidney cancers) are known, but less is known about whether rare urinary tract cancer subtypes are also familial and if urinary tract cancers share familial risk for other (discordant) cancers. Objective: To investigate the impact of family history on urinary tract cancers (International Classification of Diseases version 7 code 181) and discordant cancers. Design, setting, and participants: The Swedish Family-Cancer Database, the largest family data set in the world, was used to assess familial risks between 86 058 patients with urinary tract cancers and patients with other cancers between 1958 and 2015. Outcome measurements and statistical analysis: A Poisson regression model was used to generate relative risks (RRs). Results and limitations: Some 7.0% of patients with urinary tract cancers had a parent or sibling diagnosed with the same cancer, yielding an RR of 1.81 (95% confidence interval [CI] 1.68–1.94). As novel familial findings, we also found that ureter (RR 1.62, 95% CI 1.04–2.53) and transitional cell in situ tumors (RR 2.04, 95% CI 1.49–2.80) were associated with urinary tract cancers. The most consistent discordant familial associations of urinary tract cancers were with smoking-related sites of cancer: lung, stomach, and kidney. Internally consistent familial associations not related to smoking were found for endometrial and thyroid cancers. Familial associations with urinary tract cancers were also found for rare anal, female genital, and cervical cancers. The main limitation was a lack of data on smoking. Conclusions: Smoking-related cancers were associated with urinary tract cancer. We speculate that familial clustering of endometrial and thyroid cancers with urinary tract cancers may be ascribed to obesity. Patient summary: Diagnosis of bladder cancer in a close family member may be a sign of higher risk among other family members. Patients and family members should be told that bladder cancer is smoking-related and they should be counseled to recognize blood in urine as a possible early sign. The relative risk of familial urinary tract cancer was 1.81 for individuals with a parent or sibling diagnosed with the same cancer. Such familial cases accounted for 7.0% of patients with urinary tract cancers. Familial risk was equally high for ureter and transitional cell in situ tumors. The incidence of some other cancers, particularly smoking-related cancers, was higher among families of patients with urinary tract cancer.
  • Yu, Hongyao, et al. (författare)
  • Other cancers in lung cancer families are overwhelmingly smoking-related cancers
  • 2017
  • Ingår i: ERJ Open Research. - European Respiratory Society. - 2312-0541. ; 3:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Familial risks of lung cancer are well-established, but whether lung cancer clusters with other discordant cancers is less certain, particularly beyond smoking-related sites, which may provide evidence on genetic contributions to lung cancer aetiology. We used a novel approach to search for familial associations in the Swedish Family-Cancer Database. This involved assessment of familial relative risk for cancer X in families with increasing numbers of lung cancer patients and, conversely, relative risks for lung cancer in families with increasing numbers of patients with cancers X. However, we lacked information on smoking. The total number of lung cancers in the database was 125 563. We applied stringent statistical criteria and found that seven discordant cancers were associated with lung cancer among family members, and six of these were known to be connected with smoking: oesophageal, upper aerodigestive tract, liver, cervical, kidney and urinary bladder cancers. A further novel finding was that cancer of unknown primary also associated with lung cancer. We also factored in histological evidence and found that anal and connective tissue cancers could be associated with lung cancer for reasons other than smoking. For endometrial and prostate cancers, suggestive negative associations with lung cancer were found. Although we lacked information on smoking it is prudent to conclude that practically all observed discordant associations of lung cancer were with cancers for which smoking is a risk factor.
  • Zhang, Luyao, et al. (författare)
  • Comparison of Familial Clustering of Anogenital and Skin Cancers Between In Situ and Invasive Types
  • 2019
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Literature on familial risk of carcinomas in situ (CISs) is limited because many cancer registries do not collect information on CIS. In Sweden CISs are collected, and we used these data to analyze familial relative risks (RRs) for concordant (CIS-CIS) types of anogenital (cervical, other female and male genital and anal) and skin squamous cell CIS; additionally RRs were assessed between CIS types and between CIS and invasive forms. RRs were calculated for the offspring generations when family members were diagnosed CIS. Case numbers for CIS ranged from 330 in anal to 177,285 in cervical CIS. Significant concordant CIS-CIS RRs were 2.74 for female genital, 1.77 for cervical and 2.29 for SCC skin CISs. The CIS forms associated also with each other, except for cervical and skin CIS types. RRs for concordant CIS-invasive cancer associations were lower than CIS-CIS associations. Cervical CIS associated with non-Hodgkin CIS which may suggest immune dysfunction as a contributing factors. The results for anogenital CIS types suggest that life style related human papilloma virus infections contributed to the observed familial associations. Lower risks for CIS-invasive cancer than CIS-CIS suggest that CIS and invasive cancers share only partially risk factors that underlie familial clustering.
  • Zhang, Luyao, et al. (författare)
  • Familial Associations in Testicular Cancer with Other Cancers
  • 2018
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Familial risks for testicular cancer (TC) are among the highest of all cancers. However, data are limited for histological types of TC and for possible familial associations of TC with other cancers. We used the nationwide Swedish Family-Cancer Database for years 1958 to 2015 to analyse familial relative risks (RR) for 11,138 TC patients when first-degree relatives were diagnosed with TC or other cancer in reference to those without a family history. A total of 191 familial TCs were found, which accounted for 2.0% of all TC. The RR was 5.06 when one family member was diagnosed with TC with no significant difference between seminoma and nonseminoma. However, the risk for nonseminoma was 33.59 when two family members were affected. Internally consistent familial associations of TC, particularly of seminoma, were found with breast and nervous system cancers and melanoma. Individual significant associations were found for a number of sites, including ovarian, endometrial and prostate cancers. Our results suggest that nonseminoma may have a stronger genetic background than seminoma but seminoma shares more familial associations with discordant cancers. Clustering of TC with hormone-dependent cancers of the breast, ovary, endometrium and prostate may suggest mechanistic links and possibly gene-environment interactions.
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