| 1. |
- Leo, P. J., et al.
(författare)
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Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study
- 2017
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately > 7.1% risk, and those in the highest 5% have approximately > 21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.
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| 2. |
- Frank, C, et al.
(författare)
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Search for familial clustering of multiple myeloma with any cancer.
- 2016
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 30, s. 627-632
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a disease of immunoglobulin producing plasma cells which reside mainly in the bone marrow. Family members of MM patients are at a risk of MM but whether other malignancies are in excess in family members is not established and is the aim of this study. MM patients (24,137) were identified from the Swedish Cancer Registry from years 1958-2012. Relative risks (RRs) were calculated for MM defined by any cancer diagnosed in first degree relatives and compared to individuals whose relatives had no cancer. MM was reliably associated with relative's colorectal, breast and prostate cancers, non-thyroid endocrine tumors, leukemia and cancer of unknown primary; additionally MM was associated with subsites of bone and connective tissue tumors and of non-Hodgkin lymphoma, including lymphoplasmacytic lymphoma/Waldenström macroglobulinema (RR 3.47). MM showed a strong association (RR 1.91) in colorectal cancer families, possibly as part of an unidentified syndrome. All the associations of MM with discordant cancers are novel suggesting that MM shares genetic susceptibility with many cancers. The associations of MM bone and connective tissue tumors were supported by at least two independent results. Whether the results signal bone-related biology shared by MM and these tumors deserves further study.Leukemia accepted article preview online, 09 October 2015. doi:10.1038/leu.2015.279.
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| 3. |
- Hemminki, Kari, et al.
(författare)
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The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias : Etiologic Implications
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenström macroglobulinemia (WM) and light chain AL amyloidosis, are characterized by clonal expansion of plasma cells which produce a vast amount of an immunoglobulin-derived M-protein. We noted that MGUS diagnosis often coincided with diagnoses of senile cataract and glaucoma and tested the associations of MGUS, MM, WM and AL amyloidosis with subsequent eye diseases identified from the Swedish patient registers between 1997 and 2012. Standardized incidence ratios (SIRs) for senile cataract was significantly increased to 1.80 after MGUS, 1.70 after MM, 1.85 after WM and 2.31 after AL amyloidosis. The SIR for glaucoma was 1.60 after MGUS, 1.76 after WM and 2.18 after AL amyloidosis. All SIRs decreased systematically from age below 60 years to over 79 years, but most risks were also significant in age group over 79 years. The M-protein and the related increase in blood viscosity could be a novel etiologic discovery for these common eye diseases. As MGUS prevalence is around 3% at 60 years and close to 10% at age over 80 years, its contribution to the eye disease burden is expected to be remarkably high.
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| 4. |
- Pettersson-Kymmer, Ulrika, et al.
(författare)
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HLA and KIR Associations of Cervical Neoplasia
- 2018
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 218:12, s. 2006-2015
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognised by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk.Methods: Here, we used HLA and KIR dosages imputed from SNP genotype data from 2,143 cervical neoplasia cases and 13,858 healthy controls of European decent.Results: Four novel HLA alleles were identified in association with cervical neoplasia: HLA-DRB3*9901 (OR=1.24, P=2.49×10-9), HLA-DRB5*0101 (OR=1.29, P=2.26×10-8), HLA-DRB5*9901 (OR=0.77, P=1.90×10-9) and HLA-DRB3*0301 (OR=0.63, P=4.06×10-5), due to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles. We also found homozygosity of HLA-C1 group alleles is a protective factor for HPV16-related cervical neoplasia (C1/C1, OR=0.79, P=0.005). This protective association was restricted to carriers of either KIR2DL2 (OR=0.67, P=0.00045) or KIR2DS2 (OR=0.69, P=0.0006).Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.
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| 5. |
- Went, Molly, et al.
(författare)
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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
- 2018
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:1
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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.
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| 6. |
- Hemminki, Kari, et al.
(författare)
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Germline genetics of cancer of unknown primary (CUP) and its specific subtypes
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:16, s. 22140-22149
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Tidskriftsartikel (refereegranskat)abstract
- Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10(-7) and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5' UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.
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| 7. |
- Hemminki, Kari, et al.
(författare)
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Surveillance Bias in Cancer Risk after Unrelated Medical Conditions : Example Urolithiasis
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- We analysed cancer risks in patients with urinary tract stones but some features of the generated results alarmed us about possible surveillance bias, which we describe in this report. We used nationwide Swedish hospital records to identify patients with urinary tract stones (N = 211,718) and cancer registration data for cancer patients for years 1987 to 2012. Standardized incidence ratios (SIRs) for cancer were calculated after the last medical contact for urinary tract stones. All cancers were increased after kidney (SIR 1.54, 95%CI: 1.50-1.58), ureter (1.44, 1.42-1.47), mixed (1.51, 1.44-1.58) and bladder stones (1.63, 1.57-1.70). The risk of kidney cancer was increased most of all cancers after kidney, ureter and mixed stones while bladder cancer was increased most after bladder stones. All SIRs decreased steeply in the course of follow-up time. Tumour sizes were smaller in kidney cancer and in situ colon cancers were more common in patients diagnosed after urinary tract stones compared to all patients. The results suggest that surveillance bias influenced the result which somewhat surprisingly appeared to extend past 10 years of follow-up and include cancers at distant anatomical sites. Surveillance bias may be difficult to avoid in the present type of observational studies in clinical settings.
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| 8. |
- McGee, Emma E., et al.
(författare)
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Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 144:4, s. 707-717
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Tidskriftsartikel (refereegranskat)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.
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| 9. |
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| 10. |
- Yu, Hongyao, et al.
(författare)
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Familial Urinary Bladder Cancer with Other Cancers
- 2018
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Ingår i: European Urology Oncology. - : Elsevier BV. - 2588-9311. ; 1:6, s. 461-466
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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.
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