| 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. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- Kharazmi, Elham, et al.
(författare)
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Importance of tumor location and histology in familial risk of upper gastrointestinal cancers : A nationwide cohort study
- 2018
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Ingår i: Clinical Epidemiology. - 1179-1349. ; 10, s. 1169-1179
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Tidskriftsartikel (refereegranskat)abstract
- Background: Familial clustering of upper gastrointestinal (UGI) cancers and the significance of family history has been addressed previously. We aimed to elucidate the familial risk based on the specified tumor location and histology. Method: In the Swedish Family-Cancer Database, we determined the familial risk of UGI cancer patients diagnosed (1958–2015) with esophageal and gastric cancer by tumor location using standardized incidence ratios (SIRs). Results: Risk of esophageal cancer in first-degree relatives (FDRs) of patients with esophageal cancer increased 2.4-fold (SIR 95% CI 2.0–2.8), whereas risk of esophageal cancer in cases with family history of cancer in the middle third of the esophagus increased 3.4-fold (SIR 95% CI 2.1–5.1). Risk of gastric cancer in FDRs increased 1.6-fold (SIR 95% CI 1.5–1.7), occurrence of concordant subsite gastric cancer in the antrum, body, and cardia was 5.5-fold (SIR 95% CI 2.4–11), 4.6-fold (SIR 95% CI 2.6–7.4), and 1.7-fold (SIR 95% CI 1.1–2.5), respectively. Familial risk of concordant histological subtype in esophageal cancer was 4.1-fold for squamous cell carcinoma (SIR 95% CI 3.2–5.2) and 3.6-fold for adenocarcinoma (SIR 95% CI 2.5–5.1). The risk of concordant gastric adenocarcinoma was 1.6-fold for one affected FDR (SIR 95% CI 1.5–1.7), 6.1-fold for two FDRs (SIR 95% CI 4.4–8.4), and 8.6-fold among twins (SIR 95% CI 2.3–22). Conclusion: Family history of cancer in the lower third of the esophagus and stomach cancer in specific locations such as the antrum, body, and cardia can be considered as important predictive evidence for cancer in the same location in relatives. Our findings might guide endoscopy-based surveillance by introducing subgroups of populations with a higher risk for UGI cancer with particular attention to concordance of location of lesions, which could be a reasonable strategy for early detection, and thus help save more lives.
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| 6. |
- Riihimäki, Matias, et al.
(författare)
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Metastatic spread in patients with gastric cancer
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:32, s. 52307-52316
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Tidskriftsartikel (refereegranskat)abstract
- Background: The epidemiology of metastatic gastric cancer is unexplored because cancer registries seldom cover metastatic involvement apart from "present or not". We used a novel approach by utilizing Swedish registers to assess metastatic spread in gastric cancer. To our knowledge, this is the first nationwide description of metastases in gastric cancer. Results: The most common sites of metastasis were liver (in 48% of metastatic cancer patients), peritoneum (32%), lung (15%), and bone (12%). Metastases to the lung, nervous system, and bone were more frequent in cardia cancer and men, whereas non-cardia cancer more frequently metastasized within the peritoneum. Signet ring adenocarcinomas more frequently metastasized within the peritoneum, bone and ovaries, and less frequently to the lungs and liver compared with generic adenocarcinoma. The liver and the peritoneum were commonly single metastases while lung metastases occurred frequently together with liver metastases. The median survival in metastatic gastric cancer was 3 months, worst among those with bone and liver metastases (2 months). Methods: A total of 7,559 patients with gastric cancer were identified. Metastatic patterns and survival depending on sex, age, stage, anatomical location (cardia and non-cardia), and histological type were assessed. Conclusions: The patterns of metastasis differ notably depending on histological type. Cardia cancer exhibits a completely different metastatic behavior than noncardia cancer. Awareness of the differing patterns may guide in tailored diagnosis of metastases. Survivors from cardia cancer would benefit from increased surveillance of extraperitoneal metastases. Bone metastases should be considered in patients with signet ring adenocarcinoma if symptoms emerge.
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| 7. |
- Chen, Tianhui, et al.
(författare)
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Risk of second primary cancers in women diagnosed with endometrial cancer in German and Swedish cancer registries
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 141:11, s. 2270-2280
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Tidskriftsartikel (refereegranskat)abstract
- Along with the increasing incidence and favorable prognosis, more women diagnosed with endometrial cancer may develop second primary cancers (SPCs). We aimed at investigating risk of SPCs after endometrial cancer in Germany and Sweden to provide insight into prevention strategies for SPCs. Endometrial cancer patients diagnosed at age ≥15 years in Germany during 1997–2011 and in Sweden nationwide during 1997–2012 were selected. Standardized incidence ratios (SIRs), calculated as the ratio of observed to expected numbers of cases, were used to assess the risk of a specific second cancer after endometrial cancer for both German and Swedish datasets. Among 46,929 endometrial cancer survivors in Germany and 18,646 in Sweden, overall 2,897 and 1,706 SPCs were recorded, respectively. Significantly elevated SIRs were observed in Germany for ovarian (SIR = 1.3; 95%CI:1.1–1.5) and kidney cancers [1.6 (1.3–1.8)], while in Sweden the SIRs were 5.4 (4.6–6.3) and1.4 (1.0–1.9), respectively. Elevated risk for second ovarian endometrioid carcinoma was pronounced after early (<55 years) onset endometrial cancer in Germany [9.0 (4.8–15)] and Sweden [7.7 (5.1–11)]. In Germany elevated risks were found for second ovarian endometrioid carcinoma after endometrioid histology of first endometrial cancer [6.3 (4.0–9.4)] and for second kidney cancer after clear cell histology of endometrial cancer [4.9 (1.6–11)]. We found exceptionally elevated risk of second ovarian endometrioid carcinoma after endometrial cancer of the same histology or of early onset. Risk for second kidney cancer was also increased, particularly after endometrial cancer of clear cell histology. Cancer prevention strategies should focus on these cancers after endometrial cancer diagnosis.
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| 8. |
- 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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| 9. |
- Göhler, Stella, et al.
(författare)
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Functional germline variants in driver genes of breast cancer
- 2017
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Ingår i: Cancer Causes and Control. - Dordrecht : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 28:4, s. 259-271
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Germline mutations in tumour suppressor genes cause various cancers. These genes are also somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic breast tumours. Methods: After excluding the well-characterized breast cancer (BC) genes, we screened 15 novel genes consistently classified as BC driver genes in next-generation sequencing approaches for single nucleotide polymorphisms (SNPs). Altogether 40 SNPs located in the core promoter, 5′- and 3′-UTR or which were nonsynonymous SNPs were genotyped in 782 Swedish incident BC cases and 1,559 matched controls. After statistical analyses, further evaluations related to functional prediction and signatures of selection were performed. Results: TBX3 was associated with BC risk (rs2242442: OR = 0.76, 95% CI 0.64–0.92, dominant model) and with less aggressive tumour characteristics. An association with BC survival and aggressive tumour characteristics was detected for the genes ATR (rs2227928: HR = 1.63; 95% CI 1.00–2.64, dominant model), RUNX1 (rs17227210: HR = 3.50, 95% CI 1.42–8.61, recessive model) and TTN (rs2303838: HR = 2.36; 95% CI 1.04–5.39; rs2042996: HR = 2.28; 95% CI 1.19–4.37, recessive model). According to the experimental ENCODE data all these SNPs themselves or SNPs in high linkage disequilibrium with them (r2 ≥ 0.80) were located in regulatory regions. RUNX1 and TTN showed also several signatures of positive selection. Conclusion: The study gave evidence that germline variants in BC driver genes may have impact on BC risk and/or survival. Future studies could discover further germline variants in known or so far unknown driver genes which contribute to cancer development.
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| 10. |
- Li, Ni L., et al.
(författare)
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Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:11, s. 2556-2564
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.
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