| 81. |
- Hosen, Ismail, et al.
(författare)
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Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 137:7, s. 1621-1629
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the promoter of the telomerase reverse transcriptase (TERT) and fibroblast growth factor receptor 3 (FGFR3) genes constitute the most recurrent somatic alterations in urothelial carcinoma of bladder. In this study, we screened DNA from 327 urothelial bladder carcinomas from well-documented patients, with different stages and grades and known TERT promoter mutational status, for FGFR3 alterations and measured relative telomere length (RTL). Although, the frequency of the TERT promoter mutations was higher than those in FGFR3; however, the alterations at the two loci occurred together more frequently than per chance [Odds ratio (OR)=4.93, 95% CI=2.72-8.92, p<0.0001]. While tumors with TERT promoter and FGFR3 mutations had shorter RTL than those without mutations (p<0.0001), the TERT promoter mutations in conjunction with the common allele of the rs2853669 polymorphism defined sub-group of patients with an observed decreased overall survival (OR=2.15, 95% CI=1.00-4.61) and increased recurrence in patients with TaG1+TaG2 disease categories (OR=3.68, 95%CI=1.12-12.05). The finding of shorter telomeres in tumors with TERT promoter and/or FGFR3 mutations than without mutations implies mechanistic relevance of telomere biology in cancer progression. The observed association with recurrence and survival shows that the TERT promoter mutations can potentially be used as markers to refine selection of patients for different treatments. The overwhelming frequency of the TERT promoter mutations also represents a case for development of an eventual therapeutic target. What's New? The identification of recurrent somatic mutations in bladder cancer opens the door to the development of new prognostic and therapeutic tools. Here, the TERT promoter mutations in conjunction with a common variant, rs2853669, define a subset of patients with increased risk of recurrence and poor survival. Mutations in FGFR3, in contrast, were not independently associated with either disease recurrence or overall survival. Tumors with mutations in FGFR3 or the TERT promoter carried shorter telomeres than those without mutations. The findings highlight the prognostic potential of TERT mutations and reveal a possible etiological role for telomere biology in bladder cancer.
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| 82. |
- Hosen, Ismail, et al.
(författare)
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TERT promoter mutations in clear cell renal cell carcinoma
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:10, s. 2448-2452
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Tidskriftsartikel (refereegranskat)abstract
- We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR)=0.15, 95% confidence interval (CI)=0.03-0.72, p=0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR)=2.90, 95% CI=1.13-7.39, p=0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR=3.34, 95% CI=1.24-8.98, p=0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease-specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior. What's new? The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleoprotein complex that maintains genomic integrity. Activating somatic mutations in the promoter region of the TERT gene have been reported in many cancers. Here, the authors describe new TERT promoter mutations in clear cell renal cell carcinoma. Although present only in a proportion of the tumors, the TERT promoter mutations were independently associated with poor patient survival. The effect was enhanced by a common polymorphism within the core TERT promoter. The TERT promoter mutations may thus define a small subset of tumors with an aggressive behavior.
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| 83. |
- Huhn, Stefanie, et al.
(författare)
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Coding variants in NOD-like receptors : An association study on risk and survival of colorectal cancer
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replication analysis using data of two large genome-wide association studies (GWASs) from Germany (DACHS: 1798 cases and 1810 controls) and Scotland (2210 cases and 9350 controls) the associations found in the Czech discovery set were not confirmed. However, expression analysis in human gut-related tissues and immune cells revealed that the NLRs associated with CRC risk or survival in the discovery set were expressed in primary human colon or rectum cells, CRC tissue and/or cell lines, providing preliminary evidence for a potential involvement of NLRs in general in CRC development and/or progression. Most interesting was the finding that the enigmatic development-related NLRP5 (also known as MATER) was not expressed in normal colon tissue but in colon cancer tissue and cell lines. Future studies may show whether regulatory variants instead of coding variants might affect the expression of NLRs and contribute to CRC risk and survival.
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| 84. |
- Johnson, D C, et al.
(författare)
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Genetic factors influencing the risk of multiple myeloma bone disease.
- 2016
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 30, s. 883-888
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Tidskriftsartikel (refereegranskat)abstract
- A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totalling 3774) which had been radiologically surveyed for MBD. Each patient had been genotyped for ~600 000 SNPs with genotypes for six million common variants imputed using 1000Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio [OR]=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, OR=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.Leukemia accepted article preview online, 16 December 2015. doi:10.1038/leu.2015.342.
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| 85. |
- Johnson, David C, et al.
(författare)
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Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma.
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ∼600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 × 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors.
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| 86. |
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| 87. |
- Kharazmi, Elham, et al.
(författare)
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Familial risk of pleural mesothelioma increased drastically in certain occupations : A nationwide prospective cohort study
- 2018
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 103, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We aimed to explore the effect of occupation on familial risk of pleural mesothelioma in a nationwide cohort study design. Method: The nationwide Swedish Family-Cancer Database includes all Swedes born after 1931 and their biological parents, totalling 16.1 million individuals with about 2.3 million cancer patients. Hazards ratios (HRs) were calculated adjusting for age, sex and region of residence. Results: Having asbestos-related occupation in the absence of family history of mesothelioma increased risk of mesothelioma more than threefold (adjusted HR = 3.2, 95% confidence interval [CI]: 3.0–3.5). In those who had a history of mesothelioma in their first-degree relatives and an asbestos-related occupation, risk of mesothelioma dramatically increased compared with individuals without such occupations and family history (without chronic obstructive pulmonary disease [COPD] HR = 24, 95% CI: 15–39; with COPD 45, 95% CI: 15–141). In those who had a family history of mesothelioma and no history of an asbestos-related occupation, risk of mesothelioma did not show significant increase compared with those who had no family history of mesothelioma and no asbestos-related occupation (HR = 1.6; 95% CI: 0.7–3.8). Conclusion: First-degree relatives of patients with pleural mesothelioma had a drastic risk of developing this malignancy in case of certain occupations, which shows a gene–environment interaction is probable in risk of mesothelioma.
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| 88. |
- 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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| 89. |
- Kharazmi, Elham, et al.
(författare)
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Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: A joint study from five Nordic countries.
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 126:17, s. 1990-1995
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Tidskriftsartikel (refereegranskat)abstract
- The rarity of familial Hodgkin lymphoma (HL) has hampered detailed analyses of familial clustering. We aimed to provide the familial risk of HL by relationship, histology, age at diagnosis and sex. A cohort of 57,475 first-degree relatives of 13,922 HL patients, diagnosed between 1955 and 2009, in five European countries was followed for HL incidence. Standardized incidence ratios (SIRs) were calculated using histology-, age-, sex-, period-, and country-specific incidence rates as the reference. The lifetime cumulative risks (CR) were also calculated. The overall CR of HL in first-degree relatives of a patient with HL was 0.6%, which represents a 3-fold (SIR=3.3, 95%CI=2.8-3.9) increased risk over the general population risk. The risk in siblings (6.0-fold; 4.8-7.4) was significantly higher than in parents/children (2.1-fold; 1.6-2.6). Very high lifetime risk of HL was found for those with multiple affected first-degree relatives (13-fold; 2.8-39) and for same-sex twins (57-fold; 21-125). We found high familial risks between some concordant histological subtypes of HL [lymphocyte-rich (81-fold, 30-177) and nodular sclerosis (4.6-fold, 2.9-7.0)] and also between some discordant subtypes. The familial risk in sisters (9.4-fold; 5.9-14) was higher than in brothers (4.5-fold; 2.9-6.7) or unlike-sex siblings (5.9-fold; 4.3-8.1). The lifetime risk of HL was higher when first-degree relatives were diagnosed at early ages (before age 30). This study provides tangible absolute risk estimates for relatives of HL patients, which can be used as a sex-, age-, and family history-based risk calculator for classical Hodgkin lymphoma by oncologists and genetic counselors.
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| 90. |
- Kharazmi, Elham, et al.
(författare)
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Survival in familial and non-familial breast cancer by age and stage at diagnosis.
- 2016
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 52, s. 10-18
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to compare the survival in familial and sporadic breast cancer (BC) patients who were diagnosed at an identical age and TNM stage. The Nationwide Swedish Family-Cancer Database including all Swedes born after 1931 and their biological parents, totalling >14.7 million individuals, was used. Hazard ratios (HRs) were calculated for women with BC in a first-degree relative (FDR) versus BC patients without positive family history. There was no difference in survival of familial BC patients who were diagnosed at higher TNM status or older age (>40) compared to sporadic BC cases diagnosed at the same late TNM stage. Young BC patients (age <40) in early stages had the worst survival when their FDR was diagnosed with single (HR: 2.0-3.7) or multiple (HR: 2.4-7.1) BC at any age. We concluded that there is no difference in survival of familial and non-familial BC patients who are diagnosed at higher TNM status or older ages (>40). Young familial BC patients (age <40), diagnosed at early stage, have the poorer survival compared to sporadic cases. Our results urge the need for identifying the underling genetic component for such a difference in survival of familial BC.
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