| 1. |
- Alexandrov, Ludmil B., et al.
(författare)
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Signatures of mutational processes in human cancer
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Tidskriftsartikel (refereegranskat)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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| 2. |
- Arnesen, Thomas, et al.
(författare)
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Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway
- 2013
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Ingår i: Langenbeck's archives of surgery (Print). - : Springer Verlag (Germany). - 1435-2443 .- 1435-2451. ; 398:6, s. 869-874
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Tidskriftsartikel (refereegranskat)abstract
- Primary aldosteronism (PA) is a frequent cause (about 10 %) of hypertension. Some cases of PA were recently found to be caused by mutations in the potassium channel KCNJ5. Our objective was to determine the mutation status of KCNJ5 and seven additional candidate genes for tumorigenesis: YY1, FZD4, ARHGAP9, ZFP37, KDM5C, LRP1B, and PDE9A and, furthermore, the surgical outcome of PA patients who underwent surgery in Western Norway. less thanbrgreater than less thanbrgreater thanTwenty-eight consecutive patients with aldosterone-producing adrenal tumors (20 patients with single adenoma, 8 patients with unilateral multiple adenomas or hyperplasia) who underwent surgery were included in this study. All patients were operated on by uncomplicated laparoscopic total adrenalectomy. Genomic DNA was isolated from tumor and non-tumor adrenocortical tissue, and DNA sequencing revealed the mutation status. less thanbrgreater than less thanbrgreater thanTen out of 28 (36 %) patients with PA displayed tumor mutations in KCNJ5 (p. G151R and L168R) while none were found in the corresponding non-tumor samples. No mutations were found in the other seven candidate genes screened. The presence of KCNJ5 mutations was associated with lower blood pressure and a higher chance for cure by surgery when compared to patients harboring the KCNJ5 wild type. less thanbrgreater than less thanbrgreater thanKCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).
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| 3. |
- Birkeland, Einar, et al.
(författare)
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Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma
- 2013
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Ingår i: Clinical and Experimental Metastasis. - : Springer Science and Business Media LLC. - 1573-7276 .- 0262-0898. ; 30:7, s. 867-876
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p < 0.001) compared to patients with tumors wild-type for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and < 0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01), low BRAF levels were associated with improved overall survival only among patients with tumors wild-type for BRAF (p = 0.013). These findings indicate that BRAF and NRAS expression levels may influence responses to DTIC as well as prognosis in patients with advanced melanoma.
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| 4. |
- Jönsson, Göran B, et al.
(författare)
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Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome.
- 2010
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:13, s. 3356-3367
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. While spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers selecting patients for immune therapy. Experimental design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus and NRAS/BRAF mutation screening. RESULTS: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation or stromal composition genes. Even though all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (p<0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by high frequency of CDKN2A homozygous deletions (p<0.01). We observed different prognosis between the subtypes (p=0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared to the others (p = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III/IV melanomas. Moreover, low expression of an a priori-defined gene set associated to immune response signaling was significantly associated to poor outcome (p=0.001). CONCLUSIONS: Our data reveal a biologically-based taxonomy of malignant melanomas with prognostic impact and support an influence of the anti-tumoral immune response on outcome.
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| 5. |
- Knappskog, Stian, et al.
(författare)
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SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer.
- 2012
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Ingår i: European journal of cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 48:13, s. 1988-1996
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The MDM2 promoter polymorphism (SNP309T>G) extends a binding site for the transcription factor Sp1 and has been linked to elevated cancer risk and/or young age at cancer diagnosis, especially in females. Recently, we reported an adjacent polymorphism (SNP285G>C). SNP285C antagonises the effect of SNP309G by reducing Sp1 binding and lowers the risk of breast and ovarian cancer. METHODS: We assessed the potential gender specificity in the effect of this polymorphism. We performed in silico predictions of transcription factor binding sites in the MDM2 promoter and analysed MDM2 SNP285 and SNP309 status in two independent cohorts of endometrial (n=438 and 472) and 666 prostatic cancer patients, and compared to 3.140 healthy controls. RESULTS: We identified three oestrogen-receptor binding elements (EREs) within the MDM2 intronic promoter, one of which overlapping the Sp1 binding-site harbouring SNP285. The SNP285C/309G haplotype was associated with a reduced Odds Ratio (OR) for endometrial cancer (OR1: 0.55; Confidence Interval (CI) 0.32-0.97; OR2: 0.65; CI 0.40-1.08, especially for ER+ tumours; OR: 0.48; CI 0.28-0.87) but not for prostatic cancer among SNP309TG heterozygotes. SNP309G (SNP309TG or SNP309GG genotype) was associated with a moderately increased risk of endometrial cancer (OR: 1.17; CI 1.00-1.37) compared to SNP309TT homozygotes. Removing individuals harbouring the SNP309G-counteracting SNP285C polymorphism from the analysis strengthened this association (OR: 1.20; CI 1.02-1.41). CONCLUSION: The finding of an ERE overlapping with the Sp1-binding site affected by SNP285, taken together with the significant impact of SNP285 on the risk of breast, ovarian and now endometrial cancer but not prostatic cancer, suggests a gender specific effect of SNP285C on cancer risk.
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| 6. |
- Welin, Staffan, et al.
(författare)
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Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy
- 2011
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 117:20, s. 4617-4622
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first-line palliative chemotherapy. There are, however, no published studies concerning second-line treatment of the disease. Temozolomide has shown clinical effect in well-differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first-line treatment. METHODS: Twenty-five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively. RESULTS: One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression-free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation. CONCLUSIONS: Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first-line chemotherapy. These results indicated that temozolomide may be used as second-line treatment in PDEC.
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