| 1. |
- Hall, Per, et al.
(författare)
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Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis : a cohort study
- 2006
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 4, s. 16-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. Methods: We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. Results: HRT use in patients with estrogen receptor ( ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. Conclusion: Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.
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| 2. |
- Ivshina, Anna V., et al.
(författare)
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Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer
- 2006
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 66:21, s. 10292-10301
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Tidskriftsartikel (refereegranskat)abstract
- Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (W) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable with that of lymph node status and tumor size. When incorporated into the Nottingham prognostic index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low- and high-grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression.
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| 3. |
- La Fleur, Linnea, et al.
(författare)
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Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
- 2019
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
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| 4. |
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| 5. |
- Pawitan, Yudi, et al.
(författare)
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Gene expression profiling spares early breast cancer patients from adjuvant therapy : derived and validated in two population-based cohorts
- 2005
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 7:6, s. R953-64
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction. METHODS: We obtained the gene expression profiles of 159 population-derived breast cancer patients, and used hierarchical clustering to identify the signature associated with prognosis and impact of adjuvant therapies, defined as distant metastasis or death within 5 years. Independent datasets of 76 treated population-derived Swedish patients, 135 untreated population-derived Swedish patients and 78 Dutch patients were used for validation. The inclusion and exclusion criteria for the studies of population-derived Swedish patients were defined. RESULTS: Among the 159 patients, a subset of 64 genes was found to give an optimal separation of patients with good and poor outcomes. Hierarchical clustering revealed three subgroups: patients who did well with therapy, patients who did well without therapy, and patients that failed to benefit from given therapy. The expression profile gave significantly better prognostication (odds ratio, 4.19; P = 0.007) (breast cancer end-points odds ratio, 10.64) compared with the Elston-Ellis histological grading (odds ratio of grade 2 vs 1 and grade 3 vs 1, 2.81 and 3.32 respectively; P = 0.24 and 0.16), tumor stage (odds ratio of stage 2 vs 1 and stage 3 vs 1, 1.11 and 1.28; P = 0.83 and 0.68) and age (odds ratio, 0.11; P = 0.55). The risk groups were consistent and validated in the independent Swedish and Dutch data sets used with 211 and 78 patients, respectively. CONCLUSION: We have identified discriminatory gene expression signatures working both on untreated and systematically treated primary breast cancer patients with the potential to spare them from adjuvant therapy.
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| 6. |
- Smeds, Johanna, et al.
(författare)
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Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events : analysis of loss of heterozygosity
- 2005
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 44:1, s. 41-9
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Tidskriftsartikel (refereegranskat)abstract
- To compare chromosomal alterations in ductal carcinoma in situ (DCIS) of different histopathological grades and to study aberrations between primary DCIS and corresponding ipsi- or contralateral new in situ or invasive tumours, a study was undertaken of the pattern of loss of heterozygosity (LOH) at chromosomal regions in which LOH has previously been described in invasive breast cancer. LOH was analysed using 19 microsatellite markers located on chromosomes 3p, 6q, 8p, 8q, 9p, 11p, 11q, 16q, 17p, and 17q in 30 women with a primary DCIS. Eleven women with DCIS of grade 1 and 19 with grade 3 according to the EORTC classification system were included. In six patients LOH was also analysed in a subsequent new breast cancer. Fractional allelic loss (FAL, the ratio of chromosomal arms where allelic loss was detected divided by the total number of chromosomal arms with informative markers) was statistically significantly higher in grade 1 DCIS compared with grade 3 (p=0.02) for the 19 loci, indicating that the amount of allelic loss does not correlate with increasing aggressiveness of the studied tumours. Also observed was a complete heterogeneity of LOH in the primary DCIS and their corresponding new events, suggesting that these events probably developed from genetically divergent clones.
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| 7. |
- Smeds, Johanna
(författare)
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Role of the CDKN2A and related cell cycle regulatory genes in melanoma and other human cancers
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main objective of this thesis has been to investigate the involvement of the CDKN2A (p16INK4a and p14ARF) and related cell cycle regulatory genes in melanoma and other types of human cancer. The CDKN2A gene represents a unique locus in the entire human genome. It encodes two separate cell cycle regulators from distinctive exon 1 alpha and exon 1 beta, that splice with common exons 2 and 3 and are translated in different reading frames. By inhibition of the cyclin D-CDK4/6 complex, p16 INK4a prevents phosphorylation of the RB protein, in turn leading to block of cell cycle progression. The p14 A F protein participates in the p53 pathway and restrains cell growth by p53 stabilization by sequestering HDM2. The locus carrying the CDKN2A gene on chromosome 9p21 is commonly altered in a number of human cancer types. This study has assessed the status of the CDKN2A (p16INK4a and p14ARF) gene in malignant melanoma and squamous cell carcinoma of esophagus (ESCC). In addition, mutations were determined in the CDKN2B, CDKN2C, CDK4, p53 and p53R2 genes. The results showed alterations of the CDKN2A gene in both primary and metastatic melanomas. In the primary melanomas a high frequency of loss of heterozygosity was detected at chromosome 9p21, while the rates of mutations and homozygous deletions in the CDKN2A gene were relatively low. A significantly increased frequency of loss of heterozygosity was found at the marker D9S736, which is located telomeric to the CDKN2A gene, suggesting the presence of an additional tumour suppressor gene. An interesting correlation was found between the frequency of loss of heterozygosity on chromosome 9 and increased patient age at diagnosis. Analysis of metastatic melanoma likewise showed low frequencies of mutations and homozygous deletions of the CDKN2A gene. The results showed an association between polymorphisms in the 3´untranslated region of the CDKN2A gene and progression of disease. One of those polymorphisms was also significantly overrepresented in sporadic primary melanomas compared to healthy controls. No mutations were found in the CDKN2B, CDKN2C, CDK4 or p53R2 genes, suggesting a limited role in melanoma. Similarly no evidence was found for the involvement of the p53 gene in malignant melanoma. The study of esophageal squamous cell carcinomas showed a very high proportion of genetic and epigenetic alterations in the CDKN2A (p16INK4a and p14ARF) and p53 genes. Of 21 cases analysed, 86% were found to have at least one alteration in the CDKN2A gene. No major alterations were detected in the CDKN2B, CDKN2C, CDK4 or p53R2 genes. However, in the 5´untranslated region of the p53R2 gene a novel polymorphism was detected. Additionally another novel polymorphism, an 8 base pair insertion in the same region was detected in control population, which was subsequently genotyped for association with different cancers. Altogether, the cancer types studied showed a complex pattern of genetic alterations, indicating the contribution of various disrupted cell cycle regulatory mechanisms. Involvement of the CDKN2A gene was found in a subset of sporadic melanoma cases. The mutation rate of the CDKN2A gene was low, albeit allelic loss at 9p21 was frequent. A prevailing theory is the existence of other tumour suppressor genes within the locus. However, candidate genes remain to be identified. Alterations of the CDKN2A (p16INK4a and p14ARF) and p53 genes were found to be major events in esophageal squamous cell carcinomas.
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| 8. |
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| 9. |
- Wennmalm, Kristian, et al.
(författare)
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Gene expression in 16q is associated with survival and differs between Sørlie breast cancer subtypes
- 2007
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:1, s. 87-97
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the relationship between gene expression and chromosomal positions in 402 breast cancer patients. Using an overrepresentation approach based on Fisher's exact test, we identified disproportionate contributions of specific chromosomal positions to genes associated with survival. Our major finding is that the gene expression in the long arm of chromosome 16 stands out in its relationship to survival. This arm contributes 36 (18%) and 55 (11%) genes to lists negatively associated with recurrence-free survival (set to sizes 200 and 500). This is a highly disproportionate contribution from the 313 (2%) genes in this arm represented on the used Affymetrix U133A and B microarray platforms (Bonferroni corrected Fisher test: P < 2.2 x 10(-16)). We also demonstrate differential expression in 16q across tumor subtypes, which suggests that the ERBB2, basal, and luminal B tumors progress along a high grade-poor prognosis path, while luminal A and normal-like tumors progress along a low grade-good prognosis path, in accordance with a previously proposed model of tumor progression. We conclude that important biological information can be extracted from gene expression data in breast cancer by studying non-random connections between chromosomal positions and gene expression. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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