Dataset Information

Tyrosine Kinase Mutations in Endometrial Cancer

ABSTRACT:

The purpose of the original study was to search for somatic mutations in the tyrosine kinome of serous and clear cell endometrial carcinomas (human). The study was conducted in two phases.

Phase 1: A mutation discovery screen, in which ~577 exons encoding the catalytic domains of 86 tyrosine kinases were PCR-amplified and bidirectionally Sanger sequenced from 24 serous, 11 clear cell, and 5 mixed histology endometrial tumors. This was followed by alignment of sequence reads to the human reference sequence and subsequent nucleotide variant calling to identify potential somatic (tumor-specific) mutations. Potential somatic mutations were confirmed by re-amplification and sequencing of the relevant tumor DNA as well as matched non-tumor ("normal") DNA from the same case.

Phase 2: A mutation prevalence screen, in which the non-catalytic regions two tyrosine kinase genes, TNK2 and DDR1, were PCR-amplified and sequenced from the 40 discovery screen tumors, and all coding exons of TNK2 and DDR1 were PCR-amplified and sequenced from another 10 clear cell, 21 serous, and 41 endometrioid endometrial tumors, in an effort to identify additional somatic mutations in each gene. Exons encoding the exonuclease domain of POLE were also sequenced to document somatic mutations.

PROVIDER: phs000841 | dbGaP |

SECONDARY ACCESSION(S): PRJNA268698PRJNA268699

REPOSITORIES: dbGaP

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	GapExchange_phs000841.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs000841.Sanger_EndometrialTumors.v1.p1.MULTI.pdf	Pdf
	manifest_phs000841.Sanger_EndometrialTumors.v1.p1.c1.DS-EC.pdf	Pdf
	datadict_v2.xsl	Other

Items per page:

1 - 5 of 15

Similar Datasets

Project description:Global gene expression patterns associated with early stage endometrial cancer have been reported, but changes in molecular expression associated with tumor grade, depth of myometrial invasion, and non-endometrioid histology have not been previously elucidated. Our group hypothesized there are unique genetic events underlying early endometrial carcinogenesis. Ninety-two samples of pathologically reviewed stage I endometrial cancers (80 endometrioid and 12 serous) with a heterogeneous distribution of grade and depth of myometrial invasion (i.e. 9 IAG1, 14 IAG2, 7 IAG3, 14 IBG1, 12 IBG2, 13 IBG3, 7 ICG1, 10 ICG2, and 6 ICG3) were examined in relation to 12 samples of atrophic endometrium from postmenopausal women. Specimens were analyzed using oligonucleotide microarray analysis and a subset of the differentially expressed transcripts was validated using quantitative PCR. Comparison of early stage cancers with normal endometrium samples by the univariate t-test with 10,000 permutations identified 900 genes that were differentially regulated by at least 4-fold at a p value of <0.001. Unsupervised analysis revealed that when compared to normal endometrium, serous and endometrioid stage I cancers appeared to have similar expression patterns. However, when compared in the absence of normal controls, they were distinct. Differential expression analysis revealed a number of transcripts that were common as well as unique to both histologic types. This data uncovers previously unrecognized, novel pathways involved in early stage endometrial cancers and identifys targets for prevention strategies that are inclusive of both endometrioid and serous histologic subtypes. Ninety-one samples of pathologically reviewed stage I endometrial cancers (79 endometrioid and 12 serous) with a heterogeneous distribution of grade and depth of myometrial invasion (i.e. 9 IAG1, 14 IAG2, 7 IAG3, 14 IBG1, 12 IBG2, 13 IBG3, 7 ICG1, 10 ICG2, and 6 ICG3) were examined in relation to 12 samples of atrophic endometrium from postmenopausal women. Specimens were analyzed using oligonucleotide array analysis.

Project description:Full title: comparison of the genomic (arrayCGH) profiles of endometrial cancer with and without prior prolonged tamoxifen treatment for primary breast cancer Purpose: Tamoxifen has been a very effective treatment for breast cancer for several decades, however, at the same time increases the risk of endometrial cancer, especially after prolonged exposure. In addition, tamoxifen has been associated with a higher proportion of unfavorable uterine tumor subtypes (carcinosarcomas and serous adenocarcinomas) with worse survival. We investigated whether endometrial tumors, which developed after prolonged tamoxifen treatment for breast cancer, are genetically different from endometrial tumors without preceding tamoxifen exposure. Experimental design: Array CGH was used on archival formalin-fixed paraffin embedded (FFPE) endometrial tumors to determine genomic aberrations. We compared the genomic profiles of 52 endometrial tumors from breast cancer patients after long-term (>=2 years) tamoxifen use (endometrioid adenocarcinomas n=26, carcinosarcomas n=14 and serous adenocarcinomas n=12) with endometrial tumors from unexposed breast cancer patients (n=45). Genomic profiles were correlated with tamoxifen exposure, tumor subtypes and histopathological characteristics of the endometrial tumors. Results: The common uterine corpus cancers of the endometrioid subtype show few genomic aberrations. Tumors with many genomic aberrations were in general ER-negative. In contrast, carcinosarcomas and serous adenocarcinomas showed many aberrations, however they were indistinguishable from each other. Tumors that developed after prolonged tamoxifen use did not show more or different aberrations than unexposed tumors. This was true for all tumor subtypes. Conclusion: Endometrial carcinomas that develop after prolonged tamoxifen use can not be distinguished from non-users on basis of their tumor genomic profile. 52 endometrial tumors from breast cancer patients after long-term (>=2 years) tamoxifen use (endometrioid adenocarcinomas n=26, carcinosarcomas n=14 and serous adenocarcinomas n=12) and 45 endometrial tumors from unexposed breast cancer patients

Project description:Intra-individual tumoral heterogeneity (ITH) is a hallmark of solid tumors and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian serous adenocarcinomas (OSAs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSA genomes using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumor lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSAs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes,. but common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSAs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both â??commonâ?? category and cancer-related genes were highly conserved in ascitic cells of OSAs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumor cells may serve as a potential resource to discover somatic mutations of primary OSA with diagnostic and therapeutic relevance. Genome wide DNA methylation profiling of ascitic cells as well as biopsies from ovarian serous adenocarcinomas cases obtained by Illumina Infinium 450k Human DNA methylation Beadchip Bisulphite converted DNA from the 16 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip

Dataset Information

Tyrosine Kinase Mutations in Endometrial Cancer

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets