Unknown,Transcriptomics,Genomics,Proteomics

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RRBS of human fetal testis treated to a mixture of DEHP/BPA

ABSTRACT: Fetal human fetal testes (8-11 weeks post-fertilization [WPF]) were cut into small pieces (~1 mm3 ) and 4-6 pieces/testis (depending of the age or size of the gonad) were insert into the muscle of the left back of two twin female mice. One week after surgery, one mouse was exposed by drinking water to a mixture of BPA (1 µM, CAS no. 80-09-1, Merck) and DEHP (1 µM, CAS no. 117-81-7, Merck) and the other was exposed by drinking water to the vehicle (absolute ethanol [ETOH] diluted at 1/1000000 in water). Mice were exposed during 6-11 weeks (corresponding to the 18 WPF equivalent age) and at the end of exposure, testes were collected and each pieces were cleaned from extracellular matrix and murine muscular tissue. One part of the pieces were used for RRBS analyses.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Homo sapiens

SUBMITTER: Marie-Justine Guerquin

PROVIDER: E-MTAB-13840 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:DCIS is a non-invasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer while others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immune suppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly ncRNA and methylation profiles reproduce changes observed post-invasion. Among the most significant findings we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and specific SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a pre-invasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. DNA from 24 out of 30 (80%) HG-DCIS samples and 5 normal breast organoids (total 29 samples) were subjected to reduced representation bisulfite sequencing analysis (RRBS) by using Illumina HiSeq2000 platform. Please note that description of samples employed for the NGS analyses including age, race, ER/PR immunohistochemistry results, ITIL/STIL scores and PAM50 classification is provided the 'Supplementary Data1_Samples data.xlsx' (available on Superseries record)

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RRBS of human fetal testis treated to a mixture of DEHP/BPA

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