Abstract C27: Whole-exome sequencing identifies potential therapeutic targets for castration-resistant prostate cancer

Background: Castration-resistant Prostate Cancer (CRPC) is a fatal disease with rapid growth. The malignancy usually presents with metastasis and poor prognosis, and causes 100% mortality. Therefore, the treatment of CRPC is extremely challenging, and its pathogenesis need to be elucidated urgently. Objective: The high throughput sequencing technology was used to sequence the whole exome associated with CRPC, to explore the molecular mechanism of CRPC, and to find the potential therapeutic targets. Methods: We performed whole-exome sequencing of FFPE tissue from 11 Chinese adult male patients. Genomic DNA was fragmented and enriched for whole-exome sequencing using the QiAamp DNA FFPE Tissue KIT, sequenced on an Illumina HiSeq2000 platform, and the relevant genes were analyzed using biological information. Finally, immunohistochemistry method was used to detect the phosphorylation level of LATS1 in CRPC tissues of MST1 mutant and non-mutant patients. Results: We have screened 85 significant mutant genes with relatively high mutation rates of TP53, AR, KMT2, DMAPK1, PIK3R1, SH2B3, WHSC1, KMT2D, MST1 and MAPK1. We first found that MST1 has multiple mutations in CRPC patients, and the MST1 plays an important role in the Hippo pathway. Immunohistochemistry results showed that the phosphorylation level of LATS1 in the mutant patients was significantly lower than that in the non-mutant patients. Conclusion: We speculate that MST1 would be a new potential target for the treatment of CRPC by regulating Hippo signaling pathway. The results provided an important clue to the molecular mechanism of CRPC.

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Somatic copy number alterations by whole-exome sequencing implicatesYWHAZandPTK2in castration-resistant prostate cancer

The Journal of Pathology ◽

10.1002/path.4274 ◽

2013 ◽

Vol 231 (4) ◽

pp. 505-516 ◽

Cited By ~ 19

Author(s):

Roopika Menon ◽

Mario Deng ◽

Kerstin Rüenauver ◽

Angela Queisser ◽

Martin Pfeifer ◽

...

Keyword(s):

Prostate Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Copy Number ◽

Copy Number Alterations ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Whole Exome ◽

Somatic Copy Number Alterations

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Abstract LB-122: Tumor heterogeneity in castration resistant neuroendocrine prostate cancer from whole exome sequencing of circulating tumor DNA

10.1158/1538-7445.am2017-lb-122 ◽

2017 ◽

Author(s):

Himisha Beltran ◽

Alssandro Romanel ◽

Nicola Casiraghi ◽

Michael Sigouros ◽

Matteo Benelli ◽

...

Keyword(s):

Prostate Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Tumor Heterogeneity ◽

Circulating Tumor Dna ◽

Castration Resistant ◽

Whole Exome ◽

Neuroendocrine Prostate Cancer ◽

Tumor Dna

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Whole-exome sequencing of single circulating tumor cells is a useful tool for studying the intrapatient genetic heterogeneity in metastatic prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.148 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 148-148 ◽

Cited By ~ 3

Author(s):

Vincent Faugeroux ◽

Celine Lefebvre ◽

Emma Pailler ◽

Valerie Pierron ◽

Fanny Billiot ◽

...

Keyword(s):

Prostate Cancer ◽

Single Cell ◽

Exome Sequencing ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Whole Exome Sequencing ◽

Genetic Heterogeneity ◽

Castration Resistant Prostate Cancer ◽

Illumina Hiseq ◽

Whole Exome

148 Background: Molecular characterization of metastatic castration resistant prostate cancer (mCRPC) is limited by tumor tissue availability. The analysis of circulating tumor cells (CTC) offers an attractive noninvasive surrogate option to analyze molecular alterations. We report whole exome sequencing (WES) of CTCs at the single cell level in mCRPC patients. Methods: Blood samples were drawn from 11 enzalutamide or abiraterone pre-treated mCRPC patients enrolled in the clinical program MOSCATO (NCT02613962). CTC enrichment, immunofluorescent detection and single cell isolation were performed using three methods (ISET filtration, CellSearch and the VyCap puncher system and RosetteSep enrichment) to obtain pools of 1-10 CTCs with distinct epithelial or mesenchymal phenotypes. After Whole Genome Amplification (WGA), WES was performed on the Illumina HiSeq 2000 platform. GATK Haplotype Caller enabled identification of germline polymorphisms from each patient in normal DNA, metastatic sample and CTCs in order to consider WGA induced bias. The detection of sSNV in tumor biopsies and CTCs was assessed with Mutect and IndelGenotyper respectively. Results: 189 WGA of CTC pools were performed. 34 pools of phenotypically different CTCs from 7 patients were selected and sequenced. Mean coverage of 51% was obtained at a sequencing depth of 10X. Allelic drop out was lower for CTC pools containing 5-10 cells. 17/34 (50%) CTC samples had shared sSNV with the paired tumor sample (range 0.35%-68%) Epithelial CTCs had more shared sSNV with metastatic biopsies than CTCs of other phenotypes but shared sSNV were also detected in large non epithelial CTC pointing out a high level of genetic heterogeneity between CTC. Overall, 89 deleterious protein-coding mutations were found only in pools of CTC, including mutations affecting oncogenic drivers such as MAPK1, HSP90AB1 or KDM5B. Conclusions: We present single cell WES of CTCs harboring distinct phenotypes. The detection of shared sSNV between CTC pools and corresponding biopsy could validate the use of CTCs as a liquid biopsy. The finding of sSNV specific to CTCs could offer additional data on tumor heterogeneity.

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