Association of Somatic Mutations of<i>ADAMTS</i>Genes With Chemotherapy Sensitivity and Survival in High-Grade Serous Ovarian Carcinoma

Liu, Yuexin; Yasukawa, Maya; Chen, Kexin; Hu, Limei; Broaddus, Russell R.; Li, Ding; Mardis, Elaine R.; Spellman, Paul T.; Levine, Douglas A.; Mills, Gordon B.; Shmulevich, Ilya; Sood, Anil K.; Zhang, Wei

doi:10.1001/jamaoncol.2015.1432

Cited by 34 publications

(34 citation statements)

References 42 publications

(69 reference statements)

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“…Most recently, Liu et al comprehensively investigated mutation data of 512 OvCa patients and successfully identified mutations in eight ADAMTS genes as potential markers of prognosis and drug sensitivity. They further revealed ADAMTS-mutated cases exhibited a distinct mutation spectrum and were significantly associated with hypermutated tumors [30]. These studies provide potential assays/markers of selecting patients for genetic testing or recruitment to clinical trials of PARPis.…”

Section: Discussionmentioning

confidence: 99%

Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

Zhang

Liu

Xue

et al. 2016

Gynecologic Oncology

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Objective To identify novel prognostic and therapeutic markers for PARP inhibitors in BRCA wild type ovarian cancer (OvCa). Methods BRCAness status was defined by analyzing whole-exome deep sequencing data from 220 BRCAwt OvCa cases in TCGA. Thirty-three DNA-repair genes were screened in an integrated manner for BRCA-independent mechanism of BRCAness using multiple-dimensional genomic data. Publicly available databases and siRNA knock-down were used for external validation and evaluation of drug response in OvCa cell lines. Results In 220 BRCAwt OvCa patients, tumors exhibiting the BRCAness signature have enhanced OS (HR [95% CI]=0.33 [0.15-0.69], P=0.004) and PFS (HR [95% CI]=0.51 [0.24-1.08], P=0.077), strongly suggesting a BRCA-independent mechanism of drug sensitivity in those patients. Systematic screening of driving molecular events of BRCAness revealed that RAD50 deletion is a marker of BRCAness. The RAD50 deletion occurred in 18% of BRCAwt OvCa patients. RAD50 deletion led to its decreased mRNA expression in tumors (Fold Change=0.63, P=3.56 × 10-13). In BRCAwt patients, RAD50 deletion was associated with significantly better OS (HR [95% CI]=0.44 [0.25-0.78], P=0.005) and PFS (HR [95% CI]=0.60 [0.37-0.99], P=0.044), adjusted by age and stage. Knockdown of RAD50 expression augmented OvCa cell's responses to cisplatin and olaparib. Among 19 OvCa cell lines, the RAD50 copy number deletion is significantly associated with better responses to two structurally distinct PARPis (i.e. olaparib and rucaparib). Conclusion Our study identified the copy number deletion of RAD50 as a candidate marker for survival and response to PARPis in BRCAwt OvCa tumors.

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Section: Discussionmentioning

confidence: 99%

Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

Zhang

Liu

Xue

et al. 2016

Gynecologic Oncology

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“…Furthermore, expression of full-length ADAMTS-1 reversed this inhibition of metastatic activity [57]. Using genomic and clinical data, a recent ovarian cancer study showed that somatic mutations in ADAMTS may result in better outcome in ovarian cancer cases and may have important clinical implications [23]. …”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Lima¹,

Santos²,

Turri³

et al. 2016

Pathobiology

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Background: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome. Objective: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed. Methods: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas. Results: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival. Conclusions: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.

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“…Meanwhile, somatic mutations of ADAMTS genes are associated with chemotherapy sensitivity and patients' survival [20,21]. To gain further insight into the mutation, copy-number alterations, and expression profile of ADAMTS, we examined the TCGA (provisional) cohort by cBioPortal (http://www.cbioportal.org/).…”

Section: Differentially Expressed Adamts4 Predicts a Poor Prognosis Imentioning

confidence: 99%

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

Chen

Luo

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. Methods: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. Results: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. Conclusion: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.

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Association of Somatic Mutations ofADAMTSGenes With Chemotherapy Sensitivity and Survival in High-Grade Serous Ovarian Carcinoma

Cited by 34 publications

References 42 publications

Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages

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