Systematic Analysis of Drug Vulnerabilities Conferred by Tumor Suppressor Loss

Ding, H.; Zhao, Jie; Zhang, Yanli; Yu, Jiao; Liu, Mingxian; Li, Xiaoxi; Xu, Lu; Lin, Meixia; Liu, Chuan; He, Zhengjin; Chen, Shishuang; Jiang, Hai

doi:10.1016/j.celrep.2019.05.043

Cited by 23 publications

(18 citation statements)

References 64 publications

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“…SETD2 is a histone-modifying enzyme responsible for all trimethylation of H3K36 (H3K36me3). Decreases in H3K36me3 lead to chromosomal instability, such as MMRdeficient tumors [30], and cause drug vulnerabilities [31]. Therefore, some MCT-SCC patients might obtain a new therapeutic strategy for SETD2 mutation in the future.…”

Section: Discussionmentioning

confidence: 99%

“…For five frozen samples (samples #1, #2, #3, #4, and #5), HPV-DNA testing targeting 16 high-and low-risk HPV genotypes (genotypes 6,11,16,18,30,31,33,35,39,45,51,52,56,58,59, and 66) was performed using the multiplex PCR method (PapiPlex) at the GLab Pathology Center Co., Ltd (Sapporo, Japan) [48]. In addition, for three FFPE samples (sample #6, #7, and #8), HPV-16 and HPV-18 viral sequences were analyzed by using CANCER-PLEX® as previously described [23].…”

Section: Hpv Genotypingmentioning

confidence: 99%

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XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary

et al. 2020

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Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Hpv Genotypingmentioning

confidence: 99%

XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary

et al. 2020

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“…Indeed, systematic drug sensitivity analyses have proven drug vulnerabilities associated with loss of tumor suppressor genes. This could lead to expanding precision cancer medicine in tumors with a basis on mutations of tumor suppressor genes [66].…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma

Carril-Ajuria

Santos

Roldán-Romero

et al. 2019

Cancers

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Renal cell carcinoma (RCC) is the most frequent kidney solid tumor, the clear cell RCC (ccRCC) being the major histological subtype. The probability of recurrence and the clinical behavior of ccRCC will greatly depend on the different clinical and histopathological features, already incorporated to different scoring systems, and on the genomic landscape of the tumor. In this sense, ccRCC has for a long time been known to be associated to the biallelic inactivation of Von Hippel-Lindau (VHL) gene which causes aberrant hypoxia inducible factor (HIF) accumulation. Recently, next generation-sequencing technologies have provided the bases for an in-depth molecular characterization of ccRCC, identifying additional recurrently mutated genes, such as PBRM1 (≈40-50%), SETD2 (≈12%), or BAP1 (≈10%). PBRM1, the second most common mutated gene in ccRCC after VHL, is a component of the SWI/SNF chromatin remodeling complex. Different studies have investigated the biological consequences and the potential role of PBRM1 alterations in RCC prognosis and as a drug response modulator, although some results are contradictory. In the present article, we review the current evidence on PBRM1 as potential prognostic and predictive marker in both localized and metastatic RCC.

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“…Though the WNT/ β-catenin pathway is potentially therapeuticallytargetable, (Krishnamurthy and Kurzrock, 2018) it will be critical to determine how to best modulate this pathway to impact residual cancer cell survival. A general principle our data highlight is that by employing targeted treatments that take advantage of specific cell states we may be able to engineer cancer cell fate(s) to improve therapeutic responses in Loss of Tumor suppressors Targeting acquired vulnerabilities (Ding et,al., 2019) 8…”

Section: R a F Tmentioning

confidence: 99%

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

Maynard

McCoach

Rotow

et al. 2019

Preprint

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Systematic Analysis of Drug Vulnerabilities Conferred by Tumor Suppressor Loss

Abstract: Highlights d A heatmap describing drug sensitivities conferred by tumor suppressor loss d SETD2 deficiency sensitized cells to CDK7 inhibitor d CREBBP deficiency conferred resistance to EGFR inhibitors d BAP1 loss sensitized cells to DNMT1 inhibitors

Cited by 23 publications

References 64 publications

XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary

XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary

Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma

Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing

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