Abstract 5106: A HHIP derived gene expression signature for the prediction of patient survival after adjuvant chemotherapy of pancreatic cancer

7517 Background: Genomic profiling of SqCC in TCGA identified somatic alterations that activate the NRF2 transcriptional program – a master regulator of the oxidative stress response – in ~35% of tumors (NFE2L2 mutations/amplifications, KEAP1 or CUL3 mutations/deletions). This pathway has been implicated in resistance to chemotherapy. To evaluate the clinical significance of this molecular subset, we developed a gene expression classifier and tested this signature as a predictor of adjuvant chemotherapy benefit with cisplatin/vinorelbine (cis/vin) in a subset of SqCC patients with microarray data from the NCIC JBR.10 Phase III clinical trial. Methods: Logistic regression (LR) and SAM analysis were independently applied to 104 TCGA SqCC cases that had both microarray gene expression and mutation data to identify genes associated with NRF2 pathway mutational status. Overlapping genes were used to define the signature, which was then tested in 3 independent SqCC datasets (62 JBR.10; 54 UHN; 129 UM) to evaluate the prognostic and predictive values of putative NRF2 pathway activation. Results: 29 genes comprising the signature were identified by overlap between LR (291 genes) and SAM (45 genes). The signature consistently separated SqCC into 2 groups in all datasets, corresponding to putatively activated and wild type (WT) NRF2 pathway tumors. No prognostic effect of the activated signature was observed in independent datasets (UHN HR 0.86, 95%CI 0.28 – 2.67; UM HR 1.43, 95%CI 0.82 – 2.48). Similarly, in JBR10, no prognostic effect was observed in the observation arm (n=24, HR 0.66, 95%CI 0.13 – 3.29). A trend toward improved survival with adjuvant chemotherapy was observed in patients with the WT signature (HR 0.34, 95%CI 0.08 – 1.78, p=0.13), but not in patients with the activated signature (HR 1.16, 95%CI 0.19 – 6.97, p=0.87; interaction p=0.18). Conclusions: A gene expression signature based on mutational activation of the NRF2 pathway may be predictive of benefit from adjuvant cis/vin in SqCC. Patients with NRF2 pathway activating somatic alterations may have reduced benefit from this therapy. Validation of this potentially "actionable" finding in additional datasets is necessary.

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HOXA4/HOXB3 gene expression signature as a biomarker of recurrence in patients with high-grade serous ovarian cancer following primary cytoreductive surgery and first-line adjuvant chemotherapy

Gynecologic Oncology ◽

10.1016/j.ygyno.2018.01.022 ◽

2018 ◽

Vol 149 (1) ◽

pp. 155-162 ◽

Cited By ~ 10

Author(s):

Katherine R. Miller ◽

Jai N. Patel ◽

Qing Zhang ◽

Eric J. Norris ◽

James Symanowski ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Adjuvant Chemotherapy ◽

Cytoreductive Surgery ◽

Gene Expression Signature ◽

High Grade ◽

Serous Ovarian Cancer ◽

First Line ◽

Expression Signature

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Association of YAP1 activation with poor patient prognosis and effect on chemoresistance in gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4113 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4113-4113

Author(s):

Sung Sook Lee ◽

Sang Cheul Oh ◽

Woojin Jeong ◽

Sang Ho Lee ◽

Sang-Bae Kim ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Adjuvant Chemotherapy ◽

Therapeutic Target ◽

Notch Pathway ◽

Gene Expression Signature ◽

Expression Signature ◽

Tumor Subtypes ◽

Attractive Therapeutic Target ◽

Patient Prognosis

4113 Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.

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A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer

BMC Cancer ◽

10.1186/s12885-017-3821-4 ◽

2017 ◽

Vol 17 (1) ◽

Cited By ~ 7

Author(s):

Bangrong Cao ◽

Liping Luo ◽

Lin Feng ◽

Shiqi Ma ◽

Tingqing Chen ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Gene Expression Signature ◽

Stage Ii ◽

Expression Signature ◽

Predictive Gene ◽

Stage Ii Colorectal Cancer

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A prognostic eight‐gene expression signature for patients with breast cancer receiving adjuvant chemotherapy

Journal of Cellular Biochemistry ◽

10.1002/jcb.29550 ◽

2019 ◽

Vol 121 (8-9) ◽

pp. 3923-3934 ◽

Cited By ~ 2

Author(s):

Qiuxia Cui ◽

Jianing Tang ◽

Dan Zhang ◽

Deguang Kong ◽

Xing Liao ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Adjuvant Chemotherapy ◽

Gene Expression Signature ◽

Expression Signature

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Use of gene expression profile and mitotic index of metastatic melanoma lesions as an adjunct to TNM staging in predicting patient survival

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.9014 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 9014-9014

Author(s):

D. Bogunovic ◽

D. O'Neill ◽

I. Belitskaya-Levy ◽

V. Vacic ◽

S. Adams ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Gene Expression Profiling ◽

Metastatic Melanoma ◽

Expression Profiling ◽

Patient Survival ◽

Gene Expression Signature ◽

Tnm Staging ◽

Expression Signature ◽

Metastatic Lesions

9014 Background: Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling of metastatic lesions to search for a molecular basis for this observation, and to develop improved methods for predicting patient survival. Methods: We analyzed gene expression profiles of 44 metastatic melanoma specimens collected from 38 patients (median follow-up of 20 months after surgery). We used the False Discovery Rate (FDR) approach to identify genes significantly associated with post-recurrence survival. We then evaluated matching H&E stained tissue samples for the presence of tumor-infiltrating leukocytes (TILs) and mitotic index, (MI). Support vector machines and multi-variable Cox regression analysis was used to examine the relative ability of the pre-validated gene expression predictor, TILs, MI and TNM staging to predict survival. Results: We identified a group of approximately 300 genes associated with survival. Genes associated with immune response (ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1 etc.) or with cell proliferation (PDE4D, CDK2, GREF1, NUSAP1, SPC24 etc.) were highly represented .Prolonged survival was associated with the elevated expression of immune response genes and decreased expression of genes associated with proliferation. Furthermore, any of the three additional parameters (pre-validated gene expression signature, TILs or MI) improved the ability of TNM staging to predict post-recurrence survival; MI was the most significant contributor (HR = 2.65, p = 0.003) followed by the gene expression signature (HR = 2.71, p = 0.05). Conclusions: Gene expression profiling and MI of metastatic lesions can both be utilized to improve upon current staging of metastatic melanoma to predict patient survival. Gene expression signature and analysis of TILs indicate immune surveillance as a mechanism for prolonged survival in these patients. No significant financial relationships to disclose.

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