Evaluation of tumor gene expression and K-Ras mutations in FFPE tumor tissue as predictors of response to cetuximab in metastatic colorectal cancer

Purpose The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab. Patients and Methods One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies. Results Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively). Conclusion Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

Download Full-text

Dual Hypergraph Regularized PCA for Biclustering of Tumor Gene Expression Data

IEEE Transactions on Knowledge and Data Engineering ◽

10.1109/tkde.2018.2874881 ◽

2019 ◽

Vol 31 (12) ◽

pp. 2292-2303 ◽

Cited By ~ 1

Author(s):

Xuesong Wang ◽

Jian Liu ◽

Yuhu Cheng ◽

Aiping Liu ◽

Enhong Chen

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Expression Data ◽

Tumor Gene Expression ◽

Tumor Gene

Download Full-text

ASO Author Reflections: RAS Mutations in Metastatic Colorectal Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-018-7020-6 ◽

2018 ◽

Vol 25 (S3) ◽

pp. 850-851 ◽

Cited By ~ 1

Author(s):

Guillaume Passot ◽

Jean-Nicolas Vauthey ◽

Yun Shin Chun

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Ras Mutations

Download Full-text

KRAS and NRAS mutational gene profile of metastatic colorectal cancer patients in Jordan: Molecular spectrum, frequency and distribution pattern

10.21203/rs.2.11767/v1 ◽

2019 ◽

Author(s):

Muhammad Awidi ◽

Nidaa Ababneh ◽

Maha Shomaf ◽

Feras Al Fararjeh ◽

Laila Owaidi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Distribution Pattern ◽

Cancer Patients ◽

Molecular Spectrum ◽

Kras Mutations ◽

Exon 2 ◽

Ras Mutations ◽

Colorectal Cancer Patients ◽

Kras Exon

Abstract Background A constitutively active RAS protein in the absence of stimulation of the epidermal growth factor receptor (EGFR) is the result of mutations in KRAS and NRAS genes. Mutations in the KRAS exon 2 and outside exon 2 have been found to predict the resistance to anti-EGFR monoclonal therapy. A substantial proportion of metastatic colorectal cancer cases (mCRC) exhibit RAS mutations outside KRAS exon 2, particularly in KRAS exon 3 and 4 and NRAS exons 2, 3. No data about RAS mutations outside KRAS exon 2 are available for Jordanian patients with mCRC. We aim to study the molecular spectrum, frequency, and distribution pattern of KRAS and NRAS mutations in Jordanian patients with mCRC. Methods A cohort of 190 Jordanian metastatic colorectal cancer patients were enrolled in the trial. We detected mutations in exon 2 of the KRAS and NRAS gene as well as mutations outside of exon 2 using the StripAssay technique. The KRAS StripAssay covered 29 mutations and 22 NRAS mutations. Results Mutations were observed in 92 (48.42%) cases, and KRAS exon 2 accounted for 76 cases (83.69%). KRAS G12D was the most common mutation, occurring in 18 cases, followed by KRAS G12A in 16 cases, and G12T in 13 cases. Mutations outside of KRAS exon 2 represented 16.3% of the mutated cases. Among those, 6 cases (6.48%) carried mutations in NRAS exon 2, 3 and 10 cases (10.87%) in KRAS exon 3 and 4. Conclusion The frequency of NRAS and KRAS mutations outside of exon 2 appears to be higher in Jordanian patients in comparison with patients from western countries. KRAS mutations outside of exon 2 should be tested routinely to identify patients who should not be treated with anti-EGFR antibodies.

Download Full-text

Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data

eLife ◽

10.7554/elife.26476 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 107

Author(s):

Julien Racle ◽

Kaat de Jonge ◽

Petra Baumgaertner ◽

Daniel E Speiser ◽

David Gfeller

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Immune Cell ◽

Expression Profiles ◽

Cell Types ◽

Response To Therapy ◽

Expression Data ◽

Cell Type ◽

Tumor Gene Expression ◽

Tumor Gene

Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type-specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research (http://epic.gfellerlab.org).

Download Full-text

Biological Insights into Chemotherapy Resistance in Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092131 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2131 ◽

Cited By ~ 2

Author(s):

Michelle A. Glasgow ◽

Peter Argenta ◽

Juan E. Abrahante ◽

Mihir Shetty ◽

Shobhana Talukdar ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Expression Profiles ◽

Rna Extraction ◽

Chemotherapy Resistance ◽

Gene Expression Profiles ◽

Gene Set Enrichment Analysis ◽

Before And After ◽

Tumor Gene Expression ◽

Tumor Gene

The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. The objective of this study was to compare tumor gene expression profiles in patients before and after treatment with neoadjuvant chemotherapy (NACT). Tumor samples were collected from six patients diagnosed with HGSOC before and after administration of NACT. RNA extraction and whole transcriptome sequencing was performed. Differential gene expression, hierarchical clustering, gene set enrichment analysis, and pathway analysis were examined in all of the samples. Tumor samples clustered based on exposure to chemotherapy as opposed to patient source. Pre-NACT samples were enriched for multiple pathways involving cell cycle growth. Post-NACT samples were enriched for drug transport and peroxisome pathways. Molecular subtypes based on the pre-NACT sample (differentiated, mesenchymal, proliferative and immunoreactive) changed in four patients after administration of NACT. Multiple changes in tumor gene expression profiles after exposure to NACT were identified from this pilot study and warrant further attention as they may indicate early changes in the development of chemotherapy resistance.

Download Full-text