Next generation sequencing identifies ‘interactome’ signatures in relapsed and refractory metastatic colorectal cancer

Johnson, Benny; Cooke, Laurence; Mahadevan, Daruka

doi:10.21037/jgo.2016.09.05

Cited by 14 publications

(7 citation statements)

References 36 publications

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“…In CRC, PDGFRA overexpression is associated with advanced disease and lymph node involvement (30). Moreover, mutations identified by NGS have recently been described in therapy refractory CRC (31).…”

Section: Discussionmentioning

confidence: 99%

Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery

Schweiger¹,

Liebmann-Reindl²,

Glueck³

et al. 2018

J. Thorac. Dis

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Background: Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease.Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables.Methods: Case-matched, formalin-fixed paraffin embedded surgical specimens of lung metastases (n=47) and matched primary CRC (n=24) were sequenced using the TruSeq Amplicon Cancer Panel (Illumina platform). Penalized Cox regression models were applied to identify mutations with prognostic impact.Results: Mutations were found most frequently in APC, TP53 and KRAS, in both PM and matched primary tumors. Concordance between primary tumors and PM was 83.5%. Adaptive elastic-net regularized Cox regression models identified mutations being prognostic for time to pulmonary recurrence (EGFR, GNAQ, KIT, MET, and PTPN11) and for overall survival (OS) (PDGFRA, SMARCB1, and TP53).Conclusions: Our findings suggest that CRC PM harbor a variety of conserved and de novo mutations. We could identify a mutational profile predicting clinical outcome after pulmonary metastasectomy. Moreover, our data provide a rationale for future targeted therapies of patients with CRC lung metastases.

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Section: Discussionmentioning

confidence: 99%

Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery

Schweiger¹,

Liebmann-Reindl²,

Glueck³

et al. 2018

J. Thorac. Dis

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“…Not only RAS gene status but also other genes, such as BRAF, HER2, MET, and ALK, play an important role in treatment decision for CRC patients. NGS could help physicians capture whole genetic pictures of tumors and guide their clinical treatment decisions [13]. Using tumor tissue from a formalin-fixed paraffin-embedded (FFPE) sample for sequencing is the standard method.…”

Section: Discussionmentioning

confidence: 99%

Colorectal Cancer with EML4-ALK Fusion Gene Response to Alectinib: A Case Report and Review of the Literature

Hsiao

Weng

et al. 2021

Case Rep Oncol

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Anti-epithelial growth factor receptor or anti-vascular endothelial growth factor agents combined with chemotherapy were the standard of treatment for metastatic colorectal cancer (CRC). However, increasing evidence of molecularly stratified treatment makes the complexity of treatment. Anaplastic lymphoma kinase (ALK) gene alternation is one of potential target for biomarker-guided therapy for CRC. We present a case of a 56-year-old man who suffered from advanced ascending colon cancer, harboring echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion gene E21; A20 variant, a rare variant in EML4-ALK fusion gene in lung cancer. We also detected this fusion gene from different tissue types including circulating tumor DNA (ctDNA) and ascites fluid. The patient was offered alectinib, an ALK inhibitor, with partial response in lung, liver, and peritoneal metastasis for 8 months. Tumor heterogeneity, especially in gastrointestinal tract cancer, raise our interest in comprehensive genetic profiling in clinical practice. Convenience and reliability of next-generation sequencing, including using ctDNA, help physicians deal with clinical dilemma. ALK-positive CRC is rare. However, advanced CRC with ALK gene alteration responds to ALK inhibitor. It is reasonable to check ALK gene alteration in clinical practice for CRC.

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“…α -Spectrin and ß -spectrin are assembled into spectrin, which is an actin crosslinking and molecular scaffold protein that determines cell shape and membrane protein location [42, 43]. Alterations in SPTA1 are associated with colorectal cancer [44, 45] and small-cell lung cancer [42]. However, to date, the carcinogenic mechanism of mutated SPTA1 remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Identifying Mutually Exclusive Gene Sets with Prognostic Value and Novel Potential Driver Genes in Patients with Glioblastoma

Gao

Cui

Shen

et al. 2019

BioMed Research International

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The pathogenesis and prognosis of glioblastoma (GBM) remain poorly understood. Mutual exclusivity analysis can distinguish driver genes and pathways from passenger ones. The purpose of this study was to identify mutually exclusive gene sets (MEGSs) that have prognostic value and to detect novel driver genes in GBM. The genomic alteration profile and clinical information were derived from The Cancer Genome Atlas, and the MEGSA method was used to identify the MEGS. Next, we performed survival analysis and constructed a risk prediction model for prognostic stratification. Leave-one-out cross-validation and permutation test were used to evaluate its performance. Finally, we identified 21 statistically significant MEGSs. We found that the MEGS in the RB pathway was significantly associated with poor prognosis, after adjusting for age and gender (HR = 1.837, 95% CI: 1.192–2.831). Based on the risk prediction model, 208 (80.9%) and 49 (19.1%) patients were assigned to high- and low-risk groups, respectively (log-rank: p < 0.001, adjusted p=0.001). Additionally, we found that SPTA1, a novel gene involved in the MEGS, was mutually exclusive with members of cell cycle, P53, and RB pathways. In conclusion, the MEGS in the RB pathway had considerable clinical value for GBM prognostic stratification. Mutated SPTA1 may be involved in GBM development.

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Next generation sequencing identifies ‘interactome’ signatures in relapsed and refractory metastatic colorectal cancer

Cited by 14 publications

References 36 publications

Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery

Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery

Colorectal Cancer with EML4-ALK Fusion Gene Response to Alectinib: A Case Report and Review of the Literature

Identifying Mutually Exclusive Gene Sets with Prognostic Value and Novel Potential Driver Genes in Patients with Glioblastoma

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