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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Next-generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in
Michael T Tetzlaff1,2, Rajesh R Singh3, Elena G Seviour4
1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Sebaceous carcinoma (SC) is a rare but aggressive malignancy with frequent recurrence and metastases. Surgery is the mainstay of therapy, but effective systemic therapies are lacking because the molecular alterations driving SC remain poorly understood. To identify these, we performed whole-exome next-generation sequencing of 409 cancer-associated genes on 27 SCs (18 primary/locally recurrent ocular, 5 paired metastatic ocular, and 4 primary extraocular) from 20 patients. In ocular SC, we identified 139 non-synonymous somatic mutations (median/lesion 3; range 0-23). Twenty-five of 139 mutations (18%) occurred in potentially clinically actionable genes in 6 of 16 patients. The most common mutations were mutations in TP53 (n = 9), RB1 (n = 6), PIK3CA (n = 2), PTEN (n = 2), ERBB2 (n = 2), and NF1 (n = 2). TP53 and RB1 mutations were restricted to ocular SC and correlated with aberrant TP53 and RB protein expression. Systematic pathway analyses demonstrated convergence of these mutations to activation of the PI3K signalling cascade, and PI3K pathway activation was confirmed in tumours with PTEN and/or PIK3CA mutations. Considerable inter-tumoural heterogeneity was observed between paired primary and metastatic ocular SCs. In primary extraocular SC, we identified 77 non-synonymous somatic mutations (median/lesion 22.5; range 3-29). This overall higher mutational load was attributed to a microsatellite instability phenotype in three of four patients and somatically acquired mutations in mismatch repair genes in two of four patients. Eighteen of 77 mutations (23%) were in potentially clinically actionable genes in three of four patients, including BTK, FGFR2, PDGFRB, HRAS, and NF1 mutations. Identification of potentially clinically actionable mutations in 9 of 20 SC patients (45%) underscores the importance of next-generation sequencing to expand the spectrum of genotype-matched targeted therapies. Frequent activation of PI3K signalling pathways provides a strong rationale for application of mTOR inhibitors in the management of this disease. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Insights
This study analyzed sebaceous carcinoma (SC) genetic mutations using next-generation sequencing. Key findings reveal actionable mutations and PI3K pathway activation, suggesting new targeted therapy options for this rare cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Sebaceous carcinoma (SC) is a rare, aggressive cancer with high recurrence and metastasis rates.
- Current systemic therapies are limited due to poor understanding of SC's molecular drivers.
- Effective treatment strategies require identification of actionable genetic alterations.
Purpose of the Study:
- To identify molecular alterations driving sebaceous carcinoma (SC) using whole-exome sequencing.
- To uncover potentially clinically actionable mutations for targeted therapy development.
- To investigate differences in molecular profiles between ocular and extraocular SC.
Main Methods:
- Whole-exome next-generation sequencing of 409 cancer-associated genes was performed on 27 SC samples (20 patients).
- Samples included primary/recurrent ocular, metastatic ocular, and primary extraocular SC.
- Somatic mutations and pathway analyses were conducted to identify genetic drivers.
Main Results:
- Ocular SC showed 139 somatic mutations, with TP53 and RB1 being most common. PI3K pathway activation was frequently observed.
- Extraocular SC exhibited a higher mutational load, with some cases showing microsatellite instability and mismatch repair gene mutations.
- Potentially actionable mutations were identified in 45% of all SC patients, including alterations in TP53, RB1, PIK3CA, and others.
Conclusions:
- Genetic analysis reveals actionable mutations and PI3K pathway activation in sebaceous carcinoma.
- These findings support the use of next-generation sequencing for genotype-matched targeted therapies.
- Targeting PI3K signaling pathways, potentially with mTOR inhibitors, is a promising therapeutic strategy for SC.
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