Next-generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma.
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.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael T
MT
Tetzlaff
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rajesh R
RR
Singh
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Elena G
EG
Seviour
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jonathan L
JL
Curry
Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Courtney W
CW
Hudgens
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Diana
D
Bell
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Daniel A
DA
Wimmer
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jing
J
Ning
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Bogdan A
BA
Czerniak
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Li
L
Zhang
Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael A
MA
Davies
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Victor G
VG
Prieto
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Russell R
RR
Broaddus
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Prahlad
P
Ram
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rajyalakshmi
R
Luthra
Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Bita
B
Esmaeli
D018266:Adenocarcinoma, Sebaceous / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis / Q000379:methods*; D005134:Eye Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053842:Microsatellite Instability; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D056286:Retinoblastoma Binding Proteins / Q000235:genetics; D012626:Sebaceous Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase
Muir-Torre syndrome; PI3-kinase; mismatch repair; next-generation sequencing; sebaceous carcinoma