Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations

Autor: Siraj M. Ali, Juliann Chmielecki, Philip J. Stephens, Doron Lipson, Sumanta K. Pal, Vincent A. Miller, Jamie Buell, Roman Yelensky, Edward Dow, Garrett M. Frampton, Julia A. Elvin, Mark Bailey, Rachel Squillace, Kai Wang, Norma Alonzo Palma, Peter M. Howley, Jeffrey S. Ross, Deborah Morosini, Jie He, Eric M. Sanford
Rok vydání: 2015
Předmět:
Male
0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
Cancer Diagnostics and Molecular Pathology
Class I Phosphatidylinositol 3-Kinases
medicine.medical_treatment
medicine.disease_cause
Targeted therapy
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
CDKN2A
Internal medicine
Penile Carcinoma
medicine
Humans
Penile cancer
Molecular Targeted Therapy
Receptor
Notch1
Penile Neoplasms
Cyclin-Dependent Kinase Inhibitor p16
Aged
Neoplasm Staging
Aged
80 and over
Mutation
Chemotherapy
business.industry
Gene Expression Profiling
Point mutation
food and beverages
High-Throughput Nucleotide Sequencing
Cancer
Exons
Middle Aged
medicine.disease
ErbB Receptors
Gene Expression Regulation
Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
sense organs
business
Zdroj: The Oncologist. 21:33-39
ISSN: 1549-490X
1083-7159
Popis: Background Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs). Materials and methods DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 692× for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials. Results Twenty male patients with a median age of 60 years (range, 46-87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (2.2 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), PIK3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), RICTOR amplifications (10%), and FBXW7 point mutations (10%). Conclusion CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and PIK3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients. Implications for practice Few treatment options exist for patients with advanced penile squamous cell carcinoma (PSCC). Outcomes are dismal with platinum-based chemotherapy, with median survival estimated at 1 year or less across multiple series. Biological studies of patients with PSCC to date have principally focused on human papillomavirus status, but few studies have elucidated molecular drivers of the disease. To this end, comprehensive genomic profiling was performed in a cohort of 20 patients with advanced PSCC. Findings of frequent mutations in CDKN2A, NOTCH1, PIK3CA, and EGFR (all in excess of 20%) point to potential therapeutic avenues. Trials of targeted therapies directed toward these mutations should be explored.
Databáze: OpenAIRE
Externí odkaz: