title: Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations.
abstract: 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).
  
  
  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%).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA Siraj@Foundationmedicine.com.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Norma A
authors.initials: NA
authors.lastname: Palma
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanford
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bailey
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Squillace
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Dow
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Buell
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Howley
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009367:Neoplasm Staging; D010412:Penile Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Genomic profiling; Human papillomavirus; Mutation; Penile cancer; Sequencing; Targeted therapy