title: Comprehensive genomic profiling of relapsed and metastatic adenoid cystic carcinomas by next-generation sequencing reveals potential new routes to targeted therapies.
abstract: We hypothesized that next-generation sequencing could reveal actionable genomic alterations (GAs) and potentially expand treatment options for patients with advanced adenoid cystic carcinoma (ACC). Genomic profiling using next-generation sequencing was performed on hybridization-captured, adapter ligation libraries derived from 28 relapsed and metastatic formalin-fixed paraffin-embedded ACC. The 3230 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer were fully sequenced using the Illumina HiSeq 2000. All classes of GAs were evaluated. Actionable GAs were defined as those impacting targeted anticancer therapies on the market or in registered clinical trials. A total of 44 GAs were identified in the 28 ACC tumors, with 12 of 28 (42.9%) of tumors harboring at least 1 potentially actionable GA. The most common nonactionable GAs were identified in KD6MA (5 cases; 18%), ARID1A (4 cases; 14%), RUNX1 (2 cases; 7%), and MYC (2 cases; 7%). Actionable GAs included NOTCH1 (3 cases; 11%), MDM2 (2 cases; 7%), PDGFRA (2 cases; 7%), and CDKN2A/B (p16) (2 cases; 7%). Other potentially actionable GAs identified in a single case included: mutations in AKT1, BAP1, EGFR, and PIK3CA, homozygous deletion of FBXW7, and amplifications of CDK4, FGFR1, IGF1R, KDR, KIT, and MCL1. The frequency of GA in ACC is lower than that seen in the more common solid tumors. Comprehensive genomic profiling of ACC can identify actionable GAs in a subset of patients that could influence therapy for these difficult-to-treat progressive neoplasms.
authors.affiliation: *Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY †Foundation Medicine Inc., Cambridge, MA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Janna V
authors.initials: JV
authors.lastname: Rand
authors.forename: Christine E
authors.initials: CE
authors.lastname: Sheehan
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Jennings
authors.forename: Rami N
authors.initials: RN
authors.lastname: Al-Rohil
authors.forename: Geoff A
authors.initials: GA
authors.lastname: Otto
authors.forename: John C
authors.initials: JC
authors.lastname: Curran
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.forename: Sean R
authors.initials: SR
authors.lastname: Downing
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Lazaro
authors.initials: L
authors.lastname: Garcia
authors.forename: Kristen
authors.initials: K
authors.lastname: Mahoney
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary*; D005091:Exons; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D016612:Paraffin Embedding; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D016707:Tissue Fixation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005404:Fixatives; D005557:Formaldehyde