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.

High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis

“…However, two tumors contained a third alteration (E794 à and N390fs à 243) toward the 5 0 end of NOTCH1, likely disrupting one allele and suggestive that the other two alterations are in cis. Collectively, other genomic studies have investigated 111 total ACC tumors, including 28 samples also represented within this dataset, and reported NOTCH1 missense and nonsense alterations in 5-10% of samples (19)(20)(21). This analysis confirms findings from smaller studies that NOTCH1 is the most commonly altered gene in ACCs at approximately 24% and extends it by providing multiple examples of cooccurring PEST and HD domain alterations.…”

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

“…(4–7) A t(6;9)(q22–23;p23–24) chromosomal translocation resulting in fusion of the MYB and NFIB genes has been described in 29–86% of cases. (4, 5, 8–11) Whether the MYB oncogene or the transcription factor encoded by NFIB is responsible for the selective advantage afforded by these translocations is unknown.…”

“…Frequent alteration of genes involved in chromatin regulation, Notch signaling and several other pathways have also been reported. (5–7) Whole-genome sequencing, which is capable of revealing chromosomal rearrangements not detectable by traditional cytogenetic techniques, has been applied to a limited number of tumors. (5, 12)…”

Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma

“…We also noted that 3 of 4 PEST domain mutations fell in codon 2466 or 2467, a site that is mutated at low frequency in other tumors, such as T-ALL (27). Of note, of 9 NOTCH1 exon 34 mutations reported in ACC by other groups, 5 affected codon 2467 (9, 10), suggesting that this is a mutational hotspot in ACC. Enrichment for specific PEST domain mutations is not a prominent feature in T-ALL, but is characteristic of chronic lymphocytic leukemia, in which approximately 90% of mutations are a del(CT) involving codon 2514 (30, 31); the same del(CT) mutation also appears to be mutational hotspot in mantle cell lymphoma (32).…”