Whole exome sequencing of adenoid cystic carcinoma

Abstract

Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.

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.…”

Mutation signature of adenoid cystic carcinoma: evidence for transcriptional and epigenetic reprogramming

“…The identification of the signature MYB-NFIB fusion (3) together with the comprehensive mutation profiling by Stephens et al (1) are key events in the unraveling of the molecular landscape of ACC. As MYB-NFIB fusion is the obvious driver for this cancer type, the transcriptional reprogramming that it causes will be a key focus of future…”

Cancer stem cells and differentiation therapy

“…63,64 Gain-of-function mutations in Notch2 were reported in diffused large B-cell lymphomas. 65,66 Moreover, accelerated Notch4 receptor activity and loss or downregulation of Notch signaling regulator Numb have been reported in CSCs in breast cancer. 67,68 JAK/STAT signaling also plays an important role in both adult tissue homeostasis and tumorigenesis.…”