Dataset Information

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.

ABSTRACT: Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95% CI, 41%-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (P = 0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared with those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.

SUBMITTER: Rettig EM

PROVIDER: S-EPMC4818686 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.

Rettig Eleni M EM Talbot C Conover CC Sausen Mark M Jones Sian S Bishop Justin A JA Wood Laura D LD Tokheim Collin C Niknafs Noushin N Karchin Rachel R Fertig Elana J EJ Wheelan Sarah J SJ Marchionni Luigi L Considine Michael M Ling Shizhang S Fakhry Carole C Papadopoulos Nickolas N Kinzler Kenneth W KW Vogelstein Bert B Ha Patrick K PK Agrawal Nishant N

Cancer prevention research (Philadelphia, Pa.) 20160209 4

Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor ...[more]

PMID: 26862087

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Project description:Adenoid cystic carcinoma (ACC) is a slow growing, but relentless cancer. Due to its rarity and lack of understanding of its molecular etiology, no standard chemotherapy for ACC currently exists and many patients suffer from recurrent and/or metastatic disease. As such, development of safe and effective therapies is imperative. To describe and summarize existing clinical trial studies and preclinical discoveries, we surveyed the PubMed on developmental therapeutics for ACC. Objective response rates to monotherapy with cytotoxic agents were approximately 10% with cisplatin, 5-FU, gemcitabine, mitoxantrone, epirubicin, vinorelbine and paclitaxel. The most studied combination therapies were cyclophosphamide-doxorubicin-cisplatin (CAP) and cisplatin-vinorelbine, with an objective response rate of 18-31%. Among molecularly targeted drugs, the most studied drugs are inhibitors targeting the vascular endothelial growth factor receptor (VEGFR) to inhibit tumor angiogenesis. Among those, lenvatinib and axitinib showed a relatively high objective response rate of 11-16% and 9-17%, respectively. Given high recurrence rates and chemoresistance of ACC, treatments targeting cancer stem cells (CSC), which function as tumor-initiating cells and drive chemoresistance, may be particularly valuable. CSC have been shown to be targetable via MYB, Notch1, p53 and epigenetic mechanisms. Myb overexpression is characteristic in ACC but was previously thought to present a difficult target due to its nature as a transcription factor. However, due to the development Myb-targeted inhibitors and an ongoing clinical trial of MYB-targeted cancer vaccine therapy, MYB is becoming an increasingly attractive therapeutic target. Drugs targeting NOTCH signaling demonstrated 5-17% response rate in phase I clinical trials. Within the field of epigenetics, treatment with PRMT5 inhibitors has shown 21% partial response rate in phase I clinical trial. Immunotherapies, such as PD-1 inhibitors, are also associated with CSC, but have not been effective against ACC. However, clinical trials of cancer vaccine therapies are actively being conducted. In addition to conventional chemotherapies and inhibitors of angiogenesis, the emergence of new therapies such as immunotherapy and those targeting cancer stemness is expected to bring clinical benefits to patients in the future.

Dataset Information

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.

Publications

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.

Similar Datasets

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