Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma

Abstract

PurposeTo identify genomic mutations in lacrimal gland adenoid cystic carcinoma (LGACC) samples from patients.MethodsGenomic DNA was extracted from LGACC specimens. Whole exome sequencing (exome-seq) was conducted to screen for mutations. Capillary sequencing was performed to verify mutations in genes shared by multiple samples. Luciferase assays were used to evaluate functional consequences of NOTCH1 mutations.ResultsThe mutation profile of LGACC was complicated. The most frequently mutated gene observed (28.6%) was bromodomain PHD finger transcription factor (BPTF). No mutation was identified in common cancer genes such as TP53, KRAS, and BRAF. However, mutations predicted to be functionally severe were accumulated in the Notch signaling pathway including NOTCH1 and NOTCH2, of which mutations have been reported in head/neck adenoid cystic carcinoma (ACC). Of 14 LGACC samples, five samples carry mutations in Notch pathway genes. Capillary sequencing verified all the mutations in the two NOTCH genes identified by exome-seq. Compared to the wild-type NOTCH1, three frame shifting mutations and two missense mutations (C387W and L1600Q) increased luciferase activity approximately 10- to 25-fold.ConclusionsMajor genomic mutation profiles in LGACC were uncovered by exome-seq. Although preliminary in nature, the Notch pathway could be a potential therapeutic target for LGACC.

Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

“…Molecular genotyping in ACC is primarily performed in research settings, and numerous studies have outlined relevant mutational profiles [17,[57][58][59]. In addition, various biological [12,17,60], diagnostic [60][61][62][63][64], prognostic [16,54,64], and therapeutic advances [14,15,59] have been proposed. It is important to note that our study did not focus on identification or description of novel biomarkers.…”

“…Numerous studies have delineated key molecular profiles of ACC [8][9][10][11][12][13] and collectively indicate pathways for genotype-stratified therapies [14][15][16][17][18]. The concept, to match each patient according to the tumor pathway profile to the most effective (biologically sound) and least toxic treatment, rests on the prevalence of actionable alterations [14,[19][20][21].…”

Molecular features of adenoid cystic carcinoma with an emphasis on microRNA expression

“…Using immunohistochemistry, FISH, and miRNA arrays, we investigated the molecular features of ACC arising in the salivary gland, lacrimal gland, and breast. Separate studies have shown the genetics of ACC arising in these three sites to be highly similar, but to the best of our knowledge, a head‐to‐head comparison has not previously been performed .…”

“…Adenoid cystic carcinoma is not a disease that is exclusive to the salivary gland, but is also found in the lacrimal gland and breast, as well as more rare locations including sweat gland, lung, and Bartholin's gland . Regardless of the site, ACC is characterized by recurrent fusion oncogenes and relatively few but diverse mutations . Lacrimal gland ACC shares the clinical characteristics of salivary gland ACC, with pronounced infiltrative growth and frequent recurrences in local as well as distant sites .…”

Successful Treatment of Erlotinib on Metastatic Adenoid Cystic Carcinoma of the Lacrimal Gland

“…By conducted whole exome sequencing in patients with LGACC, Sant et al . [ 3 ] found that functional plausible mutations were located within the NOTCH1 gene including deletions and insertions that could result in frameshifting and potential functional activation. The mutations in NOTCH genes were located in heterodimerization domain, notch intracellular domain, and epidermal growth factor (EGF)-like repeats;[ 4 ] this finding suggested the possibility of targeted therapy aimed at the EGFR pathway.…”