Genetic heterogeneity and therapeutic target detection through microdissection in solid-type adenoid cystic carcinoma

Abstract

Solid-type adenoid cystic carcinomas (ACCs) are highly aggressive and heterogeneous tumours. Because of their rarity, therapeutic strategies guided by genetic profiles based on next generation sequencing (NGS) have not been published for these tumours. Forty-nine solid-type ACCs including 43 tumours with a predominantly solid pattern, and six tumours comprising a roughly equal mixture of cribriform/tubular and solid histological forms were included in our study. The solid components from the 49 solid ACCs were enriched for mutations of genes in the NOTCH pathway (NOTCH1 61%, SPEN 24%) and chromatin remodelling pathway and the absence of myoepithelial cell differentiation. Cases with NOTCH1 mutations exhibited strong NICD expression, which was associated with poor overall and distant metastasis free survival. BRCA2 mutation and BCOR/BCORL1 mutations were observed in 20% and 18.4% of solid ACCs, respectively. In six of the solid ACCs, intratumour heterogeneity was delineated between the cribriform/tubular and solid components. NOTCH1 and FGFR2 mutations as well as NOTCH2 amplification were restricted to the solid component, indicating clonal selection within the same tumour. In two recurrent/metastatic solid ACCs, the subclones evolved in progression for local relapse and distant metastasis, although they manifested close genomic resemblance to primary tumours. Guided by the genetic profiles, the preclinical efficiency of the gamma-secretase inhibitor BMS-906024 was evaluated in patient derived xenograft models (PDXs) with activating NOTCH1 mutations and demonstrated robust antitumour effects. Our report revealed intratumour heterogeneity among solid-types within an ACC as well as the inter-tumour evolution of dominant clones among two primary and recurrent/metastatic tumours. In contrast to cribriform/tubular ACCs, solid-type ACCs should be approached with a distinct therapeutic strategy, particularly targeting NOTCH1. Microdissecting the highest grade component guided by histology is a highly recommended tumour sampling strategy and facilitates the detection of key molecular targets.

Keywords: Adenoid cystic carcinoma; heterogeneity; microdissection; solid-type; therapeutic target detection.