Endocrine Abstracts

Limited survival of patients with adrenocortical carcinoma (ACC) makes it imperative to understand the genetic basis of disease and support development of new therapies.

Between 2010–2015, tissues from nine adrenalectomy patients (5M:4F, age 30–68 years) were snap frozen in liquid nitrogen and DNA extracted. Adjacent normal adrenal tissue (n=3) excised at adrenalectomy was collected as matched ‘normal’ controls. Whole-exome sequencing of these 12 adrenal samples using Illumina Nextera library kits on HiSeq4000 next generation sequencing compared four groups: 3 ‘normal’ adrenals; 2 benign adrenocortical adenomas (bACAs); 5 ACCs; and 2 metastatic ACCs (mACCs). The ’normal’ adrenals were pairs to one ACC and both bACAs.

The average depth of sample coverage was 35x–50x, and >2000 potentially deleterious genetic mutations were identified, after excluding those also found in paired ‘normal’ samples. The mean number of mutations found in: paired bACAs was 23.5; the paired ACC was 51; unpaired ACCs was 453.5; and in mACC was 532.5. A known Multiple Endocrine Neoplasia type 1 (MEN1) mutation was confirmed in an MEN1 patient’s bACA. One ACC contained both MEN1 and beta-catenin (CTNNB1) mutations. No Beckwick-Wiedemann syndrome gene variants were found in this study, however, one ACC and one mACC harboured Li-Fraumeni syndrome mutations (TP53).

Numbers of mutually exclusive mutations found in each separate tumour group were: 24 in bACA, 1244 in ACCs and 712 in mACCs. Few mutations (0.1%) were common to both adenomas and carcinomas. However, 7.1% of mutations were found in both ACC and mACC groups. Finally, two oncogenes, MAGEC1 and PLIN4, were mutated in all three adrenal tumour groups and the most frequently mutated cancer-related genes were TYRO3 and KRT18, whose protein products are normally expressed in adrenal glands.

Thus, MAGEC1, PLIN4, TYRO3, and KRT18 are novel candidate adrenal oncogenes, and our findings supports a proposed adenoma-carcinoma sequence for adrenocortical carcinogenesis.

AcknowledgmentThis work was funded by a research grant from the British Association of Endocrine and Thyroid Surgeons (BAETS).