N. G. Nicolson1, J. M. Healy1,2, R. Korah1, T. Carling1 1Yale University School Of Medicine,Yale Endocrine Neoplasia Laboratory, Department Of Surgery,New Haven, CT, USA 2Connecticut Children’s Medical Center,Hartford, CONNECTICUT, USA
Introduction: Next-generation sequencing has provided detailed genetic profiles of sporadic adrenocortical carcinoma (ACC). However, the genetic landscapes of ACC developing in patients with tumor predisposition syndromes are not well-characterized, as they are excluded from large-scale studies. Understanding the somatic genomic events complementing the background of germline syndromes is critical for designing personalized therapeutics for these unique patients, and may shed light on the molecular underpinnings of both sporadic and syndromic ACC.
Methods: ACC tissue and matched normal adrenal from a pediatric patient with clinically characterized Beckwith-Wiedemann syndrome were subjected to whole-exome sequencing (WES). Using multi-layered bioinformatics analysis, the WES data was compared to 21 sporadic ACCs which had also undergone WES. Single nucleotide variants (SNVs) of interest were subjected to damage prediction protocols to identify potential ACC drivers, and somatic copy number variations (CNVs) were also investigated.
Results: WES analysis revealed 8 relevant germline mutations in the index case, including a TP53 mutation previously associated with Li-Fraumeni syndrome. 25 potentially damaging somatic SNVs including multiple unique novel gene variants were identified. A damaging somatic mutation was identified in tumor suppressor CACNA2D3, a calcium channel gene in the same family as those previously reported to be mutated in some adrenocortical tumors. Although the mutation burden in the index case was similar to the sporadic ACC cohort, the total absence of CNVs was distinct from sporadic cases, all of which carried CNVs.
Conclusion: This study characterizes for the first time the genomic landscape of syndromic adrenocortical carcinoma of a patient with markers of both Beckwith-Wiedemann and Li-Fraumeni syndromes. The unique SNV and CNV profiles demonstrate that syndromic adrenocortical tumors may represent a genetically distinct entity from sporadic tumors.