1. Germline EGFR variants over-represented in adolescent and young adult (AYA) females with adrenocortical carcinoma

      Adrenocortical Carcinoma (ACT) is a rare endocrine tumor with poor overall prognosis and slight overrepresentation in females. In children, ACT is associated with inherited cancer syndromes with 50-80% of childhood ACT associated with TP53 germline mutations. ACT in adolescent and young adult (AYA) are rarely due to germline TP53, IGF2, PRKAR1A and, MEN1 variants. We analyzed exome sequencing data from 21 children (C, 39y) with ACT, and retained all pathogenic, likely pathogenic, and highly prioritized Variants of Uncertain Significance. We found that 4.8% of children and 6.2% of AYA, all-female patients, harbored a germline EGFR variant, compared to only 1.7% of adult patients with ACT. Expanding our analysis to the RTK-RAS-MAPK pathway genes, we found that the RTK genes have the highest number of highly prioritized variants in these patients amongst all three pathways. We engineered a lentiviral-mutant stable ACT-cell line, harboring an EGFR variant from a 21 y/o female with aggressive bilateral ACT (p.Asp1080Asn), without germline TP53 mutation. We showed that mutant cells migrate faster and are characterized by a stem-like phenotype compared to wildtype cells. While EGFR inhibitors had no effect on the stemness of mutant cells, Sunitinib, a multi-receptor tyrosine kinase inhibitor, significantly reduced the stem-like behavior. Our data suggest that EGFR is a novel underlying germline predisposition factor for ACT, especially in the female C-AYA population. Further clinical validation can improve precision oncology management of this disease, which is known to have limited therapeutic options.
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