29MO - Germline variants NGS characterization in patients with non-syndromic adrenocortical carcinoma

Background

Adrenocortical carcinoma (ACC) is a rare cancer that can arise sporadically or in the context of hereditary syndromes. Germline variants (GVs) of cancer-associated genes are traditionally associated with cancer risk but they also show potential as prognostic factors. Data on GVs in patients (pts) with sporadic ACC are limited.

Methods

Germline DNA was extracted from 150 adult European-non Finnish pts with sporadic ACC. For NGS analysis we used a custom panel of 17 genes involved in the pathogenesis of ACC: AIP, APC, ARMC5, ARNT, BRCA1, BRCA2, CTNNB1, IGF2, MEN1, MSH2, MSH6, PDE8B, PDE11A, PRKACA, PRKACB, PRKAR1A, and TP53. All variants were studied using effect predictor tools and classified according to the ACMG criteria. GVs interpreted as pathogenic (P) or likely pathogenic (LP) were considered positive. Clinico-pathological and genomic data were analyzed in different Cox models to study prognostic impact of covariates for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS).

Results

Overall, we identified 21 unique GVs in 24/150 (16%) pts. GVs were found in 9 genes including: APC (n=3), ARMC5 (n=3), MSH2 (n=3), PDE11A (n=3), TP53 (n=3), MSH6 (n=2), PDE8B (n=2), AIP (n=1) and CTNNB1 (n=1). Eight P/LP GVs and 3 GVs with deleterious potential were found in 14/150 (9.3%) of pts. Some variants were particularly enriched, with a frequency of 0.02% compared to an overall frequency of 0.001-0.004% in the gnomAD database. Of note, we found a new GV in TP53 (G105D) and 3 GVs in ARMC5 (P731R) for the first time in ACC pts. Clinico-pathological features did not differ significantly in pts carrying or not P/LP GVs but pts with ARMC5 GVs had large cortisol-secreting tumors. P/LP GVs were associated with a shorter OS (50 vs 142 months [mo], HR 1.81 95%CI.86-3.82, p.118) and PFS (8 vs 30 mo, HR 3.11 95%CI 1.57-6.16, p.001) but not DFS (27 vs 32 mo, HR 1.07 95%CI.52-2.22, p.845). At multivariate analysis GVs remained independent predictors of PFS and OS in metastatic pts.

Conclusions

We found a 9.3% prevalence of P/LP GVs which is comparable to the 9.9% from the TCGA. The findings of GVs in genes involved in DNA repair and that GVs can affect ACC progression and survival could open new therapeutic strategies in ACC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Massimo Terzolo, MD.

Funding

Associazione Italiana Ricerca sul Cancro (AIRC).

Disclosure

All authors have declared no conflicts of interest.