SUN-485 - Genetic Predisposition Syndromes in Adrenocortical Carcinoma

A subset of adrenocortical carcinomas (ACC) arises in patients with hereditary cancer predisposition syndromes. Identification of underlying genetic variants has implications for clinical management and cancer risk among affected families. We conducted a retrospective, single-institution review to characterize germline pathogenic or likely pathogenic variants (P/LPV) in patients with ACC between 2000 and 2025.
Fifty-three patients (23M, 30F) with ACC carried at least one germline P/LPV. P/LPV were identified in Lynch syndrome–associated genes (MLH1, MSH2, and MSH6; 41.5%; 12M, 10F; mean age at diagnosis (AD) 43 years), TP53 (18.9%; 7M, 3F; mean AD 25 years), FLCN (13.2%; 2M, 5F; mean AD 44 years), and other genes (28.3%; 2M, 13F; mean AD 48 years) including APC (5.7%; 2M, 1F, mean AD 23 years) and MEN1 (3.8%, 2F, mean AD 52 years), as well as BRCA2, CHEK2, NF1, MUTYH, NBN, FH, RECQL4, and CYP21A2. The overall prevalence of pathogenic variants in ACC patients was 5.9%.
Data on ENSAT tumor stage was available for 49 patients, with an overall distribution of stage I (14.3%), stage II (34.7%), stage III (36.7%), and stage IV (16.3%). Among patients with FLCN variants, no stage I tumors were observed, with most patients presenting with stage II or IV disease (stage II 50%, stage III 16.7%, stage IV 33.3%). Ki-67 data were available for 28 patients, with an overall mean of 28.2. Mean Ki-67 index was higher in LS–associated (32.6) and TP53-associated variants (36.7) compared with FLCN (16.6), and other variants (21).
Among patients with LS-associated variants, 45.5% had a personal history of additional malignancies, including colorectal (2, 9.1%), endometrial (2, 9.1%), urothelial (2, 9.1%), and skin (4, 18.2%). Family history was available in 52 patients. For those with LS, family history was most notable for colorectal (13, 59.1%), uterine (5, 22.7%), prostate (5, 22.7%), and pancreatic cancers (2, 9.1%), along with lung (8, 36.4%), breast (6, 27.3%), and other cancers (12, 54.5%). Among patients with TP53 variants, family histories were most notable for breast (4, 40%) and lung cancers (3, 30%), while other cancers (8, 80%) were the majority. Of the patients with FLCN variants, only one patient had a family history of a renal cancer. Other tumors observed in FLCN families were lung (3, 42.9%), colorectal (3, 42.9%), prostate (2, 28.6%), and other cancers (3, 42.9%).
In summary, a minimum of 5.9% of ACC patients carry a germline P/LPV with distinct clinical, pathologic, and familial characteristics. Identification of hereditary cancer syndromes can provide opportunities for risk assessment, tailored surveillance for other associated tumors, identification of at-risk family members, and can impact therapy. Routine germline genetic testing and detailed family history assessment should be recommended in all patients with ACC.

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