Background

: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. ACC carries a dismal prognosis and surgery offers the only chance for a cure. Germline pathogenic variants among certain oncogenes have been implicated in ACC. Here, we report the first case of ACC in a patient with a pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene.

Patients and Methods

: A 56-year-old Caucasian woman with biopsy proven ACC deemed unresectable and treated with etoposide, doxorubicin and cisplatin (EDP), and mitotane presented to our institution for evaluation. The tumor specimen was examined pathologically, and genetic analyses were performed on the tumor and germline using next-generation sequencing.

Results

: Pathologic evaluation revealed an 18.0 × 14.0 × 9.0 cm low-grade ACC with tumor free resection margins. Immunohistochemistry stained for inhibin, melan-A, and chromogranin. ClinOmics analysis revealed a germline pathogenic deletion mutation of one nucleotide in ATM is denoted as c.1215delT at the cDNA level and p.Asn405LysfsX15 (N405KfsX15) at the protein level. Genomic analysis of the tumor showed loss of heterozygosity (LOH) of chromosome 11 on which the ATM resides.

Conclusion

: ACC is an aggressive malignancy for which surgical resection currently offers the only curative option. Here we report a heterozygous loss-of-function mutation in germline DNA and LOH of ATM in tumor in an ACC patient, a classic two-hit scenario in a well-known cancer suppresser gene, suggesting a pathogenic role of the ATM gene in certain ACC cases.

中文翻译：

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共济失调毛细血管扩张突变种系致病变异肾上腺皮质癌

背景

：肾上腺皮质癌 (ACC) 是一种罕见的恶性肿瘤，起源于肾上腺皮质。ACC 预后不佳，手术是治愈的唯一机会。某些致癌基因中的种系致病变异与 ACC 有关联。在这里，我们报告了第一例患有共济失调毛细血管扩张症 ( ATM ) 基因致病性变异的患者的 ACC 病例。

患者和方法

：一名 56 岁的白人女性，活检证实 ACC 不可切除，并接受依托泊苷、多柔比星和顺铂 (EDP) 以及米托坦治疗，我们的机构接受了评估。对肿瘤标本进行病理检查，并使用二代测序对肿瘤和种系进行遗传分析。

结果

：病理评估显示 18.0 × 14.0 × 9.0 cm 低级别 ACC，具有无肿瘤切除边缘。对抑制素、黑色素 A 和嗜铬粒蛋白进行免疫组织化学染色。ClinOmics 分析显示ATM中一个核苷酸的种系致病性缺失突变在 cDNA 水平上表示为 c.1215delT，在蛋白质水平上表示为 p.Asn405LysfsX15 (N405KfsX15)。肿瘤的基因组分析显示ATM所在的11 号染色体的杂合性 (LOH) 丢失。

结论

：ACC 是一种侵袭性恶性肿瘤，目前手术切除是唯一的治疗选择。在这里，我们报告了ACC 患者肿瘤中ATM 的种系 DNA 和 LOH 的杂合功能丧失突变，这是众所周知的癌症抑制基因中的经典两次打击场景，表明ATM基因在某些疾病中的致病作用ACC 案例。