Karstensen Sven, Kaiser Karsten, Poulsen Tim Svenstrup, Jochumsen Kirsten, Høgdall Claus, Marcussen Niels, Lauzsus Finn Friis, Høgdall Estrid
Womens's Health, University Hospital of Southern Denmark, Aabenraa, Denmark;
Womens's Health, University Hospital of Southern Denmark, Aabenraa, Denmark.
Anticancer Res. 2025 Jan;45(1):1-10. doi: 10.21873/anticanres.17388.
BACKGROUND/AIM: Adult granulosa cell tumor (aGCT) is a rare and challenging ovarian tumor due to its unpredictable recurrence and its associated increased risk of breast and endometrial cancer. Identifying and describing molecular alterations in tumors has become common with the advent of high-throughput sequencing. However, DNA sequencing in rare tumors, such as aGCT, often lacks statistical power due to the limited number of cases in each study, thereby clinical implications of DNA alterations are difficult to interpretate. This scoping review aims to systematically describe somatic and germline DNA alterations identified in women with aGCT.
Search terms (granulosa cell tumour AND molecular alterations) were searched in May 2024 in the following databases: MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection and Google Scholar. Screening, full-text review and data extraction were performed by two independent reviewers.
Twenty-four publications were identified. Eighteen reported on somatic DNA alterations of patholgenic mutations identified in total 1,226 tissues being sequenced. FOXL2 (c.402C>G; p.C134W) was present in 97% of aGCTs. Other pathogenic mutations in the tissues investigated were TERT promoter mutation (41%), truncating KMT2D mutations (14%) and TP53 pathogenic variant (4%). TERT promoter mutation was reported more frequently in recurrent tumors (p<0.01), whereas comparing truncating KMT2D and TP53 mutations reported in primary and recurrent tumors revealed no difference (p=0.15 and p=0.26 respectively). Tumor mutational burden (TMB) was reported in five studies and all showed a low TMB. None of the somatic mutations were candidate targets for biological treatment. Six publications reported germline variants and no shared germline pathogenic variants were described in the published literature.
The FOXL2 missense mutation was the only common somatic DNA alteration in aGCT. TERT promoter mutations were reported more frequently in recurrent aGCT but their clinical relevance remains uncertain. In contrast to previous reports, truncating KMT2D mutations were not found to be associated with recurrent aGCT. Evidence on common germline variants in aGCT is sparse. The role of somatic and germline DNA alterations in the development of other malignancies in women with aGCT remains uncertain. Further research involving matched primary and recurrent tumors, as well as other primary malignancies, is essential to better understand the mutations that drive tumor development.
背景/目的：成人颗粒细胞瘤（aGCT）是一种罕见且具有挑战性的卵巢肿瘤，因其复发难以预测，且患乳腺癌和子宫内膜癌的风险增加。随着高通量测序技术的出现，识别和描述肿瘤中的分子改变已变得很常见。然而，在诸如aGCT等罕见肿瘤中进行DNA测序时，由于每项研究中的病例数量有限，往往缺乏统计学效力，因此DNA改变的临床意义难以解释。本综述旨在系统描述在aGCT女性患者中鉴定出的体细胞和种系DNA改变。
2024年5月，在以下数据库中检索了检索词（颗粒细胞瘤与分子改变）：MEDLINE（Ovid）、Embase（Ovid）、Web of Science核心合集和谷歌学术。由两名独立的评审人员进行筛选、全文评审和数据提取。
共鉴定出24篇文献。18篇报告了在总共1226个测序组织中鉴定出的致病突变的体细胞DNA改变。97%的aGCT中存在FOXL2（c.402C>G；p.C134W）。在所研究的组织中，其他致病突变包括TERT启动子突变（41%）、KMT2D截短突变（14%）和TP53致病变异（4%）。TERT启动子突变在复发性肿瘤中报告更为频繁（p<0.01），而比较原发性和复发性肿瘤中报告的KMT2D截短突变和TP53突变，未发现差异（分别为p=0.15和p=0.26）。五项研究报告了肿瘤突变负荷（TMB），均显示TMB较低。所有体细胞突变均不是生物治疗的候选靶点。六篇文献报告了种系变异，已发表的文献中未描述共同的种系致病变异。
FOXL2错义突变是aGCT中唯一常见的体细胞DNA改变。TERT启动子突变在复发性aGCT中报告更为频繁，但其临床相关性仍不确定。与先前的报告相反，未发现KMT2D截短突变与复发性aGCT相关。关于aGCT中常见种系变异的证据很少。体细胞和种系DNA改变在aGCT女性患者发生其他恶性肿瘤中的作用仍不确定。涉及配对的原发性和复发性肿瘤以及其他原发性恶性肿瘤的进一步研究对于更好地理解驱动肿瘤发展的突变至关重要。
