Geiersbach Katherine B, Jarboe Elke A, Jahromi Mona S, Baker Christine L, Paxton Christian N, Tripp Sheryl R, Schiffman Joshua D
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Cancer Genet. 2011 Nov;204(11):596-602. doi: 10.1016/j.cancergen.2011.10.002.
Adult granulosa cell tumors (AGCTs) are a rare class of ovarian tumors with recurrent cytogenetic abnormalities including trisomy 12, trisomy 14, monosomy 16/deletion 16q, and monosomy 22. Over 90% contain a missense point mutation (C134W) in the FOXL2 gene at 3q22.3. The relationship between FOXL2 mutation and cytogenetic abnormalities is unclear, although both are presumably early events in tumorigenesis. In addition, FOXL2 C134W mutant allele imbalance has been noted in a minority of AGCTs, but the mechanism for allelic imbalance has not yet been described. We used a microarray platform designed for formalin-fixed, paraffin-embedded (FFPE) tissue specimens, the Affymetrix OncoScan FFPE Express 330K Molecular Inversion Probe (MIP) array, to explore the correlation between genomic imbalances detected by microarray and FOXL2 mutation status detected by pyrosequencing in a series of 21 archived AGCTs. Tumors were characterized by histopathologic features, stage, and alpha-inhibin expression by immunohistochemistry. All tumors were positive for inhibin, and 18/21 tumors contained a FOXL2 mutation. The most common genomic imbalances were a gain of 14q, a loss of 16q, and a loss of 22q. Three tumors showed evidence of FOXL2 mutant allele imbalance by pyrosequencing; microarray revealed a 32.5 Mb deletion encompassing FOXL2 in 1 case and a 70.9 Mb stretch of homozygosity encompassing FOXL2 in the other case. The third case, with a FOXL2 mutant allele imbalance, showed a diminished mutant allele population (32%) despite high estimated tumor content (>90%), suggesting tumor heterogeneity for the mutation. This study provides the first correlation of FOXL2 mutation status and genomic imbalances in AGCTs, and it further elucidates the mechanisms for mutant allele imbalance in cancer.
成人颗粒细胞瘤（AGCTs）是一类罕见的卵巢肿瘤，具有复发性细胞遗传学异常，包括12号染色体三体、14号染色体三体、16号染色体单体/16q缺失以及22号染色体单体。超过90%的肿瘤在3q22.3的FOXL2基因中存在错义点突变（C134W）。尽管FOXL2突变和细胞遗传学异常可能都是肿瘤发生的早期事件，但其二者之间的关系尚不清楚。此外，在少数AGCTs中已发现FOXL2 C134W突变等位基因失衡，但等位基因失衡的机制尚未见报道。我们使用了一种专为福尔马林固定、石蜡包埋（FFPE）组织标本设计的微阵列平台，即Affymetrix OncoScan FFPE Express 330K分子倒置探针（MIP）阵列，来探索在一系列21例存档AGCTs中通过微阵列检测到的基因组失衡与通过焦磷酸测序检测到的FOXL2突变状态之间的相关性。通过组织病理学特征、分期以及免疫组织化学检测α-抑制素表达对肿瘤进行了特征描述。所有肿瘤抑制素均呈阳性，21例肿瘤中有18例含有FOXL2突变。最常见的基因组失衡为14q增益、16q缺失和22q缺失。3例肿瘤通过焦磷酸测序显示存在FOXL2突变等位基因失衡；微阵列分析在1例中发现了一个包含FOXL2的32.5 Mb缺失，在另1例中发现了一个包含FOXL2的70.9 Mb纯合片段。第三例存在FOXL2突变等位基因失衡，尽管估计肿瘤含量较高（>90%），但其突变等位基因群体减少（32%），提示该突变存在肿瘤异质性。本研究首次揭示了AGCTs中FOXL2突变状态与基因组失衡之间的相关性，并进一步阐明了癌症中突变等位基因失衡的机制。
