雌激素受体阳性乳腺癌中的 RB1 基因改变:与神经内分泌分化的相关性。

IF 7.1 1区 医学 Q1 PATHOLOGY
Christopher J. Schwartz , Antonio Marra , Pier Selenica , Andrea Gazzo , Kiki Tan , Dara Ross , Pedram Razavi , Sarat Chandarlapaty , Britta Weigelt , Jorge S. Reis-Filho , Edi Brogi , Fresia Pareja , Hannah Y. Wen
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引用次数: 0

摘要

视网膜母细胞瘤易感基因(RB1)的基因改变存在于多达40%的三阴性乳腺癌(BCs)中,并经常发生在神经内分泌分化的肿瘤中,包括小细胞神经内分泌癌。有关雌激素受体(ER)阳性乳腺癌中RB1基因改变的数据很少。在这项研究中,我们试图确定雌激素受体(ER)阳性 BCs 中 RB1 基因体细胞改变的形态、免疫组化和遗传特征,重点是神经内分泌分化。在一组先前接受过定向下一代测序的6026例BC中,有不到1%的ER阳性BC存在致病性RB1基因改变,其中包括23例原发性BC(pBC)和32例复发性/转移性BC(mBC)。在可以评估野生型RB1等位基因杂合性缺失(LOH)的病例中(93%,51/55),大多数pBC(82%,18/22)和mBC(90%,26/29)表现出双等位基因RB1失活,主要是通过功能缺失突变和LOH(98%,43/44)。经组织学检查,RB1改变的肿瘤中有一部分呈现神经内分泌形态(13%,7/55),这与pBC(27%,3/11)和mBC(50%,6/12)中神经内分泌标记物的表达(39%,9/23)相关。仅在双侧 RB1 缺失的 BC 中观察到 Rb 蛋白表达缺失,在 pBC(82%,9/11)和 mBC(75%,9/12)中的频率相似。所有有神经内分泌标志物表达(9 例)和/或神经内分泌形态(7 例)的病例均存在 RB1 双倍性遗传失活,并表现出 Rb 表达缺失。TP53(53%,29/55)和PIK3CA(45%,25/55)是整个群体中最常见的共突变基因。总之,这些研究结果表明,具有双侧RB1基因改变的ER阳性BC经常表现出Rb蛋白缺失,这与部分BC的神经内分泌分化有关。这项研究深入揭示了RB1基因失活的碱性细胞癌的分子和表型异质性,强调了进一步研究与这些肿瘤相关的潜在临床影响的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
RB1 Genetic Alterations in Estrogen Receptor–Positive Breast Carcinomas: Correlation With Neuroendocrine Differentiation

Genetic alterations in the retinoblastoma susceptibility gene (RB1) are present in up to 40% of triple-negative breast cancers (BCs) and frequent in tumors with neuroendocrine differentiation, including small cell neuroendocrine carcinoma. Data on RB1 genetic alterations in estrogen receptor (ER)–positive BCs are scarce. In this study, we sought to define the morphologic, immunohistochemical, and genetic features of ER-positive BCs harboring somatic alterations in RB1, with emphasis on neuroendocrine differentiation. ER-positive BCs with pathogenic RB1 genetic alterations were identified in <1% of cases (N = 55) from a cohort of 6026 BCs previously subjected to targeted next-generation sequencing, including 23 primary BCs (pBCs) and 32 recurrent/metastatic BCs (mBCs). In cases where loss of heterozygosity of the wild-type RB1 allele could be assessed (93%, 51/55), most pBCs (82%, 18/22) and mBCs (90%, 26/29) exhibited biallelic RB1 inactivation, primarily through loss-of-function mutation and loss of heterozygosity (98%, 43/44). Upon histologic review, a subset of RB1-altered tumors exhibited neuroendocrine morphology (13%, 7/55), which correlated with expression of neuroendocrine markers (39%, 9/23) in both pBCs (27%, 3/11) and mBCs (50%, 6/12). Loss of Rb protein expression was observed in BCs with biallelic RB1 loss only, with similar frequency in pBCs (82%, 9/11) and mBCs (75%, 9/12). All cases with neuroendocrine marker expression (n = 9) and/or neuroendocrine morphology (n = 7) harbored biallelic genetic inactivation of RB1 and exhibited Rb loss of expression. TP53 (53%, 29/55) and PIK3CA (45%, 25/55) were the most frequently comutated genes across the cohort. Overall, these findings suggest that ER-positive BCs with biallelic RB1 genetic alterations frequently exhibit Rb protein loss, which correlates with neuroendocrine differentiation in select BCs. This study provides insights into the molecular and phenotypic heterogeneity of BCs with RB1 genetic inactivation, underscoring the need for further research into the potential clinical implications associated with these tumors.

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来源期刊
Modern Pathology
Modern Pathology 医学-病理学
CiteScore
14.30
自引率
2.70%
发文量
174
审稿时长
18 days
期刊介绍: Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology. Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.
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