视网膜母细胞瘤易感基因(RB1)的遗传改变存在于高达40%的三阴性乳腺癌(BC)中,并且在具有神经内分泌分化的肿瘤中很常见。包括小细胞神经内分泌癌.关于雌激素受体(ER)阳性BCs中RB1遗传改变的数据很少。在这项研究中,我们试图定义形态学,ER阳性BCs的免疫组织化学和遗传特征在RB1中具有体细胞改变,重点是神经内分泌分化。在之前接受靶向下一代测序的6,026个BCs队列中,在不到1%的病例中发现了具有致病性RB1遗传改变的ER阳性BCs。包括23个原发性BC(pBC)和32个复发/转移性BC(mBC)。在可以评估野生型RB1等位基因的杂合性丢失(LOH)的情况下(93%,51/55),大多数pBC(82%,18/22)和mBC(90%,26/29)显示双等位基因RB1失活,主要通过功能缺失突变和LOH(98%,43/44)。经过组织学检查,一部分RB1改变的肿瘤表现出神经内分泌形态(13%,7/55),与神经内分泌标志物的表达相关(39%,9/23)在两个pBC中(27%,3/11)和mBC(50%,6/12)。在仅具有双等位基因RB1损失的BCs中观察到Rb蛋白表达的损失,在pBC中频率相似(82%,9/11)和mBC(75%,9/12)。所有具有神经内分泌标志物表达(n=9)和/或神经内分泌形态学(n=7)的病例均具有RB1的双等位基因遗传失活,并表现出Rb表达丧失。TP53(53%,29/55)和PIK3CA(45%,25/55)是整个队列中最常见的共突变基因。总的来说,这些发现表明,具有双等位基因RB1遗传改变的ER阳性BCs经常表现出Rb蛋白丢失,这与部分BCs的神经内分泌分化相关。这项研究提供了对具有RB1基因失活的BCs的分子和表型异质性的见解,强调需要进一步研究与这些肿瘤相关的潜在临床意义.
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.