- Modern Pathology（Sfanos、Lotan、De Marzo 等，Johns Hopkins）：412 例根治性前列腺切除全组织切片做 p27 免疫组化，发现在 p27 着色总体保留的大结节内，常有局灶「肿瘤内 p27 蛋白完全缺失」区域（IPPL）。
- 发生率：非裔美国人（AA）18.1%，欧裔美国人（EA）12.2%；IPPL 区与原位杂交 CDKN1B mRNA 缺失、激光捕获 NGS 证实的 CDKN1B 基因组缺失高度对应——提示这种亚克隆性双等位缺失过去被整块测序低估。
- 预后：IPPL 与 ≥pT3（前列腺外侵犯/精囊受累）、pN1 相关，并在单、多因素分析中与生化复发和转移相关；按种族分层后这些关联仅在 AA 患者中显著。转移灶（公共数据集与尸检 IHC）的 p27 改变比例高于原发灶。
- 实践提示：p27 IHC 读片时应留意结节内局灶完全阴性区，作者认为值得进一步验证其作为预后生物标志物的价值。本站收录摘要；PMC 作者稿仅限合理使用，未转载正文与图。
收录范围：PubMed 摘要中英对照。PMC 版本（PMC13560498）为 NIH 作者稿，仅允许文本挖掘与合理使用，非开放许可，故未转载正文与图表，请经下方链接阅读全文。
摘要
一般认为，CDKN1B 纯合性双等位基因失活在癌症（包括前列腺癌）中少见。本研究报告：原发性前列腺癌中 CDKN1B 亚克隆性基因组缺失的发生率很可能被低估，在自报为非裔美国人或黑人（AA）的个体中尤其如此。我们对一个大型根治性前列腺切除全组织切片队列（N = 412，包括 AA 与欧裔美国人 [EA]）进行 p27 蛋白免疫组化（IHC），意外发现：在其余部分 p27 着色保留的较大肿瘤结节内，肿瘤内 p27 蛋白完全缺失区域（IPPL）出现频率很高，且在 AA 个体前列腺癌中（18.1%）比 EA 个体（12.2%）更常见。IPPL 区域与原位杂交显示的 CDKN1B 信使 RNA 缺失紧密相关；此外，对激光捕获区域进行二代测序 panel 检测，显示这些局灶 IPPL 区域与 CDKN1B 基因组缺失密切相关。IHC 检出 IPPL 与 ≥pT3 病理分期（前列腺外侵犯和精囊受累）及 pN1（区域淋巴结受累）相关；但按种族分层后，这些相关性仅在 AA 受试者中具有统计学意义。在单因素和多因素分析中，IPPL 还与初始治疗后发生生化复发及转移相关，这一关联特见于 AA 个体。在公开数据集以及我们通过 IHC 分析的尸检标本中，转移性疾病的 p27 基因组改变发生率均高于原发性前列腺癌。总之，导致 p27 蛋白完全缺失的 CDKN1B 亚克隆性双等位基因缺失，是原发性前列腺癌中最常见的双等位抑癌基因组改变之一，并可能导致前列腺癌预后更差，尤其是在 AA 个体中。我们的发现提示，应进一步探索以 IHC 检测 p27 缺失作为预后生物标志物的临床价值。
- Modern Pathology (Sfanos, Lotan, De Marzo and colleagues, Johns Hopkins): p27 IHC on whole radical prostatectomy sections from 412 patients revealed focal regions of intratumoral complete p27 protein loss (IPPL) within larger nodules otherwise retaining p27.
- Frequency: 18.1% in African-American (AA) vs 12.2% in European American (EA) patients; IPPL tracked with CDKN1B mRNA loss by ISH and CDKN1B genomic loss by NGS of laser-captured regions — subclonal biallelic loss that bulk sequencing likely underestimates.
- Outcome: IPPL associated with ≥pT3 and pN1 disease, and with biochemical recurrence and metastasis in univariate and multivariate analyses, but only significantly in AA patients. Metastases (public data sets and autopsy IHC) show more p27 alterations than primaries.
- Practice point: look for focal completely negative areas within nodules on p27 IHC; the authors call for validation as a prognostic biomarker. Abstract only here; the PMC author manuscript is fair-use only, so text and figures are not reproduced.
Scope: the PubMed abstract. The PMC version (PMC13560498) is an NIH author manuscript available for text mining and fair use only, without an open licence, so the full text and figures are not reproduced; follow the links below to read it.
Abstract
Homozygous biallelic inactivation of CDKN1B is thought to be rare in cancer, including prostate cancer. In the present study, we report that the prevalence of subclonal genomic loss of CDKN1B, especially among self-reported African-American or Black (AA) individuals, has likely been underestimated in primary prostate cancer. Using immunohistochemistry (IHC) for p27 protein and a large cohort of whole tissue sections from radical prostatectomy (N = 412) from AA and European American (EA) individuals, we discovered an unexpectedly high frequency of regions of intratumoral complete p27 protein loss (IPPL) within larger tumor nodules that otherwise showed intact p27 staining that was more prevalent among prostate cancer in AA individuals (18.1%) than EA individuals (12.2%). Regions of IPPL were tightly associated with loss of CDKN1B messenger RNA by in situ hybridization. Furthermore, these focal regions of IPPL were closely linked to CDKN1B genomic loss as detected by next-generation sequencing panel sequencing of laser-captured regions. The detection of IPPL by IHC was associated with ≥pT3 pathologic stage (extraprostatic extension and seminal vesicle involvement) and pN1 (local lymph node involvement) disease; however, when stratified by race, these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available data sets as well as in our analysis of autopsy specimens via IHC. Overall, subclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer and could contribute to worse prostate cancer outcomes, specifically in AA individuals. Our findings warrant further exploration into the clinical utility of using IHC for p27 loss as a prognostic biomarker.