Integrated Genomic Profiling of PTEN and TP53 in Cervical Neuroendocrine Carcinoma: Synergistic Roles With HER2/KRAS/PIK3CA and Implications for Precision Oncology

IF 2.3 2区医学 Q2 GENETICS & HEREDITY

Genes, Chromosomes & Cancer Pub Date : 2026-09-21 DOI:10.1002/gcc.70173

Huang-Pin Shen, Ming-Yung Lee, Yi-Ju Lee, An-Chi Chen, Chi-Kuan Chen, Wan-Ru Chao, Chih-Ping Han

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引用次数: 0

Abstract

Background

Neuroendocrine carcinoma (NEC) of the uterine cervix is a rare, highly aggressive malignancy with a poor prognosis. Expanding upon our previous work, which identified frequent mutations in HER2, KRAS, and PIK3CA in this disease, we sought to refine the genomic landscape by characterizing alterations in TP53 and PTEN, and their relationships with these oncogenic drivers.

Methods

Genomic DNA from 12 cervical NECs with ≥ 50% tumor cellularity underwent targeted next-generation sequencing (NGS) using the Qiagen GeneRead DNAseq Targeted Panels V2. Variants were filtered against COSMIC and ClinVar, and the pathogenicity of missense changes was assessed with PolyPhen-2, with scores > 0.85 considered probably damaging.

Results

PTEN alterations were identified in 25.0% (3/12) of tumors, encompassing four truncating mutations (p.W111*, p.Q171*, p.Q245*, p.R335*) and three missense variants (p.R130Q, p.E394G, p.D395V). A TP53 DNA-binding domain hotspot mutation, p.R273H, was detected in 8.33% (1/12). These tumor-suppressor lesions frequently co-occurred with oncogenic driver mutations, including HER2/PTEN (8.33%), PIK3CA/PTEN (8.33%), and a KRAS/PTEN/TP53 “triple-hit” (8.33%), underscoring multipathway genomic complexity.

Conclusions

Our findings suggest a genomic landscape consistent with a multihit hypothesis in cervical NEC, in which disruption of the reciprocal tumor-suppressive PTEN-p53 axis (25.0% and 8.33%, respectively) co-occurs with oncogenic HER2, KRAS, or PIK3CA alterations. Structural mapping indicates that TP53 p.R273H gain-of-function mutations and PTEN loss-of-function variants are associated with sustained PI3K/AKT/mTOR pathway activation. Integrating TP53 and PTEN status with oncogenic driver profiling may facilitate the identification of biologically defined subsets and inform precision therapeutic strategies for cervical NEC.

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子宫颈神经内分泌癌中PTEN和TP53的整合基因组分析：与HER2/KRAS/PIK3CA的协同作用及其对精确肿瘤学的影响

背景：宫颈神经内分泌癌（NEC）是一种罕见的、高度侵袭性的恶性肿瘤，预后较差。我们之前的研究发现了HER2、KRAS和PIK3CA在这种疾病中的频繁突变，在此基础上，我们试图通过表征TP53和PTEN的改变及其与这些致癌驱动因素的关系来完善基因组图谱。方法：使用Qiagen GeneRead DNAseq targeted Panels V2对12例肿瘤细胞≥50%的宫颈NECs的基因组DNA进行靶向下一代测序（NGS）。用COSMIC和ClinVar筛选变异，用polyphen2评估错义改变的致病性，评分为>.85，认为可能具有破坏性。结果：在25.0%（3/12）的肿瘤中发现PTEN突变，包括4个截断突变（p.W111*、p.Q171*、p.Q245*、p.R335*）和3个错义突变（p.R130Q、p.E394G、p.D395V）。8.33%（1/12）的人检测到TP53 dna结合域热点突变p.R273H。这些肿瘤抑制病变经常与致癌驱动突变共同发生，包括HER2/PTEN（8.33%）、PIK3CA/PTEN（8.33%）和KRAS/PTEN/TP53“三击”（8.33%），强调了多途径基因组的复杂性。结论：我们的研究结果表明，宫颈NEC的基因组图谱与多靶点假说相一致，其中肿瘤抑制相互作用的PTEN-p53轴的破坏（分别为25.0%和8.33%）与致癌的HER2、KRAS或PIK3CA改变共同发生。结构定位表明，TP53 p.R273H功能获得突变和PTEN功能丧失突变与PI3K/AKT/mTOR通路的持续激活有关。将TP53和PTEN状态与致癌驱动因素分析结合起来，可能有助于识别生物学上定义的亚群，并为宫颈NEC提供精确的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genes, Chromosomes & Cancer 医学-遗传学

CiteScore

7.00

自引率

8.10%

发文量

审稿时长

4-8 weeks

期刊介绍： Genes, Chromosomes & Cancer will offer rapid publication of original full-length research articles, perspectives, reviews and letters to the editors on genetic analysis as related to the study of neoplasia. The main scope of the journal is to communicate new insights into the etiology and/or pathogenesis of neoplasia, as well as molecular and cellular findings of relevance for the management of cancer patients. While preference will be given to research utilizing analytical and functional approaches, descriptive studies and case reports will also be welcomed when they offer insights regarding basic biological mechanisms or the clinical management of neoplastic disorders.