Integrated Genomic Profiling of
PTEN
and
TP53
Huang‐Pin Shen, Ming‐Yung Lee, Yi‐Ju Lee, An‐Chi Chen, Chi‐Kuan Chen, Wan‐Ru Chao, Chih‐Ping Han 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.