PIK3CA mutation and CNV status and post-chemoradiotherapy survival in patients with cervical cancer

Martell, Kevin; McIntyre, John B.; Kornaga, Elizabeth; Chan, Angela; Phan, Tien; Köbel, Martin; Enwere, Emeka K.; Dean, Michelle L.; Ghatage, Prafull; Lees‐Miller, Susan P.; Doll, Corinne

doi:10.1016/j.ygyno.2020.06.506

Cited by 19 publications

(27 citation statements)

References 31 publications

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“…In contrast to HPV-induced cervical SCC, 23,24 consistent activating somatic gene mutations appear irrelevant in HPV-negative squamous cervical carcinogenesis. Low allelic frequency of gene mutations indicates tumor heterogeneity.…”

Section: Discussionmentioning

confidence: 94%

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Regauer

Reich

Kashofer

2021

American Journal of Surgical Pathology

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Recently, the World Health Organization (WHO) recognized human papilloma virus (HPV)-independent invasive cervical squamous cell carcinoma (SCC) without recognizing the existence of precursor lesions. This is a detailed characterization of 3 preinvasive lesions and 6 invasive SCC negative for HPV-DNA (32 genotypes), HPV-mRNA (14 genotypes) and genomic HPV sequencing. We evaluated histologic features, expression of p16ink4a, p53, CK7, and CK17, aberrations in 50 cancer genes and chromosomal copy number variations. HPV-negative preinvasive lesions were extensive basaloid or highly differentiated keratinizing intraepithelial proliferations of 3 to 20 cell layers thickness, partly with prominent cervical gland involvement. Overall, 2/3 intraepithelial lesions and the in situ component of 1/6 SCC showed p16ink4a block staining, while 1/6 in situ component revealed heterogenous p16ink4a staining. All invasive components of keratinizing SCC were p16ink4a-negative. Preinvasive and invasive SCC showed inconsistent CK7 and CK17 staining. Nuclear p53 overexpression was restricted to the TP53 gene mutated SCC. The highly vascularized peritumoral stroma showed a dense inflammatory infiltrate including plasma cells and intratumoral and peritumoral eosinophilic granulocytes. Inconsistent somatic gene mutations (PIK3CA, STK11, TP53, SMARC2B, and GNAS) occurred predominantly in nonhotspot locations at low mutational frequency in 3/6 SCC. Consistent aberrations included the pathogenic (angiogenic) germline polymorphism Q472H in the KDR gene (7/9 patients), and chromosome 3q gains (4/9 patients). In conclusion, HPV-negative intraepithelial cervical precancerous lesions exist, either as highly differentiated keratinized intraepithelial proliferations reminiscent of differentiated vulvar intraepithelial neoplasia, or undifferentiated basaloid intraepithelial lesions with occasional p16ink4a block staining resembling high-grade squamous intraepithelial lesion. Gains of chromosome 3q, angiogenic germline variants the inflammatory infiltrate may contribute to progression of HPV-negative cervical carcinogenesis.

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Section: Discussionmentioning

confidence: 94%

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Regauer

Reich

Kashofer

2021

American Journal of Surgical Pathology

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“…Previous studies revealed PIK3CA mutation is frequent in cervical cancer, and is associated with a poor OS and PFS [ 8 , 20 , 21 , 22 , 23 ]. PIK3CA was mutated in 14% cervical squamous cell carcinoma patients in the study by Ojesa et al, Genomic profiling of advanced cervical cancer in the CLAP trial also showed a higher PFS in women with mutated PIK3CA receiving second line or later camrelizumab plus apatinib [ 24 ]. This clinical benefit remains inconclusive in women receiving chemotherapy [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Genomic Landscape in Cervical Cancer by Next Generation Sequencing

Qiu

Feng

et al. 2022

Genes

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Cervical cancer is the fourth leading cause of cancer-related deaths in women worldwide. Although many sequencing studies have been carried out, the genetic characteristics of cervical cancer remain to be fully elucidated, especially in the Asian population. Herein, we investigated the genetic landscape of Chinese cervical cancer patients using a validated multigene next generation sequencing (NGS) panel. We analyzed 64 samples, consisting of 32 tumors and 32 blood samples from 32 Chinese cervical cancer patients by performing multigene NGS with a panel targeting 571 cancer-related genes. A total of 810 somatic variants, 2730 germline mutations and 701 copy number variations (CNVs) were identified. FAT1, HLA-B, PIK3CA, MTOR, KMT2D and ZFHX3 were the most mutated genes. Further, PIK3CA, BRCA1, BRCA2, ATM and TP53 gene loci had a higher frequency of CNVs. Moreover, the role of PIK3CA in cervical cancer was further highlighted by comparing with the ONCOKB database, especially for E545K and E542K, which were reported to confer radioresistance to cervical cancer. Notably, analysis of potential therapeutic targets suggested that cervical cancer patients could benefit from PARP inhibitors. This multigene NGS analysis revealed several novel genetic alterations in Chinese patients with cervical cancer and highlighted the role of PIK3CA in cervical cancer. Overall, this study showed that genetic variations not only affect the genetic susceptibility of cervical cancer, but also influence the resistance of cervical cancer to radiotherapy, but further studies involving a larger patient population should be undertaken to validate these findings.

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“…The prognostic analysis revealed that the KIRC patients with high PIK3CA levels had improved overall survival, which suggested that PIK3CA may function as a potential biomarker for detection and prognostic prediction in KIRC. In cervical cancer, PIK3CA was a prognostic biomarker and associated with poor overall survival [ 28 ]. Moreover, PIK3CA in residual disease after neoadjuvant chemotherapy is associated with poor survival in breast cancer, suggesting PIK3CA as a prognostic biomarker in breast cancer [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of PIK3CA as a Marker Associated with Prognosis and Immune Infiltration in Renal Clear Cell Carcinoma

Wang

Gao

et al. 2021

Journal of Oncology

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Background. Kidney renal clear cell carcinoma (KIRC) is the most prevalent renal malignancy. The therapeutic strategies for advanced KIRC are very few, with only sunitinib being widely approved. Mutations in the PIK3CA gene can affect tumor cell proliferation, metastasis, and patients’ survival. Methods. Bioinformatics analysis was performed to explore the expression and clinical significance of PIK3CA in KIRC. Moreover, qRT-PCR was conducted to verify the result. Results. Subgroup analyses of KIRC tissue based on gender, tumor grade, and cancer stage indicated downregulation of PIK3CA mRNA expression. The KIRC patients with high PIK3CA expression indicated a better overall survival, progression-free survival, and disease-free survival. A predictive nomogram was constructed and demonstrated that the calibration plots for the 3-year and 5-year OS rates were predicted relatively well compared with an ideal model in the TCGA KIRC cohort. The validation study revealed that downregulation of PIK3CA in KIRC tissues and low PIK3CA expression had a poor overall survival with an AUC of 0.775 in the ROC curve. Moreover, Cox regression analysis revealed that PIK3CA expression and clinical stage were independent factors affecting the prognosis of KIRC patients. PIK3CA expression was found to be significantly associated with the abundance of immune cells and immune biomarker sets. PIK3CA and associated genes were found to be mainly associated with immune response and the JAK-STAT signaling pathway. Conclusion. We identified PIK3CA as a potential biomarker for prognosis correlated with immune infiltrates in KIRC. Further studies should focus on the functions of PIK3CA in KIRC carcinogenesis.

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PIK3CA mutation and CNV status and post-chemoradiotherapy survival in patients with cervical cancer

Cited by 19 publications

References 31 publications

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

HPV-negative Squamous Cell Carcinomas of the Cervix With Special Focus on Intraepithelial Precursor Lesions

Characterization of the Genomic Landscape in Cervical Cancer by Next Generation Sequencing

Identification and Validation of PIK3CA as a Marker Associated with Prognosis and Immune Infiltration in Renal Clear Cell Carcinoma

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