Abstract 2395: Expression and mutation analysis of the EGFR signaling pathway in invasive cervical carcinoma.
Authors: Bumrungthai Sureewan , Munjal Kavita , Adamson Christine S-C , Rajendran Vanitha , Peng Zhihua , Cooper Kumarasen , Evans Mark F. 
Published: August 2014

Background

Invasive cervical carcinoma (ICC) remains a major cause of female mortality worldwide claiming the lives of around 275,000 women each year. Human papillomavirus (HPV) infection is the known cause of ICC. Whilst advances have been made in the prevention of ICC by incorporating HPV testing into cervical screening programs and by the development of HPV vaccines, relatively little progress has been made in understanding ICC cellular pathway abrogation and the significance for ICC treatment. In this study, upstream elements in the PI3K and RAS signaling cascades in the EGFR pathway have been investigated.

Methods

HPV-16 positive squamous cell carcinomas from Madhya Pradesh, India were screened by immunohistochemistry (IHC) for EGFR, PIK3CA and PTEN expression. IHC data were scored in terms of the percentage of tumor cells staining (0, 1-25, 25-75, &gt;75) and in terms of staining intensity (weak, moderate, strong). Real-time PNA-clamp PCR assays were performed to screen for KRAS mutations (7 types) and PI3K mutations (9 types).

Results

KRAS mutations were undetected in any of 91 (0%) samples tested whereas PI3K mutations were detected in 19/96 (19.8%) ICCs [P&lt;0.0001]: exon 9, E452 n=3 and E454 n=15; exon 20, H1047 n=1. PI3K mutation showed a significant association with increased patient age (mutation mean age: 56.6 yrs vs. wild type mean age: 47.4 yrs [P=0.003]). Any (&gt;1% cells) EGFR staining was found in 44/94 (46.8%) ICCs and showed a significant relationship to PI3K mutation detection: 13/44 (29.6%) EGFR positive vs. 6/50 (12.0%) EGFR negative [P=0.044]; PI3K mutations were notably common in ICCs with &gt;75% of tumor cells staining (n=8/20 [40.0%]). EGFR staining was not age related [P=0.526]. Any (&gt;1%) PTEN staining was detected in 27/93 (29.0%) ICCs; most of these (n=21) showed staining of &gt;75% cells. There was no significant association of PI3K mutation detection with PTEN expression (8/27 [29.6%] PTEN positive vs. 11/66 [16.7%] PTEN negative, P=0.169). PIK3CA was abundantly expressed in all but 3 (1.1%) ICCs, one of which showed a PI3K mutation. No significant relationships were detected for any of the markers with respect to tumor grade, stage, size or lymph node status.

Conclusions

These data show that EGFR expression is relatively common in ICCs whereas KRAS mutations are absent or rare supporting the use of anti-EGFR therapies in the treatment of ICC patients. PI3K mutations were detected in nearly a fifth of cases suggesting a potential role in the progression of a significant subset of ICCs. Interestingly, PI3K mutations were associated with older age and EGFR expression. Whether PI3K mutations negatively impact anti-EGFR therapies is currently uncertain. PTEN expression was undetected in 71.0% of specimens suggesting loss of its function in suppressing AKT signaling immediately downstream of PI3K.

Citation Format: Sureewan Bumrungthai, Kavita Munjal, Christine S-C Adamson, Vanitha Rajendran, Zhihua Peng, Kumarasen Cooper, Mark F. Evans. Expression and mutation analysis of the EGFR signaling pathway in invasive cervical carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2395. doi:10.1158/1538-7445.AM2013-2395