Abstract
BackgroundAdvanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer.MethodsTwenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient’s 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest.ResultsA 2859-gene signature was identified to distinguish between responder and non-responder patients. ‘DNA Replication, Recombination and Repair’ represented one of the most important mechanisms activated in non-responsive cervical tumors, and the ‘Role of BRCA1 in DNA Damage Response’ was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples.ConclusionsOur findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the patients at risk for treatment failure.
Highlights
Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis
Patient and tumor characteristics International Federation of Gynecology and Obstetrics (FIGO) staging evaluation of the patients included in this study revealed that approximately 48% of the patients were in stage II, while the rest of 52% were in stage III
< 0.0001 we showed that BRCA1 and BRCA2 overexpression in patients with advanced cervical cancer is associated with treatment failure
Summary
One of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. We investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer. The third most commonly diagnosed cancer in women, with 529,800 cases in 2010 [1], represents a major problem in oncology due to treatment failure and distant metastasis. If detected at an early stage, cervical cancer represents one of the most successfully treated cancers. Because of the lack of screening programs in developing countries, cervical cancer is predominantly detected in advanced stages (IIB-IIIB). About half of the patients with advanced cervical cancer will develop recurrence or metastasis in the first 2 years after completion of therapy. There is an urgent need to identify new prognostic factors that could distinguish between patients with unfavorable prognoses from others with better prognoses
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