Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure

Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were divided according to the patient’s 6 months clinical response and analyzed for whole human gene expression (Agilent). A 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 ‘Role of BRCA1 in DNA Damage Response’ was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance. 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. 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. Twenty-one patients with locally advanced squamous cell carcinoma (FIGO stage IIB-IIIB) were enrolled in the genomics study. A tissue fragment from a primary biopsy specimen was harvested from each patient prior to the therapy. Tissue samples were stored in liquid nitrogen until use for RNA extraction. One-color microarray experiment was performed to measure differences in gene expression between cervical cancer samples with 6-month complete response (12 patients ) and non-complete response (9 patients). Complet response group was considered as reference.