Gene expression profiling reveals activation of the FA-BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failureReport as inadecuate




Gene expression profiling reveals activation of the FA-BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure - Download this document for free, or read online. Document in PDF available to download.

BMC Cancer

, 14:246

Genetics, genomics and epigenetics

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.

KeywordsFANCD2 RAD51 BRCA1 BRIP1 Cervical cancer Microarray Treatment response AbbreviationsAUCArea under curve

BTBrachytherapy

CRComplete response

CRTConcomitant chemoradiotherapy

Cy3Cyanine 3

DABDiamino-benzidine tetrachloride

DSBsDNA double-strand breaks

EBRTExternal beam radiotherapy

FDRFalse discovery rate

FIGOInternational Federation of Gynecology and Obstetrics

HDRHigh-dose-rate

HPVHuman papillomavirus

IHCImmunohistochemistry

IPAIngenuity pathway analysis

NCRNon-complete response

RINRNA integrity number

ROCReceiver operating characteristic.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-246 contains supplementary material, which is available to authorized users.

Ovidiu Balacescu, Loredana Balacescu contributed equally to this work.

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Author: Ovidiu Balacescu - Loredana Balacescu - Oana Tudoran - Nicolae Todor - Meda Rus - Rares Buiga - Sergiu Susman - Bogdan Fet

Source: https://link.springer.com/







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