Research Papers: Pathology:

Sensitive molecular detection of small nodal metastasis in uterine cervical cancer using HPV16-E6/CK19/MUC1 cancer biomarkers

Vanessa Samouëlian, Nawel Mechtouf, Eric Leblanc, Guillaume B. Cardin, Valérie Lhotellier, Denis Querleu, Françoise Révillion and Francis Rodier _

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Oncotarget. 2018; 9:21641-21654. https://doi.org/10.18632/oncotarget.24956

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Vanessa Samouëlian1,2,3, Nawel Mechtouf1, Eric Leblanc4, Guillaume B. Cardin1, Valérie Lhotellier5, Denis Querleu6, Françoise Révillion5,* and Francis Rodier1,7,*

1CRCHUM et Institut du cancer de Montréal, Montreal, QC, Canada

2Université de Montréal, Département d’Obstétrique Gynécologie, Montreal, QC, Canada

3CHUM, Service de Gynécologie oncologique, Montreal, QC, Canada

4Department of Surgery - Centre Oscar Lambret, Lille Cedex, France

5Laboratory of Human Molecular Oncology - Centre Oscar Lambret, Lille Cedex, France

6Institut Bergonie, Bordeaux, France

7Université de Montréal, Département de Radiologie, Radio-Oncologie et Médicine Nucléaire, Montreal, QC, Canada

*These authors contributed equally to this work

Correspondence to:

Francis Rodier, email: [email protected], [email protected]

Françoise Révillion, email: [email protected]

Vanessa Samouëlian, email: [email protected]

Keywords: diagnostic of lymph node metastasis; HPV viral oncogenes; intraoperative pcr; pretherapeutic evaluation; RT-PCR; Pathology

Received: May 01, 2016     Accepted: March 15, 2018     Published: April 24, 2018


Metastatic nodal involvement is a critical prognostic factor in uterine cervical cancer (UCC). To improve current methods of detecting UCC metastases in lymph nodes (LNs), we used quantitative PCR (qPCR) to assess mRNA expression of potential metastatic biomarkers. We found that expression of HPV16-E6, cytokeratin19 (CK19), and mucin1 (MUC1) is consistently upregulated in tumors and metastatic tissues, supporting a role for these genes in UCC progression. These putative biomarkers were able to predict the presence of histologically positive metastatic LNs with respective sensitivities and specificities of 82% and 99% (CK19), 76% and 95% (HPV16-E6), and 76% and 78% (MUC1). While the biomarkers failed to detect 1.7% to 2.2% of the histologically positive LNs when used individually, combining CK19 and HPV16-E6 enhanced sensitivity and specificity to 100% and 94%, respectively. To explore the sensitivity of qPCR-based detection of varying proportions of invading HPV16-positive UCC cells, we designed a LN metastasis model that achieved a fresh cell detection limit of 0.008% (1:12500 HPV16-positive to HPV16-negative cells), and a paraffin-embedded, formalin-fixed (PEFF) detection limit of 0.02% (1:5000 HPV16-positive to HPV16-negative cells), both of which are within the theoretical detection limit for micrometastasis. Thus, HPV E6/E7 oncogenes may be useful targets for the ultrasensitive detection of nodal involvements like micrometastases in fresh or archived tissue samples. Moreover, our results suggest that the biomarker combination of CK19/HPV-E6 could support a real-time intraoperative strategy for the detection of small, but potentially lethal, metastatic nodal involvements in fresh UCC tissues.

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