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Clinical Research

Abstract 2225: First double validation of transcription infidelity biomarkers for breast cancer diagnosis

Virginie Ogier, Marie Brulliard, Sandrine Jacquenet, Olivier Roitel, Benoit Thouvenot, Olivier Collignon, Veronique Notet, Marjorie Fougère, Fatiha Maskali, Jean Cinqualbre, Pierre Oudet, Carole Mathelin, Marion Durand, Gilles Grosdidier, Joëlle Siat, Gilles Karcher, Jean-Pierre Armand, François Amalric, Bernard Bihain, Fabrice André and Gilles Favre
Virginie Ogier
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Marie Brulliard
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Sandrine Jacquenet
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Olivier Roitel
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Benoit Thouvenot
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Olivier Collignon
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Veronique Notet
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Marjorie Fougère
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Fatiha Maskali
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Jean Cinqualbre
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Pierre Oudet
2CHRU Strasbourg, Strasbourg, France
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Carole Mathelin
2CHRU Strasbourg, Strasbourg, France
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Marion Durand
3CHU Nancy, Nancy, France
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Gilles Grosdidier
3CHU Nancy, Nancy, France
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Joëlle Siat
3CHU Nancy, Nancy, France
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Gilles Karcher
3CHU Nancy, Nancy, France
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Jean-Pierre Armand
4Institut Claudius Regaud, Toulouse, France
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François Amalric
5Institut de Pharmacologie et de Biologie structurale, Toulouse, France
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Bernard Bihain
1GENCLIS SAS, Vandoeuvre-lès-Nancy, France
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Fabrice André
6Institut Gustave Roussy, Villejuif, France.
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Gilles Favre
4Institut Claudius Regaud, Toulouse, France
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DOI: 10.1158/1538-7445.AM2011-2225 Published April 2011
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Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL

Abstract

Comparison of cancer versus normal transcriptome identified single base variations occurring at increasing rates in cancer (Brulliard et al PNAS 2007). These variations are not explained by somatic mutations, polymorphisms nor alternate splicing but are caused by errors made by RNA polymerase II while copying DNA i.e. transcription infidelity (TI). Omission of single base is the TI event that most dramatically increases in cancer. RNAs carrying these frame shifts translate into proteins with distinctive carboxy terminal AA sequences. Molecular characterisation of such variant that can not be encoded by translation of the 6 phases of human or mice genome led to its detection in mice and human cancer cell lines (LLC1, B16F10, NCI-H23 and HT29). TI proteins contain specific epitopes of IgG that are part of innate humoral immunity. Injections of cancer cells to syngenic mice elicit a shift from innate to adaptive humoral response thereby establishing a causal relationship between over production of TI proteins and humoral immune response to cancer. These pre-clinical models provide for the first time a quantitative measure of cancer induced changes in IgG with reactivity specific of TI proteins and no reactivity with proteins encoded by RNA without frame shift. Using samples collected in 2 independent centres and that included age matched [median 53 y range 30 to 70 y] controls (n=227) and breast cancers (n=285), a combination 24 TI biomarkers yielded detection of breast cancers with 95 % sensitivity and 97 % specificity. Area under receiver operating curve was 0.98. These collections contain all stages of the disease with 84 % ductal, 10 % lobular and 6 % other histologic types. Test performances were 94 %, 100 % and 88% for the each type respectively. Triple negative patients represented 14 % of breast cancers and 95 % had positive testing. There were no differences in performances between the 2 recruitment centres and no detectable interferences caused by associated non malignant pathological conditions. Two men with breast cancer not included in training set were correctly classified.

We propose that a novel mechanism -TI- increases in cancer contributing to very high heterogeneity of cancer transcriptome and proteome. TI proteins are recognized as danger signals contributing to cancer immunogenicity. The first clinical application yielded high performances blood based breast cancer diagnosis. Prospective large scale multi centres cases controls study applying standardized blood sampling procedures and optimized analytical conditions and including controls, breast cancer, as well as lung cancer patients is ongoing. Preliminary analysis indicates that sensitivity and specificity > 98 % will be achieved for both types of cancer. Further breast cancer test does not cross react with lung cancer and vice versa.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2225. doi:10.1158/1538-7445.AM2011-2225

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Cancer Research: 71 (8 Supplement)
April 2011
Volume 71, Issue 8 Supplement
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Abstract 2225: First double validation of transcription infidelity biomarkers for breast cancer diagnosis
Virginie Ogier, Marie Brulliard, Sandrine Jacquenet, Olivier Roitel, Benoit Thouvenot, Olivier Collignon, Veronique Notet, Marjorie Fougère, Fatiha Maskali, Jean Cinqualbre, Pierre Oudet, Carole Mathelin, Marion Durand, Gilles Grosdidier, Joëlle Siat, Gilles Karcher, Jean-Pierre Armand, François Amalric, Bernard Bihain, Fabrice André and Gilles Favre
Cancer Res April 15 2011 (71) (8 Supplement) 2225; DOI: 10.1158/1538-7445.AM2011-2225

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Abstract 2225: First double validation of transcription infidelity biomarkers for breast cancer diagnosis
Virginie Ogier, Marie Brulliard, Sandrine Jacquenet, Olivier Roitel, Benoit Thouvenot, Olivier Collignon, Veronique Notet, Marjorie Fougère, Fatiha Maskali, Jean Cinqualbre, Pierre Oudet, Carole Mathelin, Marion Durand, Gilles Grosdidier, Joëlle Siat, Gilles Karcher, Jean-Pierre Armand, François Amalric, Bernard Bihain, Fabrice André and Gilles Favre
Cancer Res April 15 2011 (71) (8 Supplement) 2225; DOI: 10.1158/1538-7445.AM2011-2225
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