Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma.
Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a 'cervical cancer proliferation cluster' composed of 163 highly correlated transcripts. Most of these transcripts corresponded to E2F pathway genes controlling cell division or proliferation, whereas none was known as TP53 primary target. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P = 0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus provide a biological marker useful for prognosis assessment and specific therapy of the disease.
Rosty
Christophe
C
Département de Biologie des Tumeurs, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Sheffer
Michal
M
Tsafrir
Dafna
D
Stransky
Nicolas
N
Tsafrir
Ilan
I
Peter
Martine
M
de Crémoux
Patricia
P
de La Rochefordière
Anne
A
Salmon
Rémy
R
Dorval
Thierry
T
Thiery
Jean Paul
JP
Couturier
Jérôme
J
Radvanyi
François
F
Domany
Eytan
E
Sastre-Garau
Xavier
X
D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002584:Cervix Uteri / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D019562:Viral Load
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D012334:RNA, Neoplasm