Chromosomal gains and losses in human papillomavirus-associated neoplasia of the lower genital tract - a systematic review and meta-analysis.
BACKGROUND
Overexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer.


METHODS
We performed a systematic literature review and meta-analysis of studies listed in PubMed that analysed chromosomal copy number alterations by comparative genomic hybridisation (CGH) in HPV-positive and -negative cancers or premalignant lesions of the anogenital tract (cervix, anus, vagina, penis and vulva).


RESULTS
Data were extracted and analysed from 32 studies. The most common alterations in cervical squamous cell carcinoma (SCC) (12 studies, 293 samples) were gains at 3q with a rate of 0.55 (95% confidence interval (CI) 0.43-0.70), losses at 3p (0.36, 95%CI 0.27-0.48) and losses at 11q (0.33, 95%CI 0.26-0.43). Gains at 3q were particularly frequent in HPV16-positive cervical SCC (0.84, 95%CI 0.78-0.90). Also more than one quarter of high grade cervical intraepithelial neoplasia (CIN) harboured gains of 3q (0.27, 95%CI 0.20-0.36), but the rate in low grade CIN was low (0.02, 95%CI 0.00-0.09). For HPV-associated vulvar SCC (four studies, 30 samples) the same common alterations as in cervical SCC were reported. Studies on non-cervical and non-vulvar SCC and premalignant lesions of the lower genital tract are scarce.


CONCLUSIONS
3q gains were most frequently found in HPV16-positive cervical SCC. The results suggest the selection of HPV-transformed cell clones harbouring 3q gains in high grade premalignant lesions, while alterations in low grade lesions are rare.
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Lorenz K
LK
Thomas
Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
Justo Lorenzo
JL
Bermejo
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Svetlana
S
Vinokurova
Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
Katrin
K
Jensen
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Mariska
M
Bierkens
Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Renske
R
Steenbergen
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Marion
M
Bergmann
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Magnus
M
von Knebel Doeberitz
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 224, 69120 Heidelberg, Germany. Electronic address: miriam.reuschenbach@med.uni-heidelberg.de.
Miriam
M
Reuschenbach
D002869:Chromosome Aberrations; D005260:Female; D042822:Genomic Instability; D006801:Humans; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000235:genetics / Q000821:virology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000473:pathology / Q000821:virology*
CGH; Cervical cancer; Chromosomal alterations; Genomic instability; Human papillomavirus