Genetic analysis identifies putative tumor suppressor sites at 2q35–q36.1 and 2q36.3–q37.1 involved in cervical cancer progression

Abstract

We performed comparative genomic hybridization (CGH) and high-resolution deletion mapping of the long arm of chromosome 2 (2q) in invasive cervical carcinoma (CC). The CGH analyses on 52 CCs identified genetic losses at 2q33-q36, gain of 3q26-q29, and frequent chromosomal amplifications. Characterization of 2q deletions by loss of heterozygosity (LOH) in 60 primary tumors identified two sites of minimal deleted regions at 2q35-q36.1 and 2q36.3-q37.1. To delineate the stage at which these genetic alterations occur in CC progression, we analysed 33 cervical intraepithelial neoplasia (CIN) for LOH. We found that 89% of high-grade (CINII and CINIII) and 40% of low-grade (CINI) CINs exhibited LOH at 2q. To identify the target tumor suppressor gene (TSG), we performed an extensive genetic and epigenetic analyses of a number of candidate genes mapped to the deleted regions. We did not find inactivating mutations in CASP10, BARD1, XRCC5, or PPP1R7 genes mapped to the deleted regions. However, we did find evidence of downregulated gene expression in CFLAR, CASP10 and PPP1R7 in CC cell lines. We also found reactivated gene expression in CC cell lines in vitro after exposure to demethylating and histone deacetylase (HDAC) inhibiting agents. Thus, these data identify frequent chromosomal amplifications in CC, and sites of TSGs at 2q35-q36.1 and 2q36.3-q37.1 that are critical in CC development.

Screening of microsatellite markers in penile cancer reveals differences between metastatic and nonmetastatic carcinomas

“…23 A variety of potential tumor suppressor genes like CASP10, BARD1, XRCC5 and PPP1R7 have been excluded as targets of mutational inactivation. 21 Deletions in 2q36 have been found in early cervix carcinoma and in precancerous lesions, but in contrast to our results also in PSCC in high tumor stages. A possible explanation for this discrepancy may be the rather small number of tumors investigated here.…”

“…Allelic loss on chromosome 2q36 has already been described in cervix carcinoma 21 as well as in head and neck squamous cell carcinoma. 23 A variety of potential tumor suppressor genes like CASP10, BARD1, XRCC5 and PPP1R7 have been excluded as targets of mutational inactivation.…”

“…The di-and tetranucleotide repeats studied were chosen due to different reasons like vicinity to known tumorassociated genes, for example, p16 or p53, the occurrence of chromosomal aberrations in a distinct region in penile carcinoma, 18,19 deletions in CGH studies of PSCC 10 or frequent LOH of the marker in uterine cervix carcinoma. [20][21][22] As there are only few molecular genetic results available on penile carcinoma so far, we applied in our study a rather broad spectrum of markers. In addition, carcinomas with similar pathomorphological characteristics like cervix carcinoma and squamous cell carcinomas of other anatomical regions demonstrate aberrations that are distributed over many chromosomal locations.…”

Intratumor chromosomal heterogeneity in advanced carcinomas of the uterine cervix

“…Ϫ2q22-q33, Ϫ4p14-qter, Ϫ5q13-q23, Ϫ6qcen-q24, ϩ11qcen-q13 P- 14 A, B ϩ3q, Ϫ4pcen-p15, Ϫ4q31-qter, ϩ5p, Ϫ6qcen-q14, ϩ8q22-qter, Ϫ10pcen-p13, ϩ11qcen-q13, ϩ13q21-qter, ϩ14q, ϩ15q, ϩ19, ϩ20, ϩ22q(22q13), ϪX P- 15 A, B, C ϩ1, ϩ3q, ϩ5p, ϩ6p, ϩ8, ϩ9q, ϩ16p, ϩ19(19q), ϩ20 P- 16 A, B, C ϩ1p33-pter, ϩ5p, Ϫ5q14-q23, ϩ11qcen-q13, ϩ19(19q), ϩ20, ϩ22q, ϩXq21-qter P- 18 A, B ϩ1q, Ϫ4p13-qter, ϩ5p, Ϫ5q14-q22, ϩ7p, ϩ11p13-q13, ϩ19q, ϩ20q…”

“…4 This hypothesis is based on the frequent HPV infection in these tumors, which contributes to destabilization of the genome 12 and the high number of chromosomal aberrations observed. [13][14][15] The aberrations may however equally be a consequence of a single catastrophic genomic event, resulting in an aneuploid but stable genome subsequently carried by most of the cells. 16 The aberrations would then be similar throughout the tissue.…”