Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression

Abstract

Invasive cervical carcinoma is thought to arise from cervical intraepithelial neoplasm (CIN). Genetic changes that occur during progression of CIN to cervical carcinoma are poorly understood, although they appear to be directly involved in this process. We used comparative genomic hybridization (CGH) with precise microdissection and degenerate oligonucleotide primed-polymerase chain reaction (DOP-PCR) to detect genetic alterations in normal epithelial, CIN, and invasive carcinoma tissues colocalized in tumors from 18 patients with squamous cell carcinoma of the uterine cervix. Gains on chromosome 1 and on 3q and losses on 2q, 3p, 4, 6p, 11q, and 17p were frequent alterations found in CIN and invasive carcinoma lesions. Interestingly, several of these genetic changes were observed in preinvasive carcinoma lesions. The frequency and average number of genetic alterations corresponded directly to the extent to which the cervical carcinoma had progressed. Frequent alterations were found in more than 90% of CIN III lesions. Gains on 3q and losses on 11q were the most prevalent genetic alterations found in association with uterine cervix carcinogenesis. The common regions of alteration were 3q26.1-q28 and 11q23-qter. The majority of tumor samples showed variability in genetic alterations across lesion types within a single specimen.

High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia

“…For example, 3q gain was detected in 17% (1 out of 6) VSCC compared with 70% (37 out of 53) of the CxSCC series analysed concomitantly (including 60%, 6 out of 10 of the Stage I tumours) and 100% (9 out of 9) of the Stage I and II cervical tumours investigated by Wilting et al (2006). Furthermore, frequent recurrent gain of 3q has been reported in cervical neoplasia before the acquisition of the invasive phenotype: Kirchhoff et al (1999) and Umayahara et al (2002) identified 3q gain in 35% (6 out of 17) and 61% (11 out of 18), respectively, of CIN3 samples compared with 14% (3 out of 21) high-grade VIN in this study. These combined data suggest that chromosomal aberrations characteristic of advanced SCC at several sites, including hrHPV-associated cancers such as tonsillar SCC (Oga et al, 2001;Yen et al, 2001;Dahlgren et al, 2003;Noguchi et al, 2003;Klussmann et al, 2009), commonly appear at an early stage of cervical transformation.…”

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

“…Such continuous re-organization of cellular genome eventually creates novel molecular events essential for fully malignant transformation. Although we were unable to sort out those individual cells carrying very weak telomere signals to perform comparative genomic hybridization due to technical difficulties, based on previous observations showing a high frequency of chromosomal aberrations in CINs (Southern et al, 1997;Aubele et al, 1998;Evans et al, 1998;Giannoudis et al, 2000;Umayahara et al, 2002;Heselmeyer-Haddad et al, 2003;Pihan et al, 2003), it is rational to attribute genomic alterations to substantial telomere loss in those precursor lesions of the uterine cervix. Taken together, we suggest that telomere shortening and the resultant genetic instability may be key events in the formative stages of cervical cancers, which is consistent with those seen in animal and in vitro human tumorigenic models.…”

Morphoquantitative Analysis of the Intraepithelial Neoplasic Uterine Cells by Computer Image System

“…In fact, they made us disqualify several subjects' material (61.1%) for having a totally irregular distribution of chromogen results in diverse nucleus cells and a major intensity in a specific place, perhaps, due to the different fixing agents during impregnation method (Hanselaar et al, 1992). The usage of different fixing agents with different fixation methods shows some varieties about chromogen intensity in the ionic hydrogen concentration and the hydrolise time in Feulgen's reaction (Böhm;Böhm et al, 1968) that could interfere in the condensation of chromatin's spatial distribution and, apart from tracking the DNA, does the same with proteins (Stedman & Stedman, 1950), Umayahara et al (2002). Meanwhile, uncharacteristic DNA distributions, for some authors, in comparison with results from the epithelial of the uterine cervix cytrometry and its DNA, aren't an early malignity diagnostic method, Haroske et al (2001), Ishikawa et al (2002).…”