Alternative titles; symbols
Cytogenetic location: 11q13 Genomic coordinates (GRCh38): 11:63,600,001-77,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13 | Cervical carcinoma | 191181 | 2 |
Chromosomally stable intraspecific human cell hybrids derived by the fusion of tumorigenic HeLa cells with normal human cells provided evidence that tumorigenicity is recessive (Stanbridge, 1976); the hybrids were completely nontumorigenic. After a prolonged passage in culture, rare tumorigenic segregants were isolated, possibly owing to the loss of specific chromosomes that contained tumor suppressor sequences. By cytogenetic analysis of these hybrids, Stanbridge et al. (1981) showed a correlation between the loss of a single copy each of chromosome 11 and chromosome 14 and the development of the tumorigenic phenotype. Klinger (1980, 1982) confirmed the association between the loss of chromosome 11 and a few other chromosomes and the development of the tumorigenic cells. Use of chromosome-11-specific RFLP probes permitted demonstration that the loss of a single normal chromosome 11 was sufficient for the reexpression of the tumorigenic phenotype (Srivatsan et al., 1986; Kaelbling and Klinger, 1986). Furthermore, Saxon et al. (1986) demonstrated that the introduction of a normal chromosome 11 into a tumorigenic HeLa/fibroblast hybrid cell by the microcell transfer technique suppressed the tumorigenic phenotype. A selection process involving the loss of the introduced chromosome led to the reappearance of the tumorigenic cells. Misra and Srivatsan (1989) demonstrated that tumorigenicity was regained with the loss of region 11q13-q23. By RFLP analysis, Srivatsan et al. (1991) found somatic loss of chromosome 11 heterozygosity in 10 of 33 primary cervical carcinomas (see 603956). In addition, at least 8-fold amplification of sequences was observed in one of the primary tumors in the q13 region, including sequences coding for the fibroblast growth factor-related gene INT2 (164950).
Pursuing the functional studies showing that human chromosome 11 contains a gene or genes capable of suppressing tumorigenicity in cell lines derived from different histopathologic types of cervical carcinoma, Hampton et al. (1994) carried out a systematic analysis of chromosome 11 in primary tumors of 32 patients with cervical carcinoma. To identify the likely chromosomal position of the relevant gene or genes, they used 16 highly polymorphic markers to compare matched DNA samples from noninvolved tissue and portions of tumor tissue highly enriched for neoplastic cells. Of the 32 patients examined, 14 (44%) demonstrated clonal genetic alterations resulting in loss of heterozygosity for 1 or more markers. From the fact that 7 of the clonal genetic alterations on chromosome 11 were specific to the long arm and by the overlap between these and other allelic deletions, Hampton et al. (1994) concluded that at least one suppressor gene relevant to cervical carcinoma maps to 11q22-q24.
To determine whether 11q13 rearrangement is a nonrandom event in cervical carcinomas, Jesudasan et al. (1995) studied 6 different human papilloma virus (HPV)-positive cell lines (including HeLa and Caski) and 2 different HPV-negative cell lines. Long-range restriction mapping using a number of 11q13-specific probes showed molecular rearrangements within 75-kb of an INT2 probe in 3 HPV-positive cell lines and in an HPV-negative cell line. By fluorescence in situ hybridization using an INT2 YAC, Jesudasan et al. (1995) identified a breakpoint within the sequences spanned by this YAC in HeLa and Caski cells.
Several cytogenetic and molecular genetic studies had shown that a HeLa cell line contains 2 apparently normal copies of chromosome 11 and additional 11q13-q25 material translocated onto a chromosome 3 marker. To determine the 11q13 breakpoint, Srivatsan et al. (2000) performed fluorescence in situ hybridization using 18 different 11q13-specific BACs and cosmid probes spanning a 5.6-Mb interval. FISH identified an interstitial deletion between marker D11S449 and GSTP1 (134660), an interval of 2.3 Mb, in the marker chromosome. This deletion did not include the MEN1 gene (613733). SSCP did not reveal mutations of the MEN1 gene in HeLa or in 7 other cervical cancer cell lines. Because deletions of tumor suppressor genes often occur in cancer progression, Srivatsan et al. (2000) hypothesized that the inactivation of a tumor suppressor gene other than MEN1, localized to the 2.3-Mb interval on 11q13, may play a role in the abnormal growth behavior of HeLa cells in vitro and in vivo.
No cell line has been subjected to more extensive study than has the HeLa cell. This cell line was isolated from the cervical carcinoma of a patient named Henrietta Lacks who presented to The Johns Hopkins Hospital in early 1951 at the age of 31. Hers was the only one of many cervical carcinomas from which George O. Gey (1899-1970) succeeded in establishing an immortal cell line. That it was an unusual cervical cancer was indicated by its unusual fungating appearance, suggesting a venereal lesion and prompting a dark-field analysis for spirochetes (which was negative). Although there was no evidence of invasion or metastasis at the time the patient was first seen, and although radium therapy was given, Mrs. Lacks was dead in 8 months. Review of the histology by Jones et al. (1971) indicated that the cancer was an adenosquamous carcinoma rather than the usual squamous cervical carcinoma. The genetic characteristics of the HeLa cell line, including HLA types, were determined by Hsu et al. (1976) and compared with the findings in surviving members of her family. That Mrs. Lacks was a heterozygote for G6PD deficiency, i.e., G6PD A/B, was established by the fact that she had both G6PD-deficient and G6PD-normal sons. The HeLa cell line is G6PD-deficient (i.e., G6PD-A), indicating its monoclonal origin; this fact was established by Fialkow (1977) in studies of the monoclonality of cancers. The vigor of the HeLa cell line is attested to by the extent to which it has contaminated other cell lines in laboratories around the world (Hsu et al., 1976).
Chen (1996) published the karyotype of the HeLa cell line and demonstrated that the karyotype reported for a cell line obtained from Dr. George Gey in 1970 in the laboratory of Stella Mamaeva in Russia was identical to the karyotype of the ATCC cell line which had been accessioned from Dr. Gey in 1961.
O'Brien (2001) reviewed the history of contamination of cell lines by HeLa as documented by Gold (1986). The problem was first pointed out by Gartler (1968) and was demonstrated by Nelson-Rees et al. (1974, 1980, 1981) and Nelson-Rees and Flandermeyer (1976).
Masters et al. (2001) stated that cross-contamination between cell lines is a longstanding and frequent cause of scientific misrepresentation and that up to 36% of cell lines may be of a different origin or species to that claimed. They proposed that short tandem repeat profiling is a simple method for cell line authentication that is reproducible between laboratories, is inexpensive, and can provide an international reference standard for every cell line. O'Brien (2001) recommended that science journal editors require such validation as a criterion for publication of papers describing work on cell lines.
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Hampton, G. M., Penny, L. A., Baergen, R. N., Larson, A., Brewer, C., Liao, S., Busby-Earle, R. M. C., Williams, A. W. R., Steel, C. M., Bird, C. C., Stanbridge, E. J., Evans, G. A. Loss of heterozygosity in cervical carcinoma: subchromosomal localization of a putative tumor-suppressor gene to chromosome 11q22-q24. Proc. Nat. Acad. Sci. 91: 6953-6957, 1994. [PubMed: 8041728] [Full Text: https://doi.org/10.1073/pnas.91.15.6953]
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Masters, J. R., Thomson, J. A., Daly-Burns, B., Reid, Y. A., Dirks, W. G., Packer, P., Toji, L. H., Ohno, T., Tanabe, H., Arlett, C. F., Kelland, L. R., Harrison, M., Virmani, A., Ward, T. H., Ayres, K. L., Debenham, P. G. Short tandem repeat profiling provides an international reference standard for human cell lines. Proc. Nat. Acad. Sci. 98: 8012-8017, 2001. [PubMed: 11416159] [Full Text: https://doi.org/10.1073/pnas.121616198]
Misra, B. C., Srivatsan, E. S. Localization of HeLa cell tumor-suppressor gene to the long arm of chromosome 11. Am. J. Hum. Genet. 45: 565-577, 1989. [PubMed: 2577469]
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