Identification of novel chromosome 22 tumour suppressor genes involved in ovarian and breast cancer
Chromosome 22 has long been suspected to harbour one or more tumour suppressor genes (TSGs) important in the development of several different human malignancies. Although a wealth of evidence, primarily from LOH studies, exists to support this, the critical gene(s) have remained elusive. Loss of chromosome 22 has been reported in up to 71% of ovarian cancers [1], 66% of breast cancers [2], 43% of colon cancers [3], as well as in several other cancer types. The identification of genes involved in breast and ovarian cancer development and progression is pivotal to the development of improved diagnostic and therapeutic strategies.
We employed a functional complementation approach, microcell mediated chromosome transfer (MMCT), to identify candidate TSGs on chromosome 22. MMCT was used to transfer regions of chromosome 22 into a breast (MDA-MB-231) and an ovarian (JAM) cancer cell line. The resulting hybrid clones were then assayed for their in vitro and in vivo tumorigenicity. Several hybrid clones showed dramatically reduced in vitro doubling times and a complete loss of ability to form colonies in soft agar. Furthermore, when injected subcutaneously into SCID mice these clones failed to form tumours, or formed tumours with increased latency. This provides further evidence for the presence of a chromosome 22 TSG that plays a role in breast and ovarian cancer. Through the use of high density microsatellite markers and the Affymetrix Human Mapping 50K array, identification of common regions of chromosome 22 gain in the suppressed hybrid clones has allowed us to identify candidate TSGs, including CBX7 which is a regulator of cellular lifespan. We are presently carrying out mutation and methylation analysis of this and other candidate genes.
References:
1. Cliby, W., et al., Human epithelial ovarian cancer allelotype. Cancer Research, 1993. 53(10 Suppl): 2393-8.
2. Allione, F., et al., Loss of heterozygosity at loci from chromosome arm 22Q in human sporadic breast carcinomas. International Journal of Cancer, 1998. 75(2): 181-6.
3. Duriez, C., et al., Localization of a tumor suppressor gene distal to D22S270 in colorectal cancers. Gastroenterol Clin Biol, 1997. 21(5): 358-64.