genetics: gains and losses

836 | NOVEMBER 2004 | VOLUME 4 www.nature.com/reviews/cancer

The patient then received MOPP/ABV com-bination chemotherapy and radiotherapy and was later shown to be disease free butamenorrhoeic and infertile.

Six years later, when the patient decided thatshe wanted to try for a child, the surgeon firstcreated a peritoneal window beneath the rightovary to induce angiogenesis and neovascular-ization. Both ovaries were confirmed to beatrophic. At a second laporoscopy 7 days later,half of the cortical tissue samples, which all con-tained surviving primordial follicles, werethawed and re-implanted into the peritonealwindow, which was now clearly vascularized.There is a potential risk of re-implanting malig-nant cells with this technique, but in this case no

evidence of cancer was seen 5 monthsafter re-implantation.

Concentrations of luteinizing hormone and follicle-stimulating

hormone (FSH) decreased after re-implantation, indicating fol-licular development, but theythen increased again to cas-trated levels and there was no

sign of ovarian activity. At athird laparoscopy 4 months later to

check the graft, a viable follice outside theatrophic right ovary was seen. The surgeon also

re-implanted the remaining cubes of cryopre-served tissue. Over the next 4 months, follicledevelopment followed by corpeus-luteum for-mation was seen with restoration of regularmenstruation. Then, after a surge of FSH —which probably favoured follicle recruitment— the concentration of human chorionicgonadotrophin increased and a viable pre-gancy (by natural fertilization) was confirmed.A healthy girl was born in September 2004.

There is convincing evidence that thepregnancy originated in the transplanted tis-sue, particularly because the right ovary nevershowed any ovarian activity, the only follicleseen was in grafted tissue, and a pre-ovulationfollicle was seen at the re-implantation siteduring the cycle leading to the pregnancy.

The authors conclude that all youngwomen diagnosed with cancer should be giventhe option to have their ovarian tissue cryopre-served. Another option, which is not techni-cally possible yet, would be to re-implant primordial follicles; this would decrease therisk of re-implanting malignant cells.

Ezzie Hutchinson

References and linksORIGINAL RESEARCH PAPER Donnez, J. et al. Livebirth afterorthotopic transplantation of cryopreserved ovarian tissue.Lancet 364, 5000–5005 (2004)

Aneuploidy — gains or losses of wholechromosomes — is a common feature oftumours, but it is not clear how this defectoccurs, or whether it is a cause or simply aby-product of transformation. SandraHanks et al. report that mutations in thespindle-checkpoint gene BUB1B causeaneuploidy and contribute to an inheritedcancer-predisposition syndrome.

The mitotic-spindle checkpoint is asurveillance mechanism that maintains thecorrect chromosome number during celldivision. A large number of proteins,including members of the BUB and MADfamily, regulate this process, delayinganaphase until the kinetochores of eachchromosome pair have successfullyattached to the spindle.

In a search for genetic defects that mightcause mosaic variegated aneuploidy(MVA), a recessive condition characterizedby aneuploidies and other chromosomedefects, Hanks et al. identified mutations inboth BUB1B alleles in five out of eight

families with a history of this rare disease.MVA causes several developmental defectsas well as a high risk of malignancy, withrhabdomyosarcoma, Wilms’ tumour andleukaemia reported in several cases. Fiveindividuals who were found to carrybiallelic truncating and missensemutations in BUB1B had phenotypestypical of MVA, and two of these casesdeveloped cancer. No such mutations havebeen detected in tumour cells collectedfrom patients with other types of cancer, orfrom normal cell samples.

In mice, reduced expression of BUB1R, theprotein encoded by BUB1B, results indefective spindle-checkpoint activation,aneuploidy, and predisposition to lung andcolon cancers. In some human cancers,BUB1B has been shown to be epigeneticallydownregulated. So, aneuploidy, when causedby a functional disruption of the mitotic-spindle checkpoint, seems to be an importantcontributing factor to human cancer. Furtherstudies will reveal whether defects in other

spindle-checkpoint genes also contribute toaneuploidy-associated cancers.

Kristine NovakReferences and links

ORIGINAL RESEARCH PAPER Hanks, S. et al.Constitutional aneuploidy and cancer predisposition causedby biallelic mutations in BUB1B. Nature Genet. 10 Oct 2004 (doi:10.1038/ng1449)

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Gains and losses

G E N E T I C S

Against the odds

F E RT I L I T Y

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More than 90% of girls and young women withchildhood cancer can now be cured withaggressive chemotherapy, radiotherapy andbone-marrow transplantation. However, theovaries are very sensitive to cytotoxic treatmentand women can be left infertile. JacquesDonnez et al. now report the first livebirth afterorthotopic transplantation of ovarian tissue.

Ovarian tissue was taken from a 25-year-old woman with stage IV Hodgkin’s lym-phoma, the stromal tissue was removed and70 samples of cortex were cryopreserved.