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Risky Haplotype for Treatment-Related Premature Menopause Proposed in Pediatric Cancer Survivors

CHICAGO (GenomeWeb) – A St. Jude Children's Research Hospital-led team has identified a haplotype that appears to coincide with the risk of premature menopause in pediatric cancer survivors treated with gonadotoxic drugs.

Speaking at the American Society of Clinical Oncology here yesterday, Russell Brooke, a postdoctoral researcher in epidemiology and cancer control, presented preliminary findings from a search for variants associated with premature menopause in nearly 800 childhood cancer survivors from the St. Jude Lifetime Cohort.

Premature menopause has been documented in childhood cancer survivors, he explained. Consequently, there is interest in identifying those at highest risk of the long-term complication so that they can be offered appropriate counseling and fertility maintenance options, if available.

Some forms of treatment appear to be particularly prone to late-onset reproductive consequences. For example, Brooke was co-author on a study published in the Journal of Clinical Endocrinology and Metabolism in March by investigators at St. Jude Children's Research Hospital and the Memorial Sloan Kettering Cancer Center that saw a related condition, premature ovarian insufficiency, in 10.9 percent of individuals from the St. Jude Lifetime Cohort Study in the two-dozen years after cancer diagnoses.

That study found enhanced levels of premature ovarian insufficiency in childhood cancer survivors who had been exposed to high doses of alkylating agents or ovarian radiotherapy. But there are hints that genetic contributors can influence the long-term risk associated with these drugs as well.

To explore that possibility in more detail, Brooke and his colleagues considered premature menopause diagnoses — defined as menopause prior to the age of 40 years old — in 799 St. Jude Lifetime Cohort participants, alongside information on the women's past exposure to alkylating agents and/ovarian radiotherapy exposure as well as their Affymetrix 6.0 SNP array-based genotypes.

In this group of women — who had had been cancer-free for a decade or longer — the researchers narrowed in on 16 SNPs with suspected ties to premature menopause. Although none of the variants reached genome-wide significance, Brooke explained, the team found that 13 of the candidate SNPs clustered upstream of the NPY2R gene on chromosome 4 and fell into four linkage disequilibrium blocks.

When they delved into this locus in more detail, they found that half of the premature menopause cases in childhood cancer survivors coincided with the presence of a homozygous haplotype tagged by four SNPs. That risk appeared to be particularly pronounced in women exposed to ovarian radiation as part of their pediatric cancer treatment protocol.

The team attempted to replicate these results in more than 1,600 other individuals from the Childhood Cancer Survivor Study, Brooke explained. In that group, which included individuals who had survival times of five years or longer, the self-reported rates of premature menopause were again higher in individuals carrying two copies of the newly identified haplotype.

In addition to providing a potential avenue for predicting premature menopause risk in pediatric cancer survivors, the researchers reasoned that the haplotype may offer a look at the biology behind this process. For example, their analyses of ENCODE expression, chromatin state, and other data suggested that the haplotype might enhance repressor activity at a site overlapping the transcription start site for NPY2R.

The University of Chicago's Tara Henderson, who was not involved in the study, noted that further research will be needed to define the genetic risk of premature menopause and other late cancer treatment effects. Even so, the development of a potential genetic risk profile could ultimately influence management of pediatric cancer patients, including those who are informed of a future risk of reproductive problem or offered options such as egg preservation, Henderson said during a commentary on the presentation.