Genetic mechanisms link egg ageing and cancer risk

A genomic study has identified five gene variants associated with earlier menopause and increased risk of cancer.

Researchers from University of Exeter, University of Cambridge and the Wellcome Sanger Institute found that variants in five key genes significantly increases the risk of early menopause. Women with only one copy of these new identified genes tend to experience menopause two to five and a half years earlier than the average age of 50.

'For decades, menopause has been under-researched, yet now this is a rapidly evolving area of science,' said co-author on the study, Professor Anna Murray, from the University of Exeter Medical School. 'The timing of menopause has a huge impact on women as they plan their careers and lives, and understanding the genetic changes is of particular interest in terms of potential treatments that could prolong reproductive life in future.'

The study, published in Nature, analysed DNA sequences from 106,973 post-menopausal women who participated in the UK Biobank study. The team focused on rare protein-coding genes and found nine genetic variants that are associated with age at menopause. Notably, five of the genes (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1) had not been linked to ageing of the ovaries previously.

Although these genetic variants are rare in the population, their effect on menopause is five times stronger than that of any previously identified common variant. In particular, mutation in the ZNF518A gene, which is found in one in 4000 women, had the strongest impact on menopause age, increasing age at menopause by nearly six years. It was also linked with delayed timing of first period, further reducing reproductive lifespan.

Additionally, researchers found that genes associated with menopause age are also linked with cancer, as they are involved in DNA damage repair and maintaining the stability of oncogenes BRCA1 and BRCA2.

The study also found that a mutation in the SAMHD1 gene not only delayed menopause by about one year but was also linked to an increased cancer risk in both men and women. Further, the team found that mothers with common genetic variants that previous research has associated with earlier menopause were more likely to pass new, or de novo, mutations that had arisen in their eggs to their children. However they were unable to replicate the same results when they analysed another biobank of genomic data.

To conclude their findings, the authors hypothesised that ovary ageing is driven by genetic integrity in the eggs, and that these newly found rare genetic variants leads to accumulation of DNA damage in the egg cells, resulting in egg loss and early menopause.

This finding shed light on how an individual's DNA orchestrate the underlying biological mechanism that not only determines menopause timing but also predisposes to cancer risks.

Authors warned that their findings were in a cohort that was largely made up of white Europeans, and that as age of menopause differs between people of different ancestry, these findings may not be applicable to other groups.