Countercurrents: Editorial - A new kind of breast / ovarian cancer gene mutation | Narod | Current Oncology

Article

 S.A. Narod , MD
doi: http://dx.doi.org/10.3747/co.20.1403

" So, is it helpful to add PPM1D to the growing panel of ovarian cancer susceptibility genes?"

"A fascinating article, recently published in Nature and titled “Mosaic PPM1D Mutations Are Associated with Predisposition to Breast and Ovarian Cancer” by Nazneen Rahman and her colleagues1, is a rare example of a discovery that causes a re-evaluation of our assumptions about cancer and cancer genes.

The authors set out along a path well-travelled, intending to look for rare but highly penetrant gene mutations that might help to explain some of the residual heritability in breast and ovarian cancer—that is, to explain cancer families without a BRCA mutation. They used next-generation sequencing to study a panel of 507 genes connected in some shape or form to dna repair. The experiment was an extension of earlier work, made possible by the new technology. The project was facilitated by the collection of 13,462 dna samples from many patients over many years (attesting to the prescience of the British funding authorities; I suspect that this particular experiment was never detailed in full in a grant proposal)........

"In the analysis, one gene stood out: PPM1D (p53-inducible protein phosphate) outranked all the others by sheer statistical force. A PPM1D mutation was found in 18 of 6912 women with breast cancer, in 12 of 1121 women with ovarian cancer, but in only 1 of 5861 control subjects...........First, from a clinical point of view, the risk for ovarian cancer with PPM1D mutation (although not precisely known) looks to be as high as that determined for any risk factor or gene mutation yet discovered. The lifetime risk for a mutation carrier exceeds 60%, and so a preventive oophorectomy is in order. The PPM1D gene appears to be responsible for about 1% of ovarian cancers—fewer than BRCA1 or BRCA2, but comparable to the mismatch repair genes, RAD51C and RAD51D. The clinical scenario is much different, however......