Genetic Mutations Predict Advanced Prostate Cancer

Familial prostate cancer mutations predict an increased risk of aggressive disease

medwireNews: UK researchers have identified 13 putative loss-of-function mutations in Tumour-suppressor genes that are associated with aggressive traits in familial prostate cancer.

The loss-of-function mutations significantly increased the risk of prostate cancer with a relative risk of 1.94, falling slightly to 1.80 after excluding BRCA1 and BRCA2 mutations.

“The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread,” say Zsofia Kote-Jarai, from the Institute of Cancer Research in London, and co-authors.

Overall, 14 (7.3%) of the 191 men with prostate cancer and two or more affected family members tested positive for frameshift or stop-gain mutations in BRCA2, BRIP1, CHEK2, ATM, BRCA1, MUTYH, PALB2 and PMS2.

Men with and without loss-of-function mutations were diagnosed with prostate cancer at a similar age (58.5 and 59.0 years, respectively) and had comparable prostate-specific Antigen levels on presentation (11.1 and 8.3 ng/mL, respectively). Loss-of-function status was also independent of Gleason grade.

However, men with a loss-of-function mutation were significantly more likely than men without a mutation to have node-positive disease (21.0 vs 0.7%) and metastasis (21.0 vs 3.5%).

Furthermore, logistic regression analysis revealed that mutation-positive men were 13.5 times more likely than non-carriers to  have advanced disease, defined as nodal or metastatic disease or stage IV tumours.

And this increased risk of advanced prostate cancer remained after excluding four BRCA2 mutations that are already known to predict poor prostate cancer prognosis.

“This finding could have important clinical implications as men with deleterious germline mutations in these genes should be considered for more intensive screening and treatment,” write Zsofia Kote-Jarai et al in the BMJ.

“Furthermore, some of the genes studied here are in the [homologous recombination] repair pathway, in which targeted agents such as poly (ADP-ribose) polymerase inhibitors can be considered.”

Reference

Leongamornlert D, Saunders E, Dadaev T, et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. BMJ; Advance online publication 21 February 2014.

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