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Study Finds Set of Familial Prostate Cancer Mutations Potentially Predictive of Aggressive Disease


A sequencing effort by a group from The Institute of Cancer Research, London has identified a group of mutations that may predispose men with a family history of prostate cancer toward developing tumors and are also associated with more advanced or aggressive disease.

According to the researchers, who published the results of the study in the British Journal of Cancer this month, the investigation was prompted by previous evidence that mutations in DNA repair genes associated with inherited breast and ovarian cancer, like BRCA1 and BRCA2, may also increase the risk of prostate cancer.

The group hoped that by using next-gen sequencing to investigate a subset of breast and ovarian cancer and other rare multi-organ cancer-associated DNA repair genes, and focusing on deleterious mutations likely to cause a loss of function in these genes, they might identify additional mutations linked to inherited prostate cancers.

One of the study's co-leaders, Ros Eeles said in a statement that the results "proved that testing for known cancer mutations can pick out men who are destined to have a more aggressive form of prostate cancer."

"We already have the technical capabilities to assess men for multiple mutations at once, so all that remains is for us to do further work to prove that picking up dangerous mutations early can save lives. If so, then in the future, genetic testing may be needed as part of the prostate cancer care pathway," he added.

Because of controversy over the use of PSA testing in prostate cancer screening due to its low specificity, efforts to improve on prostate cancer risk assessment in asymptomatic men using genomic markers have accelerated.

One effort, the IMPACT study, is evaluating the utility of PSA-based PrCa screening in asymptomatic BRCA1 and BRCA2 mutation carriers and in patients with Lynch syndrome.

Preliminary results of the study showed that the positive predictive value of PSA in the subset of men who are BRCA carriers is high, supporting the rationale for PSA screening in this population.

According to the ICR group, the results of its sequencing study parallel other discoveries, including the connection between BRCA mutations and poorer prostate cancer prognosis.

But importantly, the authors wrote, the effort suggests for the first time that LoF mutations across a range of DNA repair genes are associated with more advanced or serious disease, even when BRCA2, which has previously been linked to poor prognosis, is excluded.

This suggests a clinical potential for screening men for a range of LoF mutations, at least in the genes identified in the study, according to the authors.

The team also made calculations using a predictive modeling tool, which suggested that only three mutation carriers in the study would have been eligible for genetic testing in the UK based on current guidelines concerning BRCA genes. "On the basis of our result, we would therefore recommend that in the future a panel of DNA repair genes should be tested in PrCa families with three or more PrCa cases," the authors wrote.

In the study, the researchers collected DNA samples from 191 men with three or more cases of prostate cancer in their families recruited from a trial called the UK Genetic Prostate Cancer Study.

The group sequenced 22 tumor suppressor genes in these samples, including the BROCA tumor suppressor gene set containing high- and moderate-risk breast and ovarian cancer genes like BRCA1 and BRCA2, as well as genes involved in rare inherited cancer disorders like Lynch syndrome.

According to the study authors, the analysis of the results of this sequencing was focused on identifying putative loss-of-function mutations: those likely — based on their location and influence on protein sequence or structure — to inhibit the functional expression of the gene in which they are located.

The group also tried to validate any identified LoF mutations in the subjects themselves, and their family members if available, using follow-up Sanger sequencing.

Based on the results, the group picked out a total of 13 loss-of-function mutations in 8 genes in 14 of the subjects from the 191-man cohort, including four mutations in BRCA2, two in ATM, a single mutation in BRIP1 affecting two different subjects/families, and two mutation in CHEK2, as well as one mutation each in BRCA1, MUTYh, PALB3, and PMS2.

No subject carried more than one of these LoF mutations, the authors wrote, and while several of the mutations identified had been previously associated with prostate cancer, others had not.

Because the study cohort was limited to men with a strong family history of prostate cancer, the group did not find any significant difference in cancer incidence between families with a LoF mutation and those without. However, the researchers did see a statistically significant increase in cancer severity for the subjects who were mutation-positive.

According to the group, while there was no significant association between LoF mutations and age of diagnosis, presenting PSA level, Gleason score, or tumor stage, there was a significant association between carrier status and lymph node involvement. And, LoF mutation carriers had significantly higher odds of having advanced disease, with an odds ratio of 15.09.

"Any future screening program would need to assess as many of these genes as possible – more than we currently look for in women at risk of breast cancer, for example," another study co-leader, Zsofia Kote-Jarai, said in a statement.

Although a market has grown around genetic prognostic testing for men who already have prostate cancer, molecular testing for prostate cancer risk has lagged behind breast and ovarian cancer screening.

Myriad Genetics markets its BRACAnalysis primarily for hereditary breast and ovarian cancer risk testing, but does acknowledge in marketing materials that male carriers of BRCA mutations have heightened risk for prostate cancer.

And recently, several groups have looked to genetic alterations to improve prostate cancer risk prediction in healthy men, including a Northwestern University team, which looked to PSA-associated SNPs to improve upon PSA testing as a risk-prediction tool.

A Finnish team also recently published a report on using a panel of markers to predict which men with certain prostate cancer precursor lesions are most likely to progress to cancer, which they hope could be developed into a test to guide clinical decision-making.

A group from Weill Cornell Medical College similarly identified a cancer-associated gene fusion that could be used to predict which men with a different prostate cancer precursor are most likely to progress.

The ICR researchers also tested samples from their study cohort using a 25-SNP risk score developed by an international research group and published in Genetic Epidemiology in 2011.

According to the authors, risk scores from the SNP panel did not differ significantly between LoF mutation carriers and non-carriers, which suggested that presence of the LoF mutations the group identified are likely independently associated with cancer risk.