A mutation in any 1 of a suite of DNA repair pathway genes may predict not only the risk for familial prostate cancer, but also indicate the presence of a particular aggressive form of the disease, according to results of a new UK study from the Institute of Cancer Research in London (Leongamornlert D, et al. Br J Cancer. 2014 February 20. Epub ahead of print).
If validated, the clinical utility of these newly identified genetic markers will play a key role in the precautionary monitoring of men with the mutations, as well as guide treatment choice should disease onset occur.
“If we can more effectively screen these men,” wrote the investigators, “clinicians can potentially offer more tailored screening, staging and treatment pathways.”
Daniel Leongamornlert and colleagues from the Division of Genetics and Epidemiology at the Institute of Cancer Research in London, United Kingdom, found that the presence of even 1 of the so-called loss-of-function mutations increased the risk for prostate cancer by almost 2-fold compared with men without any of these mutations.
Furthermore, these mutations were more frequently associated with nodal involvement, tumor metastasis, and/or advanced disease at the time of diagnosis.
Mechanism of Genetic Risk for Prostate Cancer Similar to Breast Cancer It has long been known that certain types of breast cancers run in families, in particular tumors associated with the BRCA1/BRCA2 mutations, which are observed in 10% of all breast cancer cases. However, mutations in these genes, and the resultant loss of function of the associated proteins, have been associated with other cancers, including ovarian and prostate cancer, which was only recently understood.
“This suggests that shared genetic and/or environmental factors may be causal for multiple cancer types,” wrote the investigators, a hypothesis thought to be particularly relevant for hormonal-related malignancies.
Because genomic instability is the hallmark of most cancers, the team expanded their focus to include a comprehensive set of genes related to DNA repair pathways.
New Mutations Identified A total of 191 men in the United Kingdom with a family history of prostate cancer were selected for this study; they were screened using the genetic assay known as the BROCA Cancer Risk Panel, in combination with second-generation DNA-sequencing technology to spot deleterious mutations.
The 14 loss-of-function mutations were identified in 8 genes, including ATM, BRCA1, BRCA2, BRIP1, CHEK2, MUTYH, PALB2, and PMS2.
Of the mutations found, 5 were discovered for the first time in this investigation, and no enrolled patient had more than 1 loss-of-function mutation.
Although the predictive value of these mutations in cases of familial prostate cancer was less than that seen in the example of BRCA1/BRCA2 and breast cancer—roughly 10% in breast cancer versus 7.3% in prostate cancer—the implications for disease prognosis are striking.
“There was a significant association between LoF [loss-of-function] carrier status and the presence of nodal involvement…and metastasis,” the investigators stated. Regarding involvement of the lymph nodes, there was an incidence rate of 42.9% for patients with prostate cancer and a loss-of-function mutation versus 1.3% for men without a mutation; for tumor metastasis, the rate was 30.0% versus 6.3%, respectively.
Loss-of-function mutation carriers also had a significantly greater risk for advanced disease (odds ratio, 15.09); even after the BRCA2 mutations known to be associated with poorer prognosis were excluded, the risk for advanced disease persisted.
Significant, Inherited Risk These newly revealed mutations also showed significant, inherited genetic penetration in families. Of the 191 enrolled men with ?3 cases of prostate cancer in their family, 128 also had ?1 case of breast, ovarian, or colon cancer in their family.
One participant with a mutation in the CHEK gene had 2 brothers with prostate cancer; the family of another enrolled man with a mutation in the ATM gene had a father with colon cancer, 4 of 8 brothers with prostate cancer, and his sister was reported to have had leukemia.
Overall, even after the most common loss-of-function mutations of BRCA1/BRCA2 were excluded from the analysis, the newly discovered mutations accounted for a 1.8 increased risk for prostate cancer.
“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,” the investigators concluded.
