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Men with Certain Pathogenic Variants Had a Higher Incidence of Prostate Cancer

By LabMedica International staff writers
Posted on 17 Nov 2021
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Image: Men with Certain Pathogenic Variants Had a Higher Incidence of Prostate Cancer (Photo courtesy of UrologyAustin)
Image: Men with Certain Pathogenic Variants Had a Higher Incidence of Prostate Cancer (Photo courtesy of UrologyAustin)
Prostate cancer is one of the major causes of morbidity and mortality in men worldwide. The importance of germline genetic variation for identifying men at increased risk of prostate cancer to enable targeted screening and early detection has become increasingly recognized.

Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer.

An a large team of international scientists led by the Institute of Cancer Research (London, UK) recruited between Sept 28, 2012, and March 1, 2020, 828 men (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, they randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts.

The overall positive predictive value of biopsy using a PSA threshold of 3.0 ng/mL was 51.4%. A concurrent serum sample was taken for PSA quality assurance testing for analysis using the ProStatus PSA Free/Total DELFIA assay (PerkinElmer Life and Analytical Sciences, Boston, MA, USA). The selected mismatch repair genes were sequenced from germline DNA using targeted next-generation sequencing and analyzed for pathogenic variants using Agilent SureCall (Agilent Technologies, Santa Clara, CA, USA).

The investigators reported that of 962 men, 6% had PSA readings above 3.0 ng/mL, and 4% elected to have a biopsy. Of the 35 biopsies performed, 18 (1.9% of the entire cohort) indicated the presence of cancer. For the incidence of clinically significant prostate cancer, the rate among MSH2 carriers was 3.6% (95% CI 1.8-6.4) and 2.2% among MSH6 carriers (95% CI 0.5-6.4) compared with 0% in both non-carrier control groups. Prostate cancer incidence, using a PSA threshold of higher than 3.0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4.3% versus 0.5%) and MSH6 carriers than MSH6 non-carrier controls (3.0% versus 0%).

The authors concluded that results from the study bolster consideration of targeted PSA screening for prostate cancer in men with MSH2 and MSH6 pathogenic variants to increase the detection of prostate tumors that are highly likely to need treatment based on national and international guidelines. The study was published on November 1, 2021 in the journal The Lancet Oncology.

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