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Gene Specific Prostate Cancer Incidence Among Individuals with Lynch Syndrome
Joseph Boyle, MD1, Brittany Sears, PhD2, Katherine Crawford, MS, CGC2, Kristina Garcia, MGC, CGC2, Linda Rodgers-Fouché, MGC, CGC3, Keyan Salari, MD PhD1.
1Massachusetts General Hospital, Boston, MA, USA, 2Ambry Genetics, Aliso Viejo, CA, USA, 3Mass General Brigham Cancer Institute, Boston, MA, USA.
BACKGROUND: Lynch Syndrome (LS) is a hereditary cancer syndrome caused by germline pathogenic variants (PV) in DNA mismatch repair genes. Growing evidence demonstrates an increased risk of prostate cancer (PC) in this population, but gene-specific differences are not well understood. Here, we estimate the cumulative incidence of PC among a cohort of male LS undergoing genetic testing at a large commercial laboratory.
METHODS: Males with LS were identified from a large commercial genetic testing registry (Ambry Genetics), defined as those carrying a pathogenic/likely-pathogenic variant in
MLH1,
MSH2,
MSH6, or
PMS2. Clinical data on PC diagnosis was abstracted from test requisition forms at time of testing. Cumulative incidence of PC was estimated for the LS cohort and by individual gene, with censoring at time of genetic testing.
RESULTS: Of 1862 LS patients, 187 (10%) had a diagnosis of PC at the time of testing. The median age at genetic testing was 56 years (IQR 46-65). Among those diagnosed with PC, the median age at diagnosis was 64 years (IQR 56-70). Cumulative incidence of PC by age 75 among all LS patients was 39% (95%CI 33%-44%). There was a greater than two-fold variation in cumulative incidences by gene with the highest for
MSH2 (44%) and the lowest for
MLH1 (18%).
Median age at PC diagnosis was earliest in
MSH2 carriers at 61 years (IQR 56-68)
compared to all other genes, though this was not statistically significant
(
p=0.12).
CONCLUSIONS: In this large cohort of LS patients, PC cumulative incidence varied significantly by individual gene, reaching >40% by age 75 for
MSH2 PV carriers. These findings support gene-specific differences in PC risk that may have implications for tailored screening strategies.
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