Association analysis of germline variants in GEN1 with a susceptibility to prostate cancer in Polish men

The GEN1 gene is involved in DNA damage repair, as are several prostate cancer susceptibility genes, and is now included in several NGS clinical testing panels. The aim of our study was to investigate the role of GEN1 mutations in the etiology of prostate cancer.

First, we sequenced GEN1 in 390 Polish men with familial prostate cancer and 300 population controls using exome sequencing to identify protein-truncating variants and to analyze their possible association with prostate cancer risk. In addition, we performed a large association study of a recurrent frameshift variant of GEN1 (c.1929_1932delAAAG) among 5,857 men with unselected prostate cancer and 3,956 controls. We compared the clinical characteristics of prostate tumors in carriers of c.1929_1932delAAAG and in non-carriers. We conducted loss of heterozygosity (LOH) analysis at the GEN1 locus in prostate cancers from two men with the c.1929_1932delAAAG variant. To analyze survival, patients were followed from diagnosis to death for an average of 101 months.

We detected two frameshift variants (c.2515_2519delAAGTT (p. Lys839Glufs*2), c.1539delT (p. Asp514Ilefs*13)) by sequencing the GEN1 gene of 390 Polish patients with familial prostate cancer and 300 cancer-free controls. Neither variant was associated with increased prostate cancer risk: c.2515_2519delAAGTT was detected in 20.5% of 390 cases and in 17.1% of 300 controls (p = 0.28), c.1539delT was detected in one case (0.3%) and none of the controls (p = 1.00). The GEN1 variant, c.1929_1932delAAAG (p. Lys645Cysfs*29), was observed in 13 of 5,857 (0.22%) unselected cases and 8 of 3,956 (0.20%) controls (OR = 1.10, p = 0.84). Clinical characteristics of prostate tumors in 13 carriers of c.1929_1932delAAAG and 5,844 non-carriers were similar. All-cause survival was similar for variant carriers and non-carriers (age-adjusted HR = 0.68, p = 0.76). The wild-type GEN1 allele was not lost in two prostate tumors in men with the c.1929_1932delAAAG variant.

Our analysis suggests that GEN1 is not a prostate cancer susceptibility gene. The study has clinical implications for genetic counseling of men who tested positive for germline variants of GEN1.