Germline Variants of Prostate Cancer in Japanese Families

Abstract

Prostate cancer (PC) is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family). We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family). We identified two deleterious HOXB13 variants (F127C and G132E). Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3). The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

Fig 1. Pedigrees of the seven large PC families.

Solid black rectangles represent affected patients with PC. Patients with PC analyzed by exome-seq were numbered (from 01 to 22). PC, prostate cancer.

Fig 2. Shared genes with variants in the large PC families.

(A) Twenty-two genes in the seven large families remained after filtering and prioritizing. Known susceptibility genes (BRCA2 and HOXB13) and one novel gene (TRRAP) are shown by green rectangles. The combined scores of Exomiser are shown on the right side of the gene names. (B) Variant status of BRCA2, HOXB13, and TRRAP. ExAC_all, MAF of all subjects in the ExAC; iJGVD, MAF in the iJGVD; HGVD, MAF in the HGVD; NA, Not applicable. PC, prostate cancer.

Fig 3. Variants of HOXB13 and TRRAP in the 59 small PC families.

(A) Variant status of HOXB13 and TRRAP. ExAC_all, MAF of all subjects in the ExAC; iJGVD, MAF in the iJGVD; HGVD, MAF in the HGVD; NA, Not applicable. (B) Results of Sanger-seq for shared variants of HOXB13 and TRRAP (i) Heterozygous variant of HOXB13 G132E (c.G395A) in GFPC024. (ii) Homozygous variant of HOXB13 G132E (c.G395A) in GFPC079. (iii) Heterozygous variant of TRRAP C1217R (c.T3649C) in GFPC072. The positions of variants are indicated by red arrows. PC, prostate cancer.

Fig 4. Shared genes with variants.

(A) Heat map of the shared genes with variants. Each column shows the family identification of large PC families or PC pairs of the small PC families. Each row shows the gene names and shared variants are filled with red (deleterious) or orange (nondeleterious) color. (B) Deleterious variants of the Cancer Gene Census genes. The variant status is shown. ExAC_all, MAF of all subjects in the ExAC; iJGVD, MAF in the iJGVD; HGVD, MAF in the HGVD; NA, Not applicable; PC, prostate cancer.

Fig 5. Associations between clinical features and shared variant status.

(A) Comparison of Gleason score between the shared families and unshared families. Gleason scores were averaged in each family. One family lacking Gleason score was omitted. (B) Comparison of age at diagnosis between the shared families and unshared families. Ages at diagnosis were averaged in each family. Shared, families with shared variants; unshared, families with unshared variants.