Association of the prostate cancer risk mutation G84E in HOXB13 with the subtype of ETS fusion negative adenocarcinoma with early age of diagnosis.

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5021 Background: HOXB13 was discovered as the first prostate cancer (PrCa) specific high-risk susceptibility gene. The most prevalent HOXB13 germline mutation in PrCa patients of European descent is HOXB13G84E, which likely originated in Northern Europe. Previous molecular examination of a set of G84E driven tumors suggested a distinct somatic phenotype, where oncogenic ETS gene fusions appear at unusually low frequencies as compared to the general prevalence of ETS fusions in PrCa (22 % vs approx. 50 %). Methods: We have analyzed 942 cases from three European ancestry populations for the coincidence of HOXB13 G84E and the most common ETS fusion, TMPRSS2-ERG(T2E), in corresponding tumor samples. Results: While the prevalence of T2E fusions was similar among study sites (range: 56.5% - 60.7%), the frequency of G84E genotypes differed markedly between US (1.5%), German (3.6%) and Finnish samples (8.3%). Despite the expected frequency gradient among study populations, all subsamples showed a strong enrichment of G84E mutation carriers among T2E fusion negative cases as compared to fusion positive cases (center adjusted OR = 4.90; 95%CI = 2.19 - 11.0; p = 0.0001). Consistent with the previous study, the crude frequency of the T2E fusion in HOXB13G84E carriers was 23.5 % (range 16.7 % - 28.5 %). Examination of disease characteristics highlighted age at diagnosis, with fusion positive cases being diagnosed 1.75 (0.87 - 2.63) years earlier than negative cases (p < 0.0001). Age at diagnosis in G84E carriers did not differ significantly from non-carriers (p = 0.26). However, within the subtype of fusion negative carcinoma, which is usually associated with later ages at diagnosis, carriers of G84E were diagnosed on average 2.93 (0.49 - 5.37) years earlier (p = 0.02). No associations were seen for tumor stage, tumor grade or diagnostic PSA levels. Conclusions: This study demonstrated a tumor type specific association for HOXB13 G84E mutation carriers having a higher frequency of T2E fusion negative PrCa. Although the T2E fusion negative subtype is known to be associated with later ages of diagnosis, HOXB13 driven tumors within this subtype may represent an early onset subgroup.

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