Identification of Two Novel HOXB13 Germline Mutations in Portuguese Prostate Cancer Patients

Hereditary prostate cancer is estimated to account for 5-10% of all prostate cancer cases, but the identification of highly penetrant genes has been difficult. HOXB13 was recently identified as a susceptibility gene for prostate cancer (PrCa) when the rare, but recurrent, germline mutation [G84E, p.(Gly84Glu)] was found in men of European descent, conferring an increased PrCa risk of 4.51-fold. This variant is now considered to be a founder mutation that arose in Northern Europe and has not been found among patients with different ethnic backgrounds, who instead harbor other HOXB13 mutations. For southern European populations data is still limited and most of the previous studies have only genotyped the G84E variant. Therefore, in the present work we searched for HOXB13 germline mutations in Portuguese PrCa patients, by sequencing the entire coding region of the gene in 462 index cases from families with early-onset and/or familial/hereditary PrCa. The G84E mutation was not found in any of our patients; however, four novel heterozygous variants were found in the germline of four different patients. Besides a synonymous and an intronic variant, two non-synonymous variants were found in the germline of three probands. The first, a transversion from a cytosine to an adenosine at position 383 that leads to an amino acid substitution from alanine to aspartic acid in codon 128 [c.383C>A, p.(Ala128Asp)] was found in two non-related patients. The other, a transversion from a cytosine to an adenosine at position 720 was carried by another proband and results in an amino acid substitution from a phenylalanine to a leucine in codon 240 [c.720C>A, p.(Phe240Leu)]. Both missense variants were predicted to be deleterious by different in silico tools, and none of the alterations were found in the 132 control subjects that were genotyped. Larger case-control studies are needed to determine if germline HOXB13 mutations predispose to a more aggressive disease and to evaluate if they significantly increase the risk of other cancers. In our study, the three patients harboring HOXB13 missense variants presented either with intermediate- or high-risk disease and one of the three probands presented three different primary tumors. Our study further corroborates that geographic heterogeneity exists and that full sequencing of the HOXB13 coding region should be performed until the mutational pattern of each population is established.

Authors and Affiliations:

Sofia Maia¹, Marta Cardoso¹, Pedro Pinto¹, Manuela Pinheiro¹, Catarina Santos¹, Ana Peixoto¹, Maria José Bento^2,3,4, Jorge Oliveira⁵, Rui Henrique^4,6,7, Carmen Jerónimo^4,6, Manuel R. Teixeira^1,4

 ¹ Department of Genetics and Cancer Genetics Group–CI-IPOP, Portuguese Oncology Institute–Porto, Porto, Portugal

² Department of Epidemiology, Portuguese Oncology Institute–Porto, Porto, Portugal

³ North Region Cancer Registry, Portuguese Oncology Institute–Porto, Porto, Portugal

⁴ Biomedical Sciences Institute (ICBAS), University of Porto–Porto, Portugal

⁵ Department of Urology, Portuguese Oncology Institute–Porto, Porto, Portugal

⁶ Cancer Biology and Epigenetics Group–CI-IPOP, Portuguese Oncology Institute–Porto, Porto, Portugal

⁷ Department of Pathology, Portuguese Oncology Institute–Porto, Porto, Portugal.

Abstract:

The HOXB13 germline variant G84E (rs138213197) was recently described in men of European descent, with the highest prevalence in Northern Europe. The G84E mutation has not been found in patients of African or Asian ancestry, which may carry other HOXB13 variants, indicating allelic heterogeneity depending on the population. In order to gain insight into the full scope of coding HOXB13 mutations in Portuguese prostate cancer patients, we decided to sequence the entire coding region of the HOXB13 gene in 462 early-onset or familial/hereditary cases. Additionally, we searched for somatic HOXB13 mutations in 178 prostate carcinomas to evaluate their prevalence in prostate carcinogenesis. Three different patients were found to carry in their germline DNA two novel missense variants, which were not identified in 132 control subjects. Both variants are predicted to be deleterious by different in silico tools. No somatic mutations were found. These findings further support the hypothesis that different rare HOXB13 mutations may be found in different ethnic groups. Detection of mutations predisposing to prostate cancer may require re-sequencing rather than genotyping, as appropriate to the population under investigation.

Journal: Plos One

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132728