The reported association between D12S1034 and lung adenocarcinoma (ADCA) risk [Yanagitani N, Kohno T, Sunaga N, et al. Localization of a human lung adenocarcinoma susceptibility locus, possibly syntenic to the mouse Pas1 locus, in the vicinity of the D12S1034 locus on chromosome 12p11.2-p12.1. Carcinogenesis. 2002;23:1177-83] prompted us to carry out a case-control study in lung ADCA and healthy control subjects to test possible involvement of single-nucleotide polymorphisms (SNPs) in D12S1034 flanking genes RASSF8 and BHLHB3, whose minimal distances from D12S1034 are approximately 16-24 kb. RASSF8 contains a RAS-associated domain and is a candidate tumor suppressor, whereas BHLHB3 is a basic helix-loop-helix domain-containing protein that functions as a transcriptional repressor. We observed no significant association between common SNPs in RASSF8 (rs1546550 in the 3'-UTR and 3 intronic SNPs) and BHLHB3 (Ala298Val and rs1048155 in the 3'-UTR) with lung ADCA risk. However, patient groups carrying one or two copies of the BHLHB3 Val298 variation (i.e., Ala/Val or Val/Val genotypes) had a higher proportion of short-term survivors (hazard ratio, 1.8; 95% confidence interval, 1.2-2.7) compared with those carrying the Ala/Ala genotype. A replication study in an independent Norwegian lung cancer population of multiple cancer histotypes failed to replicate the significant association of BHLHB3 Ala298Val with survival; such association, however, was confirmed by analysis of ADCA only from both populations. Our results suggest that BHLHB3 variants may affect lung ADCA prognosis.
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