The human homolog 1 of the Drosophila neurogenic achaete-scute genes, hASH1, is specifically expressed in fetal pulmonary neuroendocrine cells and in some
neuroendocrine tumor cell lines. However, no data have been gathered regarding its in vivo expression in
tumors. hASH1
mRNA expression was investigated by in situ hybridization in 238 surgically resected lung
carcinomas, and the correlations between hASH1 expression status and immunostaining results of neuroendocrine markers
chromogranin A,
neural cell adhesion molecule,
gastrin-releasing peptide and
calcitonin, and clinical outcome were analyzed. hASH1 expression was detected in 2/20 (10%)
adenocarcinomas, 4/30 (13.3%) typical
carcinoids, 11/13 (84.6%) atypical
carcinoids, 38/67 (56.7%) large-cell neuroendocrine
carcinomas and 56/78 (71.8%)
small-cell carcinomas, respectively, but not in any
squamous cell carcinoma (0/21) or
large-cell carcinoma (0/9). The 2 hASH1+
adenocarcinomas also expressed multiple neuroendocrine markers. Thus, hASH1 expression was restricted to
lung cancers with neuroendocrine phenotypes. However, not all
neuroendocrine tumors expressed hASH1. Within the entities of large-cell neuroendocrine
carcinoma and
small-cell carcinoma, hASH1 expression correlated very closely with
chromogranin A,
gastrin-releasing peptide and
calcitonin expression (P<0.0001, r=0.852), but was not related to
neural cell adhesion molecule expression (P=0.8892), suggesting that hASH1 expression, at least in
lung cancer, is associated with endocrine phenotype expression other than 'neuroendocrine differentiation' in a broad sense. The fact that hASH1 was virtually absent in almost fully differentiated typical
carcinoids, but was expressed in most, if not all, less differentiated atypical
carcinoids as well as large-cell neuroendocrine
carcinomas and
small-cell carcinomas, suggests that hASH1 expression in
lung cancer imitates its early and transient expression in fetal development, and that hASH1 is instrumental in the establishment, but not in the maintenance, of a cellular endocrine phenotype. Finally, hASH1 expression correlated with a significantly shortened survival in
small-cell carcinoma patients (P=0.041).