title: Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors.
abstract: Association of X chromosome allelic losses with tumor malignancy has been identified in foregut but not in midgut endocrine neoplasms. The aim of this study was to investigate the association of deletions on X chromosome with malignancy in lung neuroendocrine tumors, another family of foregut neoplasms comprising four categories with increased malignancy: typical and atypical carcinoids, large cell neuroendocrine and small cell lung carcinomas. To evaluate loss of heterozygosity, DNA extracted from nine typical carcinoids, 17 atypical carcinoids, six large cell neuroendocrine carcinomas and five small cell lung carcinomas was PCR-amplified for 18 microsatellite markers spanning the whole X chromosome. All tissue samples were formalin-fixed and paraffin-embedded. X chromosome losses were absent in typical carcinoids, whereas they were found in nine out of 17 atypical carcinoids and in five out of six large cell neuroendocrine carcinomas (involving 28 and 70% of informative loci, respectively). On the contrary, deletions on X chromosome were an extremely rare event in small cell lung carcinomas. In atypical carcinoids, the presence of losses was associated with larger tumor size, higher pT status and advanced stage. No death occurred in atypical carcinoid patients without deletions on X chromosome, whereas all atypical carcinoid patients who had died from disease showed allelic losses. In conclusion, X chromosome allelic losses, absent in benign 'typical' carcinoids, progressively increased in frequency from intermediate-grade 'atypical' carcinoids to high-grade large cell neuroendocrine carcinomas. These results extend the association of deletions on X chromosome with malignancy, already demonstrated in other foregut endocrine neoplasms, to lung neuroendocrine tumors. The absence of X chromosome allelic losses in small cell lung carcinomas underlines a striking difference from large cell neuroendocrine carcinomas, possibly linked to different pathogenetic mechanisms of these two highly aggressive neuroendocrine lung tumors.
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy, University of Parma, Parma, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: D'Adda
authors.forename: Lorena
authors.initials: L
authors.lastname: Bottarelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Azzoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Pizzi
authors.forename: Massimo
authors.initials: M
authors.lastname: Bongiovanni
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pelosi
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Tommaso
authors.initials: T
authors.lastname: Antonetti
authors.forename: Guido
authors.initials: G
authors.lastname: Rindi
authors.forename: Cesare
authors.initials: C
authors.lastname: Bordi
mesh_terms: D000328:Adult; D000368:Aged; D002276:Carcinoid Tumor / Q000235:genetics / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D018895:Microsatellite Repeats; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis