RESUMEN
Pancreatic cancer-melanoma syndrome (PCMS) is an inherited condition in which mutation carriers have an increased risk of malignant melanoma and/or pancreatic cancer. About 30% of PCMS cases carry mutations in CDKN2A. This gene encodes several protein isoforms, one of which, known as p16, regulates the cell-cycle by interacting with CDK4/CDK6 kinases and with several non-CDK proteins. Herein, we report on a novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) found in an Italian family with PCMS. By segregation analysis, the c.52_57delACGGCC was proven to segregate in kindred with cutaneous melanoma (CM), in kindred with CM and pancreatic cancer, and in a single case presenting only with pancreatic cancer. In the literature, duplication mapping in the same genic region has been already reported at the germline level in several unrelated CM cases as a variant of unknown clinical significance. A computational approach for studying the effect of mutational changes over p16 protein structure showed that both the deletion and the duplication of the c.52_57 nucleotides result in protein misfolding and loss of interactors' binding. In conclusion, the present results argue that the quantitative alteration of nucleotides c.52_57 has a pathogenic role in p16 function and that the c.52_57delACGGCC is associated with PCMS.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Mutación de Línea Germinal , Melanoma/genética , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Pancreáticas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/ultraestructura , Femenino , Eliminación de Gen , Humanos , Masculino , Melanoma/etiología , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/etiología , Neoplasias Pancreáticas/etiología , Linaje , Estructura Cuaternaria de ProteínaRESUMEN
It is well established that p16(INK4A) protein acts as a cell cycle inhibitor in the nucleus. Therefore, cytoplasmic localization of p16 (INK4A) usually is disregarded by investigators as nonspecific. Three recent studies reported findings that differ from the current view concerning p16(INK4A) immunohistochemical localization. All three demonstrated that breast and colon cancers expressing cytoplasmic p16(INK4) represent distinct biological subsets. We previously detected in a percentage of non-small cell lung carcinomas simultaneous nuclear and cytoplasmic p16(INK4A) staining. In view of the reports concerning breast and colon carcinomas, we conducted an ultrastructural re-evaluation of our cases to clarify the specificity of p16(INK4A) cytoplasmic expression. We observed p16 (INK4A) immunolocalization in both the nucleus and the cytoplasm of a proportion of tumor cells. Diffuse dense nuclear staining was detected in the nucleoplasm, whereas weaker granular immunoreactivity was observed in the cytoplasm near the rough endoplasmic reticulum. Negative tumor cells also were visible. In the tumor-associated stromal, cells p16(INK4A) immunoreactivity was detected only in the nuclei. We have demonstrated that p16(INK4A) cytoplasmic staining is specific and suggest that it represents a mechanism of p16(INK4A) inactivation similar to that observed in other tumor suppressor genes.