SMAD4 Immunohistochemistry Reflects Genetic Status in Juvenile Polyposis Syndrome

摘要

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the presence of distinct juvenile polyps in the gastrointestinal tract and an increased colorectal cancer risk (1-3). On histology, juvenile polyps have a prominent stromal compartment containing distorted and cystically dilated crypts often lined by reactive epithelium (4). A germline mutation in the SMAD4 or BMPR1A gene is found in 50% of patients (5, 6). Both genes are involved in the transforming growth factor-β/ bone morphogenic protein (BMP) signaling pathway, which regulates cell proliferation and differentiation. SMAD4 is a cytoplasmic co-mediator that forms heteromeric complexes with various receptor-dependent SMADs. These complexes are translocated to the nucleus and regulate DNA transcription (7, 8). Somatic inactivation of the SMAD4 tumor suppressor gene occurs in up to 55% of pancreatic cancers and in other malignancies including colorectal cancer. This occurs through either somatic intra-genic mutation with loss of the second allele [loss of heterozygosity (LOH)] or deletion of both alleles (homo-zygous deletion; refs. 9-11).