Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers

Abstract

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about 40-50% of patients. Little is known, however, about the occurrence and nature of somatic alterations (2nd-hit) in SMAD4-/BMPR1A-related juvenile polyps. In this study, we screened 25 polyps from three patients carrying either a pathogenic SMAD4 (c.1244-1247delACAG) or BMPR1A (c.583C>T; p.Gln195*) germline mutation for somatic alterations. The SMAD4-related polyps were also analyzed for SMAD4 protein expression by immunohistochemistry. Despite comprehensive screening for loss of heterozygosity (LOH), mutations in the coding sequence, chromosomal rearrangements, and promoter methylation, no somatic alterations could be identified in 14 SMAD4-related polyps. SMAD4 protein expression, however, was lost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, the epithelial and stromal, compartments. In the BMPR1A-related polyps, five out of nine (56%) displayed LOH. Further analysis of selected polyps revealed that LOH was gene copy number neutral and had occurred in the epithelial compartment. The heterogeneity of genetic mutations and protein expression levels indicates that different modes of gene inactivation can be operational in SMAD4- and BMPR1A-related polyp formation. Our observation, that about half of BMPR1A-related polyps displayed LOH, predominantly in the epithelial compartment, is compatible with BMPR1A acting as a tumour suppressor gene. Still, it remains to be determined whether juvenile polyp development generally requires loss of BMPR1A expression or, as observed in some SMAD4-related polyps, can occur despite normal protein expression.

Bmp signaling in colonic mesenchyme regulates stromal microenvironment and protects from polyposis initiation

“…In order to develop polyps and eventually GI malignancy, these patients will ultimately have to lose the remaining healthy allele of either SMAD4 or BMPR1A . The precise cellular location of the second mutation, epithelial or mesenchymal, remains conflicting however . In this mouse model, we show that the loss of Bmpr1a in a subtype of mesenchymal cells is sufficient to reproduce some of the phenotypic changes observed in JPS patients.…”

“…The precise cellular location of the second mutation, epithelial or mesenchymal, remains conflicting however. [46][47][48] In this mouse model, we show that the loss of Bmpr1a in a subtype of mesenchymal cells is sufficient to reproduce some of the phenotypic changes observed in JPS patients. The future challenge will remain to validate this key observation made in the mouse model to myofibroblast samples isolated from a large-scale human JPS tissue biobank.…”

Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A

“…The molecular alterations involved in polyp and tumor formation in JPS are attributed to defective BMP signaling, where aberrant BMP signaling disrupts stem cell self-renewal and differentiation, contributing to tumor formation (10). Loss of heterozygosity (LOH) was reported in half of BMPR1A -related polyps, compatible with BMPR1A acting as a tumor suppressor gene (11). However, BMPR1A LOH has not been documented yet in cancerous tumors.…”

Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers

“…11 The pathogenetic events behind SMAD4-and BMPR1A-associated juvenile polyposis are still poorly understood; only scarce data are available on the putative roles of these genes as tumor suppressors and the nature of the respective somatic alterations (2nd hit) involved in polyp formation. [12][13][14][15] Despite being known for more than 50 years 16 clinical guidelines for JPS, due to its rarity, still essentially depend on clinical and genetic information gathered from single series/ center reports, mostly focused on SMAD4 PV carriers, and expert opinion. 17 Additionally, there exists no comprehensive, open access database on genetic variants in SMAD4 or BMPR1A.…”

“… 11 The pathogenetic events behind SMAD4 - and BMPR1A -associated juvenile polyposis are still poorly understood; only scarce data are available on the putative roles of these genes as tumor suppressors and the nature of the respective somatic alterations (2nd hit) involved in polyp formation. 12 – 15 …”