Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study

Abstract

Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A, however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4. In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40 years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈ 95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A, SMAD4, and more rarely PTEN. However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.

Dual primary gastric and colorectal cancer: The known hereditary causes and underlying mechanisms

“…The mechanisms underlying the development of dual GC and CRC remain controversial. Some explanations have been proposed, including both neoplasms are related to the same genetic alterations, such as APC, p53, CDH1, MSH1 and MLH1, STK11, TGF-β/SMAD, SMAD4, BMPR1A, and K-ras[ 8 , 15 , 29 , 30 , 36 , 37 ]. MSI is proposed to play a crucial role in colorectal carcinogenesis[ 38 ].…”

“…It is related to mutations of the SMAD4 gene (also called the MADH4 gene) and the BMPR1A gene. It is associated with gene mutations related to the transforming growth factor (TGF)-β/SMAD signalling pathway[ 29 , 30 ]. JPS is characterized by multiple hamartomatous polyps within the gastrointestinal tract, found in - mainly in the colorectum, and could be found in the stomach, jejunum and, ileum, and duodenum[ 31 ].…”

Phenotypic characterisation ofSMAD4variant carriers

“…8 The prevalence of SMAD4 variants in JPS is around 30%. [9][10][11] SMAD4 heterozygous loss-of-function mutations have been described in isolated JP 5 12 and combined JP-HHT syndrome. 4 13 In addition to those main phenotypes, connective tissue abnormalities such has aortic root dilation, mitral valve abnormalities and 'Marfan-like' phenotype with skeletal and cutaneous abnormalities have been described.…”