• Humans
• Male
• Smad4 Protein/genetics
• Female
• Adult
• Neoplastic Syndromes, Hereditary/genetics
• Neoplastic Syndromes, Hereditary/pathology
• Neoplastic Syndromes, Hereditary/complications
• Middle Aged
• Adolescent
• Intestinal Polyposis/genetics
• Intestinal Polyposis/congenital
• Intestinal Polyposis/pathology
• Bone Morphogenetic Protein Receptors, Type I/genetics
• Young Adult
• Child
• Aged
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Gastritis/pathology
• Gastritis/genetics
• Disease Progression
• Gastroscopy
• Germ-Line Mutation
• Cardia/pathology
• Pyloric Antrum/pathology
• Adenocarcinoma/genetics
• Adenocarcinoma/pathology

• genetics
• patient care
• pediatrics
• vascular diseases

• Humans
• Smad4 Protein/genetics
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Telangiectasia, Hereditary Hemorrhagic/pathology
• Female
• Male
• Phenotype
• Adult
• Middle Aged
• Intestinal Polyposis/genetics
• Intestinal Polyposis/congenital
• Intestinal Polyposis/pathology
• Heterozygote
• Aged
• Neoplastic Syndromes, Hereditary/genetics
• Neoplastic Syndromes, Hereditary/pathology
• Neoplastic Syndromes, Hereditary/diagnosis
• Adolescent
• Genetic Predisposition to Disease
• Mutation/genetics
• Young Adult

• JPS
• hamartomatous‐polyp
• pediatric

• Humans
• Smad4 Protein/genetics
• Bone Morphogenetic Protein Receptors, Type I/genetics
• Child
• Male
• Female
• Intestinal Polyposis/genetics
• Intestinal Polyposis/congenital
• Adolescent
• Phenotype
• Mutation
• Neoplastic Syndromes, Hereditary/genetics
• Child, Preschool
• Follow-Up Studies

• ESPGHAN Networking Grant

• cancer
• colorectal cancer
• familial syndromes
• gastric cancer
• gastrointestinal tract
• genetic variant
• hereditary
• management
• mutation
• next-generation sequencing

• Gastric juvenile polyposis
• Mosaic mutation
• Nonsense mutation
• Sanger sequencing
• Target resequencing

• Female
• Humans
• Middle Aged
• Codon, Nonsense
• Stomach Neoplasms/genetics
• Stomach Neoplasms/surgery
• Stomach Neoplasms/diagnosis
• Polyps
• Smad4 Protein/genetics
• Smad4 Protein/metabolism
• Intestinal Polyposis
• Neoplastic Syndromes, Hereditary
• Adenomatous Polyps

• Juvenile polyposis syndrome
• Pancreaticoduodenectomy
• Protein-losing gastroenteropathy
• Refractory anemia
• Total gastrectomy

• Humans
• Gastrointestinal Neoplasms/genetics
• Gastrointestinal Neoplasms/therapy
• Biomarkers, Tumor/genetics
• Precision Medicine/methods
• Mutation

• BMPR1a
• GI malignancy
• Juvenile Polyposis Syndrome
• Juvenile polyps

• SMAD4 pathogenic variants
• case report
• gastric polyposis
• juvenile polyposis
• juvenile polyposis syndrome

• Humans
• Retrospective Studies
• Neoplastic Syndromes, Hereditary/diagnosis
• Neoplastic Syndromes, Hereditary/genetics
• Phenotype
• Colorectal Neoplasms/genetics
• Smad4 Protein/genetics
• Bone Morphogenetic Protein Receptors, Type I/genetics

• Colorectal cancer
• Hereditary syndrome
• Juvenile polyposis
• Polyposis

• Colorectal Neoplasms/genetics
• Gastrointestinal Neoplasms
• Humans
• Intestinal Polyposis/congenital
• Intestinal Polyposis/diagnosis
• Intestinal Polyposis/genetics
• Intestinal Polyposis/pathology
• Neoplastic Syndromes, Hereditary/diagnosis
• Neoplastic Syndromes, Hereditary/genetics
• Peutz-Jeghers Syndrome/diagnosis
• Peutz-Jeghers Syndrome/genetics
• Peutz-Jeghers Syndrome/pathology

Juvenile polyposis syndrome (JPS), has diverse phenotypes. Aim: To assess mutation rate, clinical features and genotype-phenotype correlation among Israeli JPS kindreds from different ethnicities.

Patients’ data were extracted retrospectively from 5 centers.

Thirty five kindreds (49 patients) were included. Thirty one (89%) Jewish [10 (32%) Ashkenazi; 9 (29%) Sephardi; 11 (35%) non-Russia former Soviet-Union countries (NRFSU), one (3%) unknown]. 40/49 individuals from 27 families underwent genetic testing. Among them 34, from 21 families (85, 78%, respectively) had a pathogenic mutation: BMPR1A n = 15 (71%), SMAD4 n = 6 families (29%). While no SMAD4 mutation was described among Jewish families from NRFSU, 7 NRFSU families carried a founder mutation comprising a large genomic deletion of BMPR1A. GI involvement was reported in 42 patients (86%): colonic polyps (n = 40, 95%, > 50 polyps n = 14, 35%) and 12 underwent colonic resection. Fourteen patients (34%) had gastric or small bowel involvement (n = 5) and 4\14 underwent gastrectomy due to polyp burden. Families from NRFSU had more gastric involvement (66.7% vs. 22.2%- Sephardic and 20%- Ashkenazi Jews; p = 0.038), with more gastric polyps (p = 0.017).

We demonstrated a high rate of mutation detection in the heterogeneous population of Israel. Patients from NRFSU with BMPR1A mutation had high rate of gastric involvement.

• BMPR1A
• SMAD4
• juvenile polyposis syndrome
• polyps

• Gastric cancer
• Genetic testing
• Hereditary diffuse gastric cancer
• Lynch syndrome

Large scale genome sequencing allowed the identification of a massive number of genetic variations, whose impact on human health is still unknown. In this review we analyze, by an in silico-based strategy, the impact of missense variants on cancer-related genes, whose effect on protein stability and function was experimentally determined. We collected a set of 164 variants from 11 proteins to analyze the impact of missense mutations at structural and functional levels, and to assess the performance of state-of-the-art methods (FoldX and Meta-SNP) for predicting protein stability change and pathogenicity. The result of our analysis shows that a combination of experimental data on protein stability and in silico pathogenicity predictions allowed the identification of a subset of variants with a high probability of having a deleterious phenotypic effect, as confirmed by the significant enrichment of the subset in variants annotated in the COSMIC database as putative cancer-driving variants. Our analysis suggests that the integration of experimental and computational approaches may contribute to evaluate the risk for complex disorders and develop more effective treatment strategies.

• free-energy change
• protein function
• protein stability
• protein structure
• putative cancer driving variant
• single amino acid variant

• Computational Biology/methods
• Computer Simulation
• Humans
• Mutation, Missense/genetics
• Neoplasms/genetics
• Protein Stability
• Proteins/genetics

• helicobacter pylori
• Caudal type homeoboxes
• intestinal metaplasia
• sonic hedgehog
• sry- related high-mobility group box 2

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS.

Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband’s children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.

• BMPR1A gene
• De novo germline variant
• Juvenile polyposis syndrome
• Missense variant

Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS.

• mutation
• rare variants
• protein-protein interaction networks
• systems biology

• Alleles
• Animals
• Base Sequence
• Disease/genetics
• Gene Frequency/genetics
• Genetic Predisposition to Disease
• Genetic Variation
• Genetics, Population
• Genome, Human
• HEK293 Cells
• Humans
• Mice
• Mutation, Missense/genetics
• Phenotype
• Polymorphism, Single Nucleotide/genetics
• Protein Binding/genetics

• R01 DK115398 NIDDK NIH HHS
• R01 GM093937 NIGMS NIH HHS
• R01 CA167824 NCI NIH HHS
• R01 HD082568 NICHD NIH HHS
• R01 GM097358 NIGMS NIH HHS
• R01 GM124559 NIGMS NIH HHS
• UM1 HG009393 NHGRI NIH HHS
• R01 GM104424 NIGMS NIH HHS
• R01 GM125639 NIGMS NIH HHS
• R01 HG006849 NHGRI NIH HHS
• U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
• U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
• U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• National Science Foundation (NSF)
• Simons Foundation

The majority of mutations studied in animal models are designated as recessive based on the absence of visible phenotypes in germline heterozygotes. Accordingly, genetic studies primarily rely on homozygous loss-of-function to determine gene requirements, and a conceptually-related ‘two-hit model’ remains the central paradigm in cancer genetics. Here we investigate pathogenesis due to somatic mutation in epithelial tissues, a process that predominantly generates heterozygous cell clones. To study somatic mutation in Drosophila, we generated inducible alleles that mimic human Juvenile polyposis-associated BMPR1A mutations. Unexpectedly, four of these mutations had no phenotype in heterozygous carriers but exhibited clear tissue-level effects when present in somatic clones of heterozygous cells. We conclude that these alleles are indeed recessive when present in the germline, but nevertheless deleterious when present in heterozygous clones. This unforeseen effect, deleterious heteromosaicism, suggests a ‘one-hit’ mechanism for disease initiation that may explain some instances of pathogenesis associated with spontaneous mutation.

• BMP receptor 1A
• D. melanogaster
• Drosophila wing development
• Tkv
• cell biology
• developmental biology
• hereditary mutation
• heterozygous
• somatic mutation
• stem cells

• binding specificity
• molecular electrostatics
• protein structure comparison

Gastrointestinal (GI) tract cancers that arise due to genetic mutations affect a large number of individuals worldwide. Even though many of the GI tract cancers arise sporadically, few of these GI tract cancers harboring a hereditary predisposition are now recognized and well characterized. These include Cowden syndrome, MUTYH-associated polyposis, hereditary pancreatic cancer, Lynch syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis (FAP), attenuated FAP, serrated polyposis syndrome, and hereditary gastric cancer. Molecular characterization of the genes that are involved in these syndromes was useful in the development of genetic testing for diagnosis and also facilitated understanding of the genetic basis of GI cancers. Current knowledge on the genetics of GI cancers with emphasis on heritability and germ line mutations forms the basis of the present review.

• gastrointestinal cancers
• genetics
• heritability
• mutations

• Osler-Rendu disease
• Smad4 protein
• Smad4-related juvenile polyposis
• epistaxis
• hereditary hemorrhagic telangiectasia
• juvenile polyposis syndrome
• melena

• Adolescent
• Adult
• Aged
• Aorta/metabolism
• Aorta/pathology
• Denmark
• Female
• Gene Expression
• Heterozygote
• Humans
• Intestinal Polyposis/complications
• Intestinal Polyposis/congenital
• Intestinal Polyposis/diagnosis
• Intestinal Polyposis/genetics
• Intestinal Polyposis/surgery
• Male
• Middle Aged
• Mutation
• Neoplastic Syndromes, Hereditary/complications
• Neoplastic Syndromes, Hereditary/diagnosis
• Neoplastic Syndromes, Hereditary/genetics
• Neoplastic Syndromes, Hereditary/surgery
• Phenotype
• Registries
• Retrospective Studies
• Smad4 Protein/genetics
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/diagnosis
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Telangiectasia, Hereditary Hemorrhagic/surgery

• Genetic risks
• Mutations
• Signaling pathways
• Small intestinal adenocarcinoma
• Surveillance

• adenomatous polyposis coli
• colorectal neoplasm
• hereditary
• hereditary nonpolyposis
• neoplastic syndrome

• Cronkhite–Canada syndrome
• Familial adenomatous polyposis
• Gastric cancer
• Gastric polyp
• Hamartomatous polyp
• Juvenile polyposis
• Lynch syndrome
• McCune–Albright syndrome
• Neurofibromatosis type 1
• Peutz–Jeghers
• Polyposis

• Cancer
• Familial
• Hereditary
• Stomach
• Syndromic

• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Genetic Predisposition to Disease
• Humans
• Neoplastic Syndromes, Hereditary/genetics
• Neoplastic Syndromes, Hereditary/prevention & control
• Polyps/genetics
• Polyps/pathology
• Stomach Diseases/genetics
• Stomach Diseases/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/prevention & control

Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer; these mutations are estimated to account for only 5–6 % of colorectal cancer (CRC) cases overall. Up to 25–30 % of patients have a family history of CRC that suggests a hereditary component, common exposures among family members, or a combination of both. Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases. A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer. We describe genetics, current diagnosis and management of CRC hereditary syndromes pointing to a multidisciplinary approach to achieve the best results in patients and family outcomes.

• Adenomatous polyposis
• Colon cancer
• Hereditary colorectal cancer
• Lynch syndrome

• chemotherapy
• colon-specific drug delivery system
• colorectal cancer
• drug delivery system
• systemic drug delivery system

• gastroenterology
• hamartoma syndrome
• intestinal polyposis
• multiple
• pediatrics

• colorectal neoplasm
• genetic variant
• genetic predisposition to disease
• hereditary disease
• next-generation sequencing

• Colorectal Neoplasms/genetics
• Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
• Exome
• Genetic Counseling
• Genetic Predisposition to Disease
• Genetic Variation
• Germ-Line Mutation
• High-Throughput Nucleotide Sequencing
• Humans
• Loss of Heterozygosity
• Male
• Pedigree
• Reproducibility of Results

The development of colorectal cancer (CRC) can be influenced by genetic factors in both familial cases and sporadic cases. Familial CRC has been associated with genetic changes in high-, moderate- and low-penetrance susceptibility genes. However, despite the availability of current gene-identification techniques, the genetic causes of a considerable proportion of hereditary cases remain unknown. Genome-wide association studies of CRC have identified a number of common low-penetrance alleles associated with a slightly increased or decreased risk of CRC. The accumulation of low-risk variants may partly explain the familial risk of CRC, and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes. Understanding the predisposition to develop CRC will require investigators to address the following challenges: the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis; the classification of variants of unknown significance in known CRC-predisposing genes; and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers. We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of low- and moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches. Current challenges and future perspectives in the field of CRC predisposition are also discussed.

• Hereditary colorectal cancer
• Familial colorectal cancer
• High penetrance
• Low penetrance
• Cancer syndromes
• Cancer susceptibility
• Hereditary cancer genes
• Risk variants
• Heritability

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Genetic Predisposition to Disease
• Genetic Variation
• Heredity
• Humans
• Pedigree
• Phenotype
• Prognosis
• Risk Factors

• BMPR1A gene
• SMAD4 gene
• juvenile polyposis
• juvenile polyposis syndrome

Familial juvenile polyposis (FJP) is a rare autosomal dominant hereditary disorder that is characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract and an increased risk of cancer. Recently, germline mutations, including mutations in the SMAD4, BMPR1A, PTEN and, possibly, ENG genes, have been found in patients with juvenile polyps. We herein report a family with juvenile polyposis syndrome (JPS) with a novel germline mutation in the SMAD4 gene. A 21-year-old man presented with rectal bleeding and was found to have multiple polyps in his stomach, small bowel, and colon. His mother had a history of gastrectomy for multiple gastric polyps with anemia and a history of colectomy for colon cancer. A review of the histology of the polyps revealed juvenile polyps in both patients. Subsequently, mutation screening in DNA samples from the patients revealed a germline mutation in the SMAD4 gene. The pair had a novel mutation in exon 10 (stop codon at tyrosine 413). To our knowledge, this mutation has not been previously described. Careful family history collection and genetic screening in JPS patients are needed to identify FJP, and regular surveillance is recommended.

• Exon 10
• Familial juvenile polyposis
• Mutation
• SMAD4

• Lynch syndrome
• Peutz-Jeghers syndrome
• familial adenomatous polyposis

• hamartomatous polyposis
• juvenile polyposis syndrome
• peutz-jeghers syndrome
• cowden syndrome