Gene Summary

Gene:BMPR1A; bone morphogenetic protein receptor type 1A
Aliases: ALK3, SKR5, CD292, ACVRLK3, 10q23del
Summary:The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases that include the type I receptors BMPR1A and BMPR1B and the type II receptor BMPR2. These receptors are also closely related to the activin receptors, ACVR1 and ACVR2. The ligands of these receptors are members of the TGF-beta superfamily. TGF-betas and activins transduce their signals through the formation of heteromeric complexes with 2 different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:bone morphogenetic protein receptor type-1A
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: BMPR1A (cancer-related)

Wang L, Wang H, Wang T, et al.
Analysis of polymorphisms in genes associated with the FA/BRCA pathway in three patients with multiple primary malignant neoplasms.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1101-1112 [PubMed] Related Publications
Cases of more than three primary cancers are very rare. This study analyzed the genetic susceptibility of gene polymorphisms in three patients with multiple primary malignant neoplasms and examined the possible pathogenesis. The clinical data and whole genome sequence of three patients (1 with 5 primary cancers, 1 with 4 primary cancers, and 1 with 3 primary cancers) were aligned with a series of databases. We found the three patients contained a total of seven types of malignant tumours (endometrial cancer, ovarian cancer, breast cancer, colon cancer, ureter cancer, bladder cancer and kidney cancer). It was found that the varied genes in Patient 1 (5 primary cancers) were BRIP1, FANCG, NBN, AXIN2, SRD5A2, and CEBPA. Patient 2 (4 primary cancers) had variations in the following genes: BMPR1A, FANCD2, MLH3, BRCA2, and FANCM. Patient 3 (3 primary cancers) had variations in the following genes: MEN1, ATM, MSH3, BRCA1, FANCL, CEBPA, and FANCA. String software was used to analyze the KEGG pathway of the variations in these three samples, which revealed that the genes are involved in the Fanconi anaemia pathway. Defects in DNA damage repair may be one of the causes of multiple primary cancers.

Thutkawkorapin J, Lindblom A, Tham E
Exome sequencing in 51 early onset non-familial CRC cases.
Mol Genet Genomic Med. 2019; 7(5):e605 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi-allelic autosomal recessive pathogenic variants.
METHODS: The cohort was whole exome sequenced (WES) at 100× coverage. Both a dominant- and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young-onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss-of-function) or allele frequency.
RESULTS: We identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes (BMPR1A, BRIP1, and SRC), three truncating variants in possibly novel cancer genes (CLSPN, SEC24B, SSH2) and four candidate missense variants in ACACA, NR2C2, INPP4A, and DIDO1. We also identify five possible autosomal recessive candidate genes: ATP10B, PKHD1, UGGT2, MYH13, TFF3.
CONCLUSION: Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

Ravegnini G, Quero G, Sammarini G, et al.
Gastrointestinal juvenile-like (inflammatory/hyperplastic) mucosal polyps in neurofibromatosis type 1 with no concurrent genetic or clinical evidence of other syndromes.
Virchows Arch. 2019; 474(2):259-264 [PubMed] Related Publications
Gastrointestinal "juvenile-like (inflammatory/hyperplastic) mucosal polyps" (JLIHMPs) have been proposed as a neurofibromatosis type 1 (NF1)-specific gastrointestinal manifestation. Juvenile polyposis syndrome (JPS) has also been reported in a NF1 patient, harboring concurrent NF1 and SMAD4 germline mutations. Additionally, NF1-like cafe-au-lait spots have been described in biallelic mismatch repair deficiency, another condition featuring gastrointestinal polyps. The SMAD4 and BMPR1A genes that are involved in 50-60% of JPS cases have not been investigated in the ~ 20 published cases of NF1-associated JLIHMPs with the exception of the abovementioned patient with concomitant JPS and NF1. NF1 defects have been found in the only two cases exhaustively tested. Therefore, JLIHMP has been questioned as an independent, NF1-specific entity. Incidental associations between NF1 and gastrointestinal polyposes at risk for gastrointestinal carcinoma should not be overlooked, given their implications in terms of clinical surveillance. We describe two patients featuring JLIHMPs in clinically/genetically proven NF1, in the absence of SMAD4 and BMPR1A mutations. In one case, the intervening mucosa was markedly inflamed, unlike JPS. We suggest that JLIHMP probably represents a gastrointestinal lesion specific to NF1.

Baert-Desurmont S, Coutant S, Charbonnier F, et al.
Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes.
Eur J Hum Genet. 2018; 26(11):1597-1602 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
We have developed and validated for the diagnosis of inherited colorectal cancer (CRC) a massive parallel sequencing strategy based on: (i) fast capture of exonic and intronic sequences from ten genes involved in Mendelian forms of CRC (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, STK11, SMAD4, BMPR1A and PTEN); (ii) sequencing on MiSeq and NextSeq 500 Illumina platforms; (iii) a bioinformatic pipeline that includes BWA-Picard-GATK (Broad Institute) and CASAVA (Illumina) in parallel for mapping and variant calling, Alamut Batch (Interactive BioSoftware) for annotation, CANOES for CNV detection and finally, chimeric reads analysis for the detection of other types of structural variants (SVs). Analysis of 1644 new index cases allowed the identification of 323 patients with class 4 or 5 variants, corresponding to a 20% disease-causing variant detection rate. This rate reached 37% in patients with Lynch syndrome, suspected on the basis of tumour analyses. Thanks to this strategy, we detected overlapping phenotypes (e.g., MUTYH biallelic mutations mimicking Lynch syndrome), mosaic alterations and complex SVs such as a genomic deletion involving the last BMPR1A exons and PTEN, an Alu insertion within MSH2 exon 8 and a mosaic deletion of STK11 exons 3-10. This strategy allows, in a single step, detection of all types of CRC gene alterations including SVs and provides a high disease-causing variant detection rate, thus optimizing the diagnosis of inherited CRC.

Liu Y, Zhang RX, Yuan W, et al.
Knockdown of Bone Morphogenetic Proteins Type 1a Receptor (BMPR1a) in Breast Cancer Cells Protects Bone from Breast Cancer-Induced Osteolysis by Suppressing RANKL Expression.
Cell Physiol Biochem. 2018; 45(5):1759-1771 [PubMed] Related Publications
BACKGROUND/AIMS: Bone morphogenetic proteins (BMPs) and BMP receptors widely participate in osteolytic metastasis of breast cancer, while their role in tumor-stromal interaction is largely unknown. In this study, we investigated whether BMP receptor type 1a (BMPR1a) can alter the interaction between metastatic cancer cells and osteoclast precursors.
METHODS: Adenovirus-mediated RNA interference was used to interrupt target genes of human breast cancer cell lines and nude mice were injected intratibially with the cancer cells. Tumor-bearing mice were examined by bioluminescence imaging and microCT. Sections of metastatic legs were measured by a series of staining methods. Murine bone marrow mononuclear cells or RAW264.7 cells were cultured with conditioned media of breast cancer cells. RT-PCR, Western blotting and ELISA were used to test mRNA and protein expressions of target molecules.
RESULTS: Expression of BMPR1a of MDA-MB-231-luc cells at tumor-bone interface was apparently stronger than that of cancer cells distant from the interface. Mice injected with BMPR1a-knockdown MDA-MB-231-luc cells showed reduced tumor growth and bone destruction compared with control groups. Knockdown (KD) of BMPR1a of MDA-MB-231-luc cells or MCF-7 cells decreased the level of receptor activator for NF-κB ligand (RANKL). Level of RANKL in MDA-MB-231-luc cells or MCF-7 cells was reduced by p38 inhibitor. Compared with control group, knockdown of p38 of breast cancer cells decreased cancer-induced osteoclastogenesis.
CONCLUSION: Knockdown of BMPR1a of breast cancer cells suppresses their production of RANKL via p38 pathway and inhibits cancer-induced osteoclastogenesis, which indicates that BMPR1a might be a possible target in breast cancer-induced osteolytic metastasis.

Nejadtaghi M, Jafari H, Farrokhi E, Samani KG
Familial Colorectal Cancer Type X (FCCTX) and the correlation with various genes-A systematic review.
Curr Probl Cancer. 2017 Nov - Dec; 41(6):388-397 [PubMed] Related Publications
Familial Colorectal Cancer Type X (FCCTX) is a type of hereditary nonpolyposis colorectal cancer in accordance to Amsterdam criteria-1 for Lynch syndrome, with no related mutation in mismatch repair gene. FCCTX is microsatellite stable and is accounted for 40% of families with Amsterdam criteria-1 with a high age of onset. Thus, the carcinogenesis of FCCTX is different compared to Lynch syndrome. In addition to the microsatellite stability and the presence of less predominant tumors in proximal colon, various clinical features have also been associated with FCCTX in comparison with Lynch syndrome such as no increased risk of extra-colonic cancers, older age of diagnosis and higher adenoma/carcinoma rate. Genetic etiology of this type of cancer which is autosomal dominant is unknown. In this review, we focus on the genes and their variants identified in this type of CRC. In order to find out the correlation between FCCTX and various genes database such as PubMed and PMC, search engine such as Google scholar and portals such as Springer and Elsevier have been searched. Based on our literature search, several studies suggest that FCCTX is a heterogeneous type of disease with different genetic variants. Recent studies describe the correlation between FCCTX and genes such as BRCA2, SEMA4, NTS, RASSF9, GALNT12, KRAS, BRAF, APC, BMPR1A, and RPS20. Considering the fact that BRCA2 has the highest mutation rate (60%) and is one of the most crucial DNA repair genes, it will be considered as a big role player in this type of cancer in comparison with other genes.

Achatz MI, Porter CC, Brugières L, et al.
Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood.
Clin Cancer Res. 2017; 23(13):e107-e114 [PubMed] Related Publications
Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (

Evans DR, Green JS, Woods MO
Screening of BMPR1a for pathogenic mutations in familial colorectal cancer type X families from Newfoundland.
Fam Cancer. 2018; 17(2):205-208 [PubMed] Related Publications
The Canadian province of Newfoundland and Labrador (NL) reports one of the highest incidence rates of familial colorectal cancer (CRC) worldwide. The NL population is an invaluable resource for studying genetic disorders because of a unique ancestry, and a willingness to participate in research studies. Familial colorectal cancer type X (FCCTX) describes a cluster of families with strong predisposition for CRC, of unknown etiology. A putative link between FCCTX and BMPR1a mutations has been identified in the Finnish population; however these findings have not been independently replicated. To investigate a potential connection between BMPR1a and FCCTX, we screened a cohort of 22 probands from unrelated NL FCCTX families using Sanger sequencing. This analysis did not independently replicate findings seen in Finland; as no candidate pathogenic BMPR1a mutations were uncovered. Our findings highlight that BMPR1a mutations are not a major contributor of FCCTX incidence in NL. Further investigation of additional FCCTX populations may assist in delineating a role for BMPR1a, if any, in FCCTX globally.

Silva-Smith R, Sussman DA
Co-occurrence of Lynch syndrome and juvenile polyposis syndrome confirmed by multigene panel testing.
Fam Cancer. 2018; 17(1):87-90 [PubMed] Related Publications
Through germline multigene panel testing, we discovered the co-occurrence of Lynch syndrome due to a PMS2 mutation and juvenile polyposis syndrome due to a BMPR1A mutation in a young man with synchronous bladder and colorectal cancers and a family history of colorectal polyps. To our knowledge, this is the first report of an individual having these two hereditary colorectal cancer syndromes. This discovery highlights the benefit of multigene testing over traditional stepwise genetic testing, particularly when a clinical presentation suggests more than one underlying genetic cause. This report adds to the growing body of literature of individuals with multiple inherited cancer gene defects being identified thanks to the increasing implementation of multigene panels with next generation sequencing technologies.

Guaraldi F, Di Nardo G, Tarani L, et al.
Association of autoimmune thyroiditis and celiac disease with Juvenile Polyposis due to 10q23.1q23.31 deletion: Potential role of PI3K/Akt pathway dysregulation.
Eur J Med Genet. 2017; 60(7):380-384 [PubMed] Related Publications
Juvenile Polyposis (JP) is a rare hereditary condition characterized by diffuse hamartomatous gastrointestinal polyposis, associated with a significantly increased risk of neoplastic transformation. Most of the cases are caused by SMAD and BMPR1A mutations, while 10q23 microdeletions, encompassing both PTEN and BMPR1A oncogenes, are extremely rare, typically associated with more aggressive JP, and extraintestinal features overlapping with PTEN Hamartoma Tumor Syndrome. We present the first case of a young female with multiple autoimmune disorders (i.e. thyroiditis and celiac disease), associated with JP, cardiac defects and epilepsy, who carries a de novo heterozygous 10q23.1q23.31 deletion. The dysregulation of the PI3K/Akt pathway is advanced as the putative mechanism connecting autoimmune, malformative and neoplastic disorders. A literature review of clinical manifestation, gene alterations and the treatment of patients with 10q23 deletion is also provided, highlighting the importance of comprehensive, long-term, multi-disciplinary management, aimed at early identification and treatment of both intestinal and extraintestinal disorders.

Hirschhorn T, Levi-Hofman M, Danziger O, et al.
Differential molecular regulation of processing and membrane expression of Type-I BMP receptors: implications for signaling.
Cell Mol Life Sci. 2017; 74(14):2645-2662 [PubMed] Related Publications
The Type-I bone morphogenetic protein receptors (BMPRs), BMPR1A and BMPR1B, present the highest sequence homology among BMPRs, suggestive of functional similitude. However, sequence elements within their extracellular domain, such as signal sequence or N-glycosylation motifs, may result in differential regulation of biosynthetic processing and trafficking and in alterations to receptor function. We show that (i) BMPR1A and the ubiquitous isoform of BMPR1B differed in mode of translocation into the endoplasmic reticulum; and (ii) BMPR1A was N-glycosylated while BMPR1B was not, resulting in greater efficiency of processing and plasma membrane expression of BMPR1A. We further demonstrated the importance of BMPR1A expression and glycosylation in ES-2 ovarian cancer cells, where (i) CRISPR/Cas9-mediated knockout of BMPR1A abrogated BMP2-induced Smad1/5/8 phosphorylation and reduced proliferation of ES-2 cells and (ii) inhibition of N-glycosylation by site-directed mutagenesis, or by tunicamycin or 2-deoxy-D-glucose treatments, reduced biosynthetic processing and plasma membrane expression of BMPR1A and BMP2-induced Smad1/5/8 phosphorylation.

Rohlin A, Rambech E, Kvist A, et al.
Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing.
Fam Cancer. 2017; 16(2):195-203 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.

Sayagués JM, Corchete LA, Gutiérrez ML, et al.
Genomic characterization of liver metastases from colorectal cancer patients.
Oncotarget. 2016; 7(45):72908-72922 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFβ signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.

Zhang L, Wang P, Qin Y, et al.
RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways.
Oncogene. 2017; 36(9):1297-1308 [PubMed] Related Publications
Galectin-3 (Gal-3) has been implicated in pancreatic ductal adenocarcinoma (PDAC), and its candidacy as a therapeutic target has been evaluated. Gal-3 is widely upregulated in tumors, and its expression is associated with the development and malignancy of PDAC. In the present study, we demonstrate that a polysaccharide, RN1, purified from the flower of Panax notoginseng binds to Gal-3 and suppresses its expression. In addition, RN1 markedly inhibits PDAC cells growth in vitro, in vivo and in patient-derived xenografts. Mechanistically, RN1 binds to epidermal growth factor receptor (EGFR) and Gal-3, thereby disrupting the interaction between Gal-3 and EGFR and downregulating extracellular-related kinase (ERK) phosphorylation and the transcription factor of Gal-3, Runx1 expression. Inhibiting the expression of Runx1 by RN1, suppresses Gal-3 expression and inactivates Gal-3-associated signaling pathways, including the EGFR/ERK/Runx1, BMP/smad/Id-3 and integrin/FAK/JNK signaling pathways. In addition, RN1 can also bind to bone morphogenetic protein receptors (BMPR1A and BMPR2) and block the interaction between Gal-3 and the BMPRs. Thus, our results suggest that a novel Gal-3 inhibitor RN1 may be a potential candidate for human PDAC treatment via multiple targets and multiple signaling pathways.

Jelsig AM
Hamartomatous polyps - a clinical and molecular genetic study.
Dan Med J. 2016; 63(8) [PubMed] Related Publications
Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are rare compared to other types of GI polyps, yet they are the most common type of polyp in children. The symptoms are usually rectal bleeding, abdominal pain, obstipation, anaemia, and/or small bowel obstruction. The polyps are typically removed concurrently with endoscopy when located in the colon, rectum, or stomach, whereas polyps in the small bowel are removed during push-enteroscopy, device-assisted enteroscopy, or by surgery. HPs can be classified as juvenile polyps or Peutz-Jeghers polyps based on their histopathological appearance. Patients with one or a few juvenile polyps are usually not offered clinical follow-up as the polyp(s) are considered not to harbour any malignant potential. Nevertheless, it is important to note that juvenile polyps and HPs are also found in patients with hereditary hamartomatous polyposis syndromes (HPS). Patients with HPS have an increased risk of cancer, recurrences of polyps, and extraintestinal complications. The syndromes are important to diagnose, as patients should be offered surveillance from childhood or early adolescence. The syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and the PTEN hamartoma tumour syndrome. Currently, the HPS diagnoses are based on clinical criteria and are often assisted with genetic testing as candidate genes have been described for each syndrome. This thesis is based on six scientific papers. The overall aim of the studies was to expand the knowledge on clinical course and molecular genetics in patients with HPs and HPS, and to investigate research participants' attitude towards the results of extensive genetic testing.   Paper I: In the first paper we investigated the occurrence, anatomic distribution, and other demographics of juvenile polyps in the colon and rectum in Denmark in 1995-2014. Based on the Danish Pathology Data Bank we found that 1772 patients had 2108 JPs examined in the period, and we calculated the incidence of juvenile polyps to be between 1:45,000 and 1:65,000. The majority of patients with juvenile polyps were adults and 1% fulfilled to diagnostic criteria of JPS. The majority of patients had a single juvenile polyp. Paper II: In this paper we conducted a review of the HPS based on the current literature. Paper III: We investigated the hypothesis that patients with one or few HPs may have a HPS based on genetic screening. We de-signed a panel of 26 genes associated with HPS and used targeted next generation sequencing in 77 patients with mainly one juvenile polyp. We detected several germ line variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be classified as definitely pathogenic or likely pathogenic according to our variant classification scheme and thus we concluded that genetic screening of patients with one or few JPs are not indicated. Paper IV: In Paper IV we investigated one of the ethical aspects of next generation sequencing: the issue whether research participants in NGS studies should be offered the possibility of not re-ceiving information on incidental genetic findings (the "opting out possibility"). We conducted semi-structures interviews in 127 research participants, and found that the majority (61%) wanted information on all incidentals findings, while 36% wanted information on actionable incidental findings. Only 3% did not want information on incidental findings at all. Paper V: In this paper we wanted to gather information on all Danish patients with Peutz-Jeghers syndrome in order to investigate the phenotype and genotype. Through Danish registers we detected 43 patients of which 14 had deceased. We calculated the prevalence of Peutz-Jeghers syndrome to be approximately one in 195,000 individuals. The median age at diagnosis was 29 years with obstruction of the small bowel as the most frequent presenting symptom. We noted 18 cancer occurrences in the population in both the GI tract and at extraintestinal sites, demonstrating that these patients are predisposed to cancer at various anatomical sites. The study also underlined the wide phenotypic expression of the syndrome.   Paper VI: In the last paper we identified patients with juvenile polyposis syndrome, who carry a SMAD4 mutation, and described their genotype and phenotype. We especially investigated whether these patients have symptoms of both juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. We identified 14 Danish patients. Most of these had symptoms of both conditions and one had aortic root dilatation. Thus, this group of patients requires a multidisciplinary follow-up program.

Burmester JK, Bell LN, Cross D, et al.
A SMAD4 mutation indicative of juvenile polyposis syndrome in a family previously diagnosed with Menetrier's disease.
Dig Liver Dis. 2016; 48(10):1255-9 [PubMed] Related Publications
BACKGROUND: Menetrier's disease (MD) is a rare disease with unknown aetiology, characterized by hypertrophic folds within the fundus and body of the stomach.
AIMS: We investigated mutations of the candidate genes SMAD4, BMPR1A, TGF-α, and PDX1 within a family with MD.
METHODS: A large 4-generation family with MD was identified. This family had 5 cases of MD, 1 case of MD and juvenile polyposis syndrome (JPS) and 3 cases of JPS. Participants provided saliva for DNA extraction and completed a health questionnaire designed to assess conditions that may be found in patients with MD. Following pedigree analysis, we sequenced the coding regions of the SMAD4 and BMPR1A genes and the regulatory regions of the TGF-α and PDX1 genes in affected and non-affected family members.
RESULTS: No mutations were identified in the sequenced regions of BMPR1A, TGF-α, or PDX1. A dominant 1244_1247delACAG mutation of SMAD4 was identified in each of the subjects with JPS as well as in each of the subjects with MD. Although this mutation segregated with disease, there were also unaffected/undiagnosed carriers.
CONCLUSION: The 1244_1247delACAG mutation of SMAD4 is the cause of JPS and the likely cause of MD in a large family initially diagnosed with MD.

Jelsig AM, Brusgaard K, Hansen TP, et al.
Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps.
Scand J Gastroenterol. 2016; 51(9):1118-25 [PubMed] Related Publications
OBJECTIVE: A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can be detected in a majority of HPS patients. This study investigates whether patients with one or few hamartomatous polyps could have a syndrome based on genetic screening of relevant genes.
METHODS: We designed a gene panel including 26 hamartomatous polyposis-associated genes. Using targeted Next Generation Sequencing, DNA samples from 77 patients with 84 hamartomatous polyps were sequenced. The detected germline variants were classified into pathogenicity classes.
RESULTS: We detected several germline variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be definitely pathogenic or likely pathogenic.
CONCLUSIONS: Our study points towards that genetic testing for the Hamartomatous Polyposis Syndromes in patients with one or few polyps does not improve diagnostics, however we illustrate that the clinical significance of genetic variants can be difficult to interpret. A family history of polyps, cancer, or extraintestinal findings or a minimum of 3-5 polyps seems to be relevant information to include before genetic testing.

Basal E, Ayeni T, Zhang Q, et al.
Patterns of Müllerian Inhibiting Substance Type II and Candidate Type I Receptors in Epithelial Ovarian Cancer.
Curr Mol Med. 2016; 16(3):222-31 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The MIS pathway is a potential therapeutic target in epithelial ovarian cancer (EOC): signaling requires both type II (T2R) and type I receptors (T1R), and results in growth inhibition. MISR2 is expressed in EOC, but the prevalence and relative contributions of candidate T1R remain unknown. We sought to: a) determine expression of T1R in EOC; b) assess impact of T1R expression with clinical outcomes; c) verify MIS-dependent Smad signaling and growth inhibition in primary EOC cell cultures. Tissue microarrays (TMA) were developed for analysis of T1Rs (ALK2/3/6) and MISR2 expression. Primary cell cultures were initiated from ascites harvested at surgery which were used to characterize response to MIS. TMA's from 311 primary cancers demonstrated the most common receptor combinations were: MISR2+/ALK2+3+6+ (36%); MISR2+/ALK2+3+6- (34%); MISR2-/ALK2+3+6- (18%); and MISR2-/ALK2+3+6+ (6.8%). No differences in overall survival (OS) were noted between combinations. The ALK6 receptor was least often expressed T1R and was associated with lower OS in early stage disease only (p =0.03). Most primary cell cultures expressed MISR2 (14/22 (63.6%)): 95% of these express ALK 2 and ALK3, whereas 54.5% expressed ALK6. MIS-dependent Smad phosphorylation was seen in the majority of cultures (75%). Treatment with MIS led to reduced cell viability at an average of 71% (range: 57-87%) in primary cultures. MIS signaling is dependent upon the presence of both MISR2 and specific T1R. In the majority of EOC, the T1R required for MIS-dependent signaling are present and such cells demonstrate appropriate response to MIS.

Chang YC, Chang JG, Liu TC, et al.
Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients.
World J Gastroenterol. 2016; 22(7):2314-25 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
AIM: To investigate the driver gene mutations associated with colorectal cancer (CRC) in the Taiwanese population.
METHODS: In this study, 103 patients with CRC were evaluated. The samples consisted of 66 men and 37 women with a median age of 59 years and an age range of 26-86 years. We used high-resolution melting analysis (HRM) and direct DNA sequencing to characterize the mutations in 13 driver genes of CRC-related pathways. The HRM assays were conducted using the LightCycler® 480 Instrument provided with the software LightCycler® 480 Gene Scanning Software Version 1.5. We also compared the clinicopathological data of CRC patients with the driver gene mutation status.
RESULTS: Of the 103 patients evaluated, 73.79% had mutations in one of the 13 driver genes. We discovered 18 novel mutations in APC, MLH1, MSH2, PMS2, SMAD4 and TP53 that have not been previously reported. Additionally, we found 16 de novo mutations in APC, BMPR1A, MLH1, MSH2, MSH6, MUTYH and PMS2 in cancerous tissues previously reported in the dbSNP database; however, these mutations could not be detected in peripheral blood cells. The APC mutation correlates with lymph node metastasis (34.69% vs 12.96%, P = 0.009) and cancer stage (34.78% vs 14.04%, P = 0.013). No association was observed between other driver gene mutations and clinicopathological features. Furthermore, having two or more driver gene mutations correlates with the degree of lymph node metastasis (42.86% vs 24.07%, P = 0.043).
CONCLUSION: Our findings confirm the importance of 13 CRC-related pathway driver genes in the development of CRC in Taiwanese patients.

Kohda M, Kumamoto K, Eguchi H, et al.
Rapid detection of germline mutations for hereditary gastrointestinal polyposis/cancers using HaloPlex target enrichment and high-throughput sequencing technologies.
Fam Cancer. 2016; 15(4):553-62 [PubMed] Related Publications
Genetic testing for hereditary colorectal polyposis/cancers has become increasingly important. Therefore, the development of a timesaving diagnostic platform is indispensable for clinical practice. We designed and validated target enrichment sequencing for 20 genes implicated in familial gastrointestinal polyposis/cancers in 32 cases with previously confirmed mutations using the HaloPlex enrichment system and MiSeq. We demonstrated that HaloPlex captured the targeted regions with a high efficiency (99.66 % for covered target regions, and 99.998 % for breadth of coverage), and MiSeq achieved a high sequencing accuracy (98.6 % for the concordant rate with SNP arrays). Using this approach, we correctly identified 33/33 (100 %) confirmed alterations including SNV, small INDELs and large deletions, and insertions in APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, PMS2, and SKT11. Our approach yielded the sequences of 20 target genes in a single experiment, and correctly identified all previously known mutations. Our results indicate that our approach successfully detected a wide range of genetic variations in a short turnaround time and with a small sample size for the rapid screening of known causative gene mutations of inherited colon cancer, such as familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, and Juvenile polyposis syndrome.

Pickup MW, Hover LD, Guo Y, et al.
Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis.
Oncotarget. 2015; 6(26):22890-904 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) family. BMP ligands have been shown to be overexpressed in human breast cancers. Normal and cancerous breast tissue display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyMT oncogene with mice having conditional knockout (cKO) of BMP receptor type 1a (BMPR1a) using whey acidic protein (WAP)-Cre and found this deletion resulted in delayed tumor onset and significantly extended survival. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicates that epithelial-to-mesenchymal (EMT)-like transitions occurred in cKO tumors. We performed microarray analysis on these tumors and found changes that support EMT-like changes. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and in vivo upon implantation. cKO tumor cells had reduced migration in vitro. We analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions, and found that high BMPR1a gene expression correlates with decreased survival regardless of molecular breast cancer subtype. In conclusion, the data indicate that BMP signaling through BMPR1a functions as a tumor promoter.

Hover LD, Young CD, Bhola NE, et al.
Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.
Cancer Lett. 2015; 368(1):79-87 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.

Blatter RH, Plasilova M, Wenzel F, et al.
Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers.
Genes Chromosomes Cancer. 2015; 54(9):575-82 [PubMed] Related Publications
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.

Tomlinson I
The Mendelian colorectal cancer syndromes.
Ann Clin Biochem. 2015; 52(Pt 6):690-2 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes, have been central to our understanding of colorectal carcinogenesis in general. Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. Major functional pathways are consistently inactivated in the Mendelian CRC syndromes: certain types of DNA repair (proofreading of DNA replication errors, mismatch repair and base excision repair) and signalling (bone morphogenetic protein (BMP), Wnt signalling and mTOR). The inheritance of the CRC syndromes also varies: most are dominant but some of the DNA repair deficiencies are recessive. Some of the Mendelian CRC genes are especially important because they play a role through somatic inactivation in sporadic CRC (APC, MLH1, SMAD4, POLE). Additional Mendelian CRC genes may remain to be discovered and searches for these genes are ongoing, especially in patients with multiple adenomas and hyperplastic polyps.

Soer E, de Vos Tot Nederveen Cappel WH, Ligtenberg MJ, et al.
Massive gastric polyposis associated with a germline SMAD4 gene mutation.
Fam Cancer. 2015; 14(4):569-73 [PubMed] Related Publications
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. Polyps are most common in the colorectum (98% of patients) and the stomach (14%). Causative mutations for JPS have been identified in two genes to date, SMAD4 and BMPR1A. SMAD4 mutations are associated with a higher incidence of gastric polyposis. In this case report, we describe two patients with massive gastric polyposis associated with a SMAD4 mutation. Both presented with anaemia and both had colonic polyps. Initial endoscopic findings revealed giant rugal folds suggestive of Ménétrier disease. However, as other possible gastropathies could not be differentiated on the basis of histology, a definitive diagnosis of JPS required additional mutation analysis. In patients with polyposis predominant in or limited to the stomach, establishing a diagnosis based solely on the pathological features of polyps can be challenging due to difficulties in differentiating JPS from other hypertrophic gastropathies. Mutation analysis should be considered early in the diagnostic process in cases of suspected juvenile polyposis, thus facilitating rapid diagnosis and adequate follow-up.

Alimi A, Weeth-Feinstein LA, Stettner A, et al.
Overlap of Juvenile polyposis syndrome and Cowden syndrome due to de novo chromosome 10 deletion involving BMPR1A and PTEN: implications for treatment and surveillance.
Am J Med Genet A. 2015; 167(6):1305-8 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
We describe a patient with a severe juvenile polyposis phenotype, due to a de novo deletion of chromosome 10q22.3-q24.1. He was initially diagnosed with Juvenile polyposis syndrome (JPS) at age four after presenting with hematochezia due to multiple colonic juvenile polyps. He then re-presented at 23 years with recurrent hematochezia from juvenile polyps in his ileoanal pouch. He is one of the earliest reported cases of JPS associated with a large deletion of chromosome 10. Since his initial diagnosis of JPS further studies have confirmed an association between JPS and mutations in BMPR1A in chromosome band 10q23.2, which is in close proximity to PTEN. Mutations in PTEN cause Cowden syndrome (CS) and other PTEN hamartoma tumor syndromes. Due to the chromosome 10 deletion involving contiguous portions of BMPR1A and PTEN in our patient, he may be at risk for CS associated cancers and features, in addition to the polyps associated with JPS. This case presents new challenges in developing appropriate surveillance algorithms to account for the risks associated with each syndrome and highlights the importance of longitudinal follow-up and transitional care between pediatric and adult gastroenterology for patients with hereditary polyposis syndromes.

Chubb D, Broderick P, Frampton M, et al.
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.
J Clin Oncol. 2015; 33(5):426-32 [PubMed] Related Publications
PURPOSE: Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families.
PATIENTS AND METHODS: To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk.
RESULTS: Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2).
CONCLUSION: A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes.

Aytac E, Sulu B, Heald B, et al.
Genotype-defined cancer risk in juvenile polyposis syndrome.
Br J Surg. 2015; 102(1):114-8 [PubMed] Related Publications
BACKGROUND: Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor β signal transduction pathway, and are associated with juvenile polyposis syndrome. The effect of genotype on the pattern of disease in this syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with juvenile polyposis syndrome.
METHODS: Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed.
RESULTS: Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with juvenile polyposis syndrome and a SMAD4 mutation was 11 per cent (3 of 27).
CONCLUSION: The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in juvenile polyposis syndrome.

Kotoula V, Bobos M, Vassilakopoulou M, et al.
Intact or broken-apart RNA: an alternative concept for ALK fusion screening in non-small cell lung cancer (NSCLC).
Appl Immunohistochem Mol Morphol. 2015; 23(1):60-70 [PubMed] Related Publications
Anaplastic lymphoma kinase (ALK) break-apart fluorescent in situ hybridization (FISH) is currently used in diagnostics for the selection of non-small cell lung cancer (NSCLC) patients to receive crizotinib. We evaluated ALK status in NSCLC with a novel ALK mRNA test based on the break-apart FISH concept, which we called break-apart transcript (BAT) test. ALK5' and ALK3' transcript patterns were established with qPCR for ALK-expressing controls including fusion-negative neuroblastomas, as well as fusion-positive anaplastic large cell lymphomas and NSCLC. The BAT test was evaluated on 271 RNA samples from routinely processed paraffin NSCLC tissues. Test results were compared with ALK FISH (n=121), immunohistochemical (IHC) analysis (n=86), and automated quantitative analysis (AQUA, n=83). On the basis of the nonoverlapping ALK BAT patterns in ALK-expressing controls (P<0.0001), 8/174 adenocarcinomas (4.6%) among 259 informative NSCLC were predicted as fusion positive. Overall concordance for paired method results was high (94.1% to 98.8%) but mainly concerned negative prediction because of the limited availability of positive-matched cases. Tumors with 100% cytoplasmic IHC staining of any intensity (n=3) were positive for AQUA, FISH, and BAT test; tumors with lower IHC positivity and different staining patterns were AQUA-negative. Upon multiple reevaluations, ALK gene status was considered as originally misinterpreted by FISH in 3/121 cases (2.5%). Tumors with >4 ALK gene copies were associated with longer overall survival upon first-line chemotherapy. In conclusion, application of the ALK BAT test on routinely processed NSCLC tissues yields the same fusion partner independent information as ALK break-apart FISH but is more robust and cost-effective. The BAT concept may be considered for the development of further drug-predictive translocation tests.

Yamaguchi J, Nagayama S, Chino A, et al.
Identification of coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome.
Jpn J Clin Oncol. 2014; 44(10):1004-8 [PubMed] Related Publications
Juvenile polyposis syndrome is an autosomal dominant inherited disorder characterized by multiple juvenile polyps arising in the gastrointestinal tract and an increased risk of gastrointestinal cancers, specifically colon cancer. BMPR1A and SMAD4 germline mutations have been found in patients with juvenile polyposis syndrome. We identified a BMPR1A mutation, which involves a duplication of coding exon 3 (c.230+452_333+441dup1995), on multiple ligation dependent probe amplification in a patient with juvenile polyposis syndrome. The mutation causes a frameshift, producing a truncated protein (p.D112NfsX2). Therefore, the mutation is believed to be pathogenic. We also identified a duplication breakpoint in which Alu sequences are located. These results suggest that the duplication event resulted from recombination between Alu sequences. To our knowledge, partial duplication in the BMPR1A gene has not been reported previously. This is the first case report to document coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome.

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