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SCOPUS: no.j, info:eu-repo/semantics/published

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 TGS, 152 RNA-Seq, 67 SNP Arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA and RB1 mutations; MDM4, MYC amplifications; ARID1A deletions. An increase in clonality was observed in driver genes like ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-Enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune permissive cells. High TMB correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could impact treatment strategies in MBC., SCOPUS: ar.j, info:eu-repo/semantics/published

Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data.

Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data., info:eu-repo/semantics/published

Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. Results of high-throughput molecular profiling studies have subsequently revealed the true extent of this heterogeneity. Further complicating this scenario, the heterogeneous expression of the oestrogen receptor (ER), progesterone receptor (PR), and HER2 has been reported in different areas of the same tumour. Furthermore, discordance, in terms of ER, PR and HER2 expression, has also been reported between primary tumours and their matched metastatic lesions. High-throughput molecular profiling studies have confirmed that spatial and temporal intratumour heterogeneity of breast cancers exist at a level beyond common expectations. We describe the different levels of tumour heterogeneity, and discuss the strategies that can be adopted by clinicians to tackle treatment response and resistance issues associated with such heterogeneity, including a rationally selected combination of agents that target driver mutations, the targeting of deleterious passenger mutations, identifying and eradicating the 'lethal' clone, targeting the tumour microenvironment, or using adaptive treatments and immunotherapy. The identification of the most-appropriate strategies and their implementation in the clinic will prove highly challenging and necessitate the adoption of radically new practices for the optimal clinical management of breast malignancies., SCOPUS: re.j, info:eu-repo/semantics/published

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients., SCOPUS: re.j, info:eu-repo/semantics/published

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients., SCOPUS: re.j, info:eu-repo/semantics/published

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Lymphedema is caused by dysfunction of lymphatic vessels, leading to disabling swelling that occurs mostly on the extremities. Lymphedema can be either primary (congenital) or secondary (acquired). Familial primary lymphedema commonly segregates in an autosomal dominant or recessive manner. It can also occur in combination with other clinical features. Nine mutated genes have been identified in different isolated or syndromic forms of lymphedema. However, the prevalence of primary lymphedema that can be explained by these genetic alterations is unknown. In this study, we investigated 7 of these putative genes. We screened 78 index patients from families with inherited lymphedema for mutations in FLT4, GJC2, FOXC2, SOX18, GATA2, CCBE1, and PTPN14. Altogether, we discovered 28 mutations explaining 36% of the cases. Additionally, 149 patients with sporadic primary lymphedema were screened for FLT4, FOXC2, SOX18, CCBE1, and PTPN14. Twelve mutations were found that explain 8% of the cases. Still unidentified is the genetic cause of primary lymphedema in 64% of patients with a family history and 92% of sporadic cases. Identification of those genes is important for understanding of etiopathogenesis, stratification of treatments and generation of disease models. Interestingly, most of the proteins that are encoded by the genes mutated in primary lymphedema seem to act in a single functional pathway involving VEGFR3 signaling. This underscores the important role this pathway plays in lymphatic development and function and suggests that the unknown genes also have a role.

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Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor beta. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.

Venous malformations are the most frequent vascular anomalies among patients in specialized centers, characterized by localized bluish lesions in the skin and the mucosae. While these are predominantly sporadic in nature, 1 to 2% occur as an autosomal dominantly inherited trait termed cutaneomucosal venous malformation (VMCM). The angiopoeitin receptor TIE2 has been identified as the causative gene for VMCM in five families. In each family, one of two specific substitutions (R849W or Y897S) in the kinase domain of TIE2 co-segregates with the disorder. These mutations result in increased ligand-independant phosphorylation of the receptor, and altered downstream signaling. Here, we studied twelve new families with VMCM: six bear the R849W substitution, five have a novel mutation in the tyrosine kinase domain and one in the carboxy-terminal end of the receptor. Overexpression of each of these mutants in COS-7 cells resulted in ligand independent hyper-phosphorylation of the receptor, suggesting that this is a general feature of VMCM-causing TIE2 mutations. Interestingly, we also discovered a somatic deletion in a resected VM tissue sample from one patient with the inherited R849W mutation. This somatic alteration partially deletes the ligand binding domain of the receptor in the allele that does not bear the R849W mutation. This is the first report of a double-hit mutation in VMCM. Moreover, we demonstrate that the somatic deletion does not result in hyper-phosphorylation, nor does it cause an increase in the phosphorylation of the R849W allele. Thus, this deletion rather seems to cause an elimination of the wild-type allele that is able to protect from the deleterious effects of the mutant, inherited allele. In conclusion, the focal development of VMCM is likely due to the combination of various predisposing germline mutations that cause hyperphosphorylation of the receptor, and a somatic second-hit, hallmarks of paradominant inheritance. (miikka.vikkula@uclouvain.be)

Venous malformations are the most frequent vascular anomalies among patients in specialized centers, characterized by localized bluish lesions in the skin and the mucosae. While these are predominantly sporadic in nature, 1 to 2% occur as an autosomal dominantly inherited trait termed cutaneomucosal venous malformation (VMCM). The angiopoeitin receptor TIE2 has been identified as the causative gene for VMCM in five families. In each family, one of two specific substitutions (R849W or Y897S) in the kinase domain of TIE2 co-segregates with the disorder. These mutations result in increased ligand-independant phosphorylation of the receptor, and altered downstream signaling. Here, we studied twelve new families with VMCM: six bear the R849W substitution, five have a novel mutation in the tyrosine kinase domain and one in the carboxy-terminal end of the receptor. Overexpression of each of these mutants in COS-7 cells resulted in ligand independent hyper-phosphorylation of the receptor, suggesting that this is a general feature of VMCM-causing TIE2 mutations. Interestingly, we also discovered a somatic deletion in a resected VM tissue sample from one patient with the inherited R849W mutation. This somatic alteration partially deletes the ligand binding domain of the receptor in the allele that does not bear the R849W mutation. This is the first report of a double-hit mutation in VMCM. Moreover, we demonstrate that the somatic deletion does not result in hyper-phosphorylation, nor does it cause an increase in the phosphorylation of the R849W allele. Thus, this deletion rather seems to cause an elimination of the wild-type allele that is able to protect from the deleterious effects of the mutant, inherited allele. In conclusion, the focal development of VMCM is likely due to the combination of various predisposing germline mutations that cause hyperphosphorylation of the receptor, and a somatic second-hit, hallmarks of paradominant inheritance. (miikka.vikkula@uclouvain.be)

Item does not contain fulltext, Hereditary lymphedema is a developmental disorder characterized by chronic swelling of the extremities due to dysfunction of the lymphatic vessels. Two responsible genes have been identified: the vascular endothelial growth factor receptor 3 (VEGFR3) gene, implicated in congenital lymphedema, or Milroy disease, and the forkhead-related transcription factor gene FOXC2, causing lymphedema-distichiasis. We describe three families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. Using microsatellite analysis, we first excluded both VEGFR3 and FOXC2 as causative genes; we then considered the murine ragged phenotype, caused by mutations in the Sox18 transcription factor, as a likely counterpart to the human disease, because it presents a combination of hair and cardiovascular anomalies, including symptoms of lymphatic dysfunction. Two of the families were consanguineous; in affected members of these families, we identified homozygous missense mutations in the SOX18 gene, located in 20q13. The two amino acid substitutions, W95R and A104P, affect conserved residues in the first alpha helix of the DNA-binding domain of the transcription factor. In the third family, the parents were nonconsanguineous, and both the affected child and his brother, who died in utero with hydrops fetalis, showed a heterozygous nonsense mutation that truncates the SOX18 protein in its transactivation domain; this substitution was not found in genomic DNA from either parent and hence constitutes a de novo germline mutation. Thus, we show that SOX18 mutations in humans cause both recessive and dominant hypotrichosis-lymphedema-telangiectasia, suggesting that, in addition to its established role in hair and blood vessel development, the SOX18 transcription factor plays a role in the development and/or maintenance of lymphatic vessels.

Hereditary lymphedema is a developmental disorder characterized by chronic swelling of the extremities due to dysfunction of the lymphatic vessels. Two responsible genes have been identified: the vascular endothelial growth factor receptor 3 (VEGFR3) gene, implicated in congenital lymphedema, or Milroy disease, and the forkhead-related transcription factor gene FOXC2, causing lymphedema-distichiasis. We describe three families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. Using microsatellite analysis, we first excluded both VEGFR3 and FOXC2 as causative genes; we then considered the murine ragged phenotype, caused by mutations in the Sox18 transcription factor, as a likely counterpart to the human disease, because it presents a combination of hair and cardiovascular anomalies, including symptoms of lymphatic dysfunction. Two of the families were consanguineous; in affected members of these families, we identified homozygous missense mutations in the SOX18 gene, located in 20q13. The two amino acid substitutions, W95R and A104P, affect conserved residues in the first alpha helix of the DNA-binding domain of the transcription factor. In the third family, the parents were nonconsanguineous, and both the affected child and his brother, who died in utero with hydrops fetalis, showed a heterozygous nonsense mutation that truncates the SOX18 protein in its transactivation domain; this substitution was not found in genomic DNA from either parent and hence constitutes a de novo germline mutation. Thus, we show that SOX18 mutations in humans cause both recessive and dominant hypotrichosis-lymphedema-telangiectasia, suggesting that, in addition to its established role in hair and blood vessel development, the SOX18 transcription factor plays a role in the development and/or maintenance of lymphatic vessels.

Le lymphœdème est un œdème chronique dû à une déficience du système lymphatique. La maladie s’aggrave avec le temps et provoque chez les patients des souffrances psychologiques, de l’inconfort, des problèmes de mobilité et des risques accrus d’infection. Selon l’origine de la maladie, on classe les lymphœdèmes en lymphœdèmes primaires, causés par un défaut intrinsèque des voies lymphatiques, et en lymphœdèmes secondaires, résultant de l’obstruction ou de l’altération de ces voies, suite à une parasitose, un accident ou un acte chirurgical dans le traitement d’un cancer. Certaines formes de lymphœdèmes primaires sont familiales, comme le lymphœdème précoce ou maladie de Milroy, le lymphœdème tardif ou maladie de Meige, ou encore certaines formes syndromiques. L’existence de ces formes héréditaires permet d’utiliser les outils de la génétique moléculaire humaine pour tenter d’identifier les gènes responsables. Avant le début de ma thèse, des études de liaison avaient permis l’identification d’un locus pour le lymphœdème précoce héréditaire dans la bande q35 du chromosome 5. L’examen des gènes présents dans l’intervalle révèle la présence d’un excellent candidat, codant le « vascular endothelial growth factor receptor 3 » (VEGFR3). Dans l’embryon de souris, l’expression de ce récepteur tyrosine kinase est observée d’abord dans l’ensemble du système vasculaire, mais, vers le milieu de la gestation, elle devient limitée aux vaisseaux lymphatiques. En outre, la surexpression dans la peau du ligand activateur de ce récepteur, le « vascular endothelial growth factor C » (Vegfc), induit l’hypertrophie des vaisseaux lymphatiques chez la souris. Le gènes VEGFR2 avait déjà été criblé par les auteurs de l’étude de liaison, sans qu’une preuve définitive de son implication ne soit apportée. Nous avons donc entrepris l’étude d’une famille présentant la maladie pour tenter de clarifier cette situation. La famille présentait une liaison avec la région chromosomique 5q35, con, Lymphedema is a chronic swelling of tissues due to inadequate interstitial fluid drainage by the lymphatic system. The disease aggravates with time and leads to psychosocial discomfort, disability and increased risk of infection. Depending on the origin of the disease, lymphedema is classified as either primary lymphedema, caused by an intrinsic defect of the lymphatic system, or secondary lymphedema, where the lymphatic pathways are obstructed, damaged or even removed, because of parasitic disease, trauma or anti-cancer therapy. Some forms of primary lymphedema are familial, including early-onset lymphedema or Milroy's disease, puberty-onset lymphedema or Meige's disease, and syndromic forms where lymphedema is observed in association with other abnormalities. The existence of these hereditary forms allows the techniques of molecular genetics to be used for the identification of the causative genes. Before the beginning of my thesis, a locus for early-onset lymphedema had been mapped to chromosome 5q35 using linkage analyses. Examination of the genes in the linked interval revealed the presence of a promising candidate gene, encoding the vascular endothelial growth factor receptor 3 (VEGFR3). Previous studies had shown that, in the murine embryo, the expression of this receptor tyrosine kinase (RTK) is initially observed in the whole vascular system, but from about mid-gestation it becomes restricted to the lymphatic system. Moreover, when the activating ligand of this receptor, the vascular endothelial growth factor C, is over-expressed in the skin of a transgenic mouse, hyperplasic lymphatic vessels are observed. VEGFR3 was screened by the authors of the linkage analysis, but no indisputable proof of its involvement in the disease was obtained. To clarify the implication of VEGFR3 in early-onset hereditary lymphedema, we undertook the study of one family with this disorder. The family was linked to 5q35, confirming the locus, and the portion of the gene correspon, Thèse de doctorat en sciences biomédicales (SBIM 3) -- UCL, 2003

Item does not contain fulltext, Hereditary lymphedema is a developmental disorder characterized by chronic swelling of the extremities due to dysfunction of the lymphatic vessels. Two responsible genes have been identified: the vascular endothelial growth factor receptor 3 (VEGFR3) gene, implicated in congenital lymphedema, or Milroy disease, and the forkhead-related transcription factor gene FOXC2, causing lymphedema-distichiasis. We describe three families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. Using microsatellite analysis, we first excluded both VEGFR3 and FOXC2 as causative genes; we then considered the murine ragged phenotype, caused by mutations in the Sox18 transcription factor, as a likely counterpart to the human disease, because it presents a combination of hair and cardiovascular anomalies, including symptoms of lymphatic dysfunction. Two of the families were consanguineous; in affected members of these families, we identified homozygous missense mutations in the SOX18 gene, located in 20q13. The two amino acid substitutions, W95R and A104P, affect conserved residues in the first alpha helix of the DNA-binding domain of the transcription factor. In the third family, the parents were nonconsanguineous, and both the affected child and his brother, who died in utero with hydrops fetalis, showed a heterozygous nonsense mutation that truncates the SOX18 protein in its transactivation domain; this substitution was not found in genomic DNA from either parent and hence constitutes a de novo germline mutation. Thus, we show that SOX18 mutations in humans cause both recessive and dominant hypotrichosis-lymphedema-telangiectasia, suggesting that, in addition to its established role in hair and blood vessel development, the SOX18 transcription factor plays a role in the development and/or maintenance of lymphatic vessels.

Venous malformations with glomus cells are localised cutaneous lesions of vascular dysmorphogenesis. They are usually sporadic, but sometimes familial. Using five families, we mapped the locus, VMGLOM, to chromosome 1p21-p22. In order to refine this locus, spanning 4-6 Mbp, we then studied seven additional families. They exhibited linkage to VMGLOM and the combined lod score for all 12 families was 18.41 at theta = 0.0 for marker D1S188. We found a distinct haplotype shared by seven families, comprising seven alleles which are rare in the general population (P < 0.01). This indicates that the haplotype is identical by descent in all seven families, and hence the locus can be refined by inferring ancestral crossovers. Using this approach, we position the causative gene between two markers on the same non-chimeric YAC of 1.48 Mbp, a feasible size for positional cloning. As there is no known gene involved in vasculogenesis and/or angiogenesis in this YAC, the identification of the causative gene is likely to reveal a novel regulator or vascular development.

Hereditary lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, also known as "Milroy disease," has been mapped to the telomeric part of chromosome 5q, in the region 5q34-q35. This region contains a good candidate gene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiology of the disease, we have analyzed a family with hereditary lymphedema. We show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegregates with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro expression, that this mutation inhibits the autophosphorylation of the receptor. Thus, defective VEGFR3 signaling seems to be the cause of congenital hereditary lymphedema linked to 5q34-q35.

Venous malformations (VMs) are localized defects of vascular morphogenesis. They can occur in every organ system, most commonly in skin and muscle. They can cause pain and bleeding, and in some critical locations they can be life threatening. Usually venous anomalies occur sporadically, but families with dominant inheritance have been identified. Using linkage analysis, we have established in earlier reports that some families with inherited VMs show linkage to chromosome 9p21; the mutation causes ligand-independent activation of an endothelial cell-specific receptor tyrosine kinase, TIE-2. Here we show that VMs with glomus cells (known as "glomangiomas"), inherited as an autosomal dominant trait in five families, are not linked to 9p21 but, instead, link to a new locus, on 1p21-p22, called "VMGLOM" (LOD score 12.70 at recombination fraction.00). We exclude three known positional candidate genes, DR1 (depressor of transcription 1), TGFBR3 (transforming growth factor-beta receptor, type 3), and TFA (tissue factor). We hypothesize that cutaneous venous anomalies (i.e., glomangiomas) are caused by mutations in a novel gene that may act to regulate angiogenesis, in concert with the TIE-2 signaling pathway.