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9 páginas, 4 figuras, 1 tabla.-- El pdf del artículo es la versión pre-print.-- et al., The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement., This study was supported by Ministério da Saúde (Project N8 15/2007) and Liga Portuguesa Contra o Cancro. IPATIMUP was funded by Fundaçáo para a Ciência e Tecnologia, through POCI (Programa Operacional Ciència e Inovaçáo 2010). MT and WDF are supported by the Susan G. Komen Foundation for the Cure, the Jewish General Hospital Weekend to End Breast Cancer and the Fonds de la Recherche en Santé du Québec. EAV and MD are supported by grants PI061102 (Ministerio de Ciencia e Innovación) and 200820I135 (CSIC).

Kabuki syndrome (KS, OMIM 147920), also known as Kabuki make-up syndrome or Niikawa–Kuroki syndrome, is a multiple congenital anomaly/mental retardation syndrome of hitherto unknown cause [Wessels et al., 2002; Matsumoto and Niikawa, 2003]. The prevalence in the Japanese population has been estimated to be 1/32,000, and 1/86,000 in Australia and New Zealand [Adam and Hudgins, 2005]. Its complex phenotype combines characteristic facial features with dermatoglyphic, skeletal, and visceral anomalies, postnatal growth retardation and mental retardation. The single most striking feature that prompts clinical diagnosis is the particular facial appearance. Several lines of evidence point to a genetic etiology of KS, with a presumably autosomal dominant mode of inheritance [Adam and Hudgins, 2005; Armstrong et al., 2005]. Until recently, although numerous cytogenetic anomalies were identified in KS, no single abnormality was found repeatedly [Adam and Hudgins, 2005]. A number of studies [Hoffman et al., 2005; Sanlaville et al., 2005; Schoumans et al., 2005; Turner et al., 2005] questioned the potential role of a 8p microduplication, initially described in 6 unrelated patients with KS [Milunsky and Huang, 2003]. Candidate gene approaches have as yet not been undertaken to challenge the genetic etiology of KS. Based on the following reasoning, we hypothesized that the transforming growth factor b receptor (TGFBR)1 and TGFBR2 pathway might explain some of the phenotypic complexity observed in KS. TGFBR1 and TGFBR2 mutations have recently been shown to cause a disorder related to Marfan syndrome (Loeys-Dietz aneurysm syndrome or LDAS), featuring characteristic craniofacial, cardiovascular, skeletal anomalies, and developmental delay [Loeys et al., 2005]. Some of the key features of this new syndrome are also frequently present in KS patients, notably skeletal anomalies such as joint laxity and scoliosis, cleft palate and abnormal dentition, blue sclerae, heart anomalies, and finally developmental delay. In support of our reasoning, it was suggested that the interferon regulatory factor (IRF)-6 pathway could be implicated in KS [Armstrong et al., 2005]. The rationale behind this was that some overlapping features exist between KS and disorders caused by IRF-6 mutations, such as the Van der Woude syndrome (VWS) and the popliteal pterygium syndrome (PPS) [Kondo et al., 2002]. All IRFs including IRF-6 have a domain that interacts with obligatory components of the TGFBR-induced response named Smads [Moustakas and Heldin, 2003]. This so called Smad-IRF (SMIR) domain is a mutational hotspot in VWS and PPS [Kondo et al., 2002]. Therefore, biochemical and genetic interactions link the TGFBR1/TGFBR2with the IRF-6 pathway, such that impaired TGFBR-mediated signaling could also result in reduced IRF-6 function [Qing et al., 2004]. Since typical LDAS malformations such as aorta aneurysms are rare ( 1/62) in KS patients [Niikawa et al., 1988], we expected a different mutational mechanism, for instance partial loss of function mutations, insertions or deletions in TGFBR1/2. Based on these grounds, we screened 14 typical Kabuki patients for mutations in the coding region and adjacent splice sites, and for intragenic insertions

Epigenetic modifications such as methylation of CpG islands in tumor-suppressor gene promoter regions have been associated with tumor development in many human cancers. Using methylation specific multiplex ligation-dependent probe amplification method, we analyzed the methylation status of 35 different genes in 16 neuroblastoma (NB) cell lines and 50 NB tumor samples (NBs), and investigated whether specific hypermethylation was associated with biological and/or clinical parameters. Among the genes found hypermethylated, the effect of GSTP1 hypermethylation on mRNA and protein expression was also explored. The median number of hypermethylated genes was higher in cell lines compared to NBs (5.5 vs. 2). For eight genes, aberrant methylation of CpG-islands in NB was not (ESR1, PAX5, WT1, CADM1, MSH6, and CDKN2B) or very rarely (CDH13 and GSTP1) reported in literature. GSTP1 was found hypermethylated in 44% of the NB cell lines and in 33% of the stage 4-11qLOH -non MYCN-amplified high risk NBs. Hypermethylation was correlated with reduced mRNA and protein expression. In the whole NBs cohort, GSTP1 hypermethylation was less frequently detected (8%), but found to be associated with lower event-free (EFS) and overall survival. Hypermethylation of GSTP1 showed also association with lower EFS in high risk subgroups as stage 4 and older patients (≥547 days). Our results suggest that, as in several adult cancers, aberrant methylation of GSTP1 may contribute to the carcinogenetic process in NB and could be potentially used as a new marker leading to define an ultra-high risk subgroup.

Armand Bottani, Jamel Chelly, Arjan P.M. de Brouwer, Bruno Pardo, Mandy Barker, Valeria Capra, Lucia Bartoloni, Stylianos E. Antonarakis, and Bernard Conrad* Department of Genetic Medicine and Development, Geneva University Medical School and University Hospitals, Geneva, Switzerland Institut Cochin, Departement de Genetique et Pathologie Moleculaire, Equipe de Genetique et Physiopathologie des Retards Mentaux, rue du Faubourg St Jacques, Paris, France Department of Human Genetics 417, University Medical Center Nijmegen, St. Radboud, HB Nijmegen, The Netherlands U.O. Neurochirurgia, Istituto Scientifico Giannina Gaslini, Genova, Italy Division of Human Genetics and Cytogenetics, Bern University Children’s Hospital, Bern, Switzerland