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Qiryat Shemona, Israel

Palmi C.,University of Milan Bicocca | Vendramini E.,University of Padua | Silvestri D.,University of Milan Bicocca | Longinotti G.,University of Milan Bicocca | And 19 more authors.
Leukemia | Year: 2012

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (≥20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2+ patients in the IR group was high (61.1%±12.9 vs 17.6%±2.6, P<0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification. © 2012 Macmillan Publishers Limited. Source


Sagi M.,Hebrew University of Jerusalem | Eilat A.,Hebrew University of Jerusalem | Ben Avi L.,Hebrew University of Jerusalem | Goldberg Y.,Hebrew University of Jerusalem | And 5 more authors.
Familial Cancer | Year: 2011

Founder mutations in BRCA1/2 genes have been detected in several Jewish communities in Israel, including in Ashkenazi Jews and Jews who immigrated to Israel from Iraq, Yemen, Iran and Afghanistan. We analyzed DNA samples of patients of Sephardic origin (descendents of Jews from the Iberian Peninsula) with breast cancer (BC) and/or ovarian cancer (OC) and additional family history of these cancers. In this study we identified 2 mutations: p.A1708E in BRCA1 and c.67 + 1G > A (IVS2 + 1G > A) in BRCA2, each in 3 unrelated patients. The frequency of the two mutations was 26-31% among Sephardic high risk families and about 3% among the full cohort of 177 patients of this origin who were tested in our center. Based on haplotype analysis we concluded that these mutations are most probably founder mutations in Sephardic Jews. We recommend testing the two mutations in women of Sephardic origin who apply for BRCA testing because of personal and/or family history of BC and/or OC. Furthermore, we suggest adding them to the 5 mutations included in "The Jewish panel" of BRCA1/2 mutations that are being tested in Israel. © 2010 Springer Science+Business Media B.V. Source


Rosner G.,Tel Aviv Sourasky Medical Center | Rosner G.,Tel Aviv University | Bercovich D.,Migal Galilee Bio Technology Center | Bercovich D.,Tel-Hai Academic College | And 12 more authors.
Familial Cancer | Year: 2015

Bi-allelic MUTYH gene mutations are associated with a clinical phenotype of multiple colorectal adenomas and an increased risk for colorectal cancer (CRC). It is unclear whether mono-allelic MUTYH gene carriers (heterozygotes) are also at increased risk for even few adenomas or cancer. In order to clarify an association between MUTYH heterozygotes and adenomas, we evaluated the frequency and types of MUTYH mutations and variants in 72 North-African Jews having few (≥3) colorectal adenomas with or without early onset (<50 years) CRC compared to 29 healthy controls. Germ-line DNA was analyzed for a panel of 6 MUTYH mutations and variants, and Sanger sequencing of the entire MUTYH gene was performed for mono-allelic MUTYH mutation carriers. APC gene mutations and Lynch syndrome were excluded in the relevant cases according to accepted clinical criteria. Twenty-two of the 72 adenoma subjects (30.5 %) had MUTYH mutations or variants. Nine were homozygotes or compound heterozygotes: all had >10 adenomas and one had CRC. Thirteen others were mono-allelic carriers (heterozygotes) of a single MUTYH mutation: six had more than ten adenomas and seven had less than ten adenomas; of these 13 mono-allelic carriers, six had a neoplasm: three CRCs and three extra-intestinal tumors. Eleven of the thirteen mono-allelic carriers with adenomas had a family history of cancer in first or second degree relatives. A multivariable model showed positive correlation between G396D, Y179C and 1186 ins GG mutations and number of adenomas (OR 8.6, 10.2 and 14.4, respectively). The Q324H variant was negatively associated with the number of adenomatous polyps (OR −5.23). In conclusion, MUTYH mutations are prevalent among Jews of North-African origin with colorectal adenomas with or without early onset CRC. Mono-allelic MUTYH carriers with a family history of cancer had a clinical phenotype that varied from having only few adenomas to multiple (>10) adenomas. These findings support MUTYH testing in patients with even few adenomas and suggest the consideration of increased surveillance in mono-allelic carriers with a family history of cancer. © 2015, Springer Science+Business Media Dordrecht. Source


Goldberg Y.,Hebrew University of Jerusalem | Porat R.,Hebrew University of Jerusalem | Kedar I.,Raphael Recanati Genetics Institute | Shochat C.,Migal Galilee Bio Technology Center | And 13 more authors.
Familial Cancer | Year: 2010

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic workup for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984-3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984-3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984-3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984-3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome. ©Springer Science+Business Media B.V. 2009. Source


Shochat C.,Childhood Leukemia Research Institute | Shochat C.,Migal Galilee Bio Technology Center | Shochat C.,Tel Aviv University | Shochat C.,Tel-Hai Academic College | And 23 more authors.
Blood | Year: 2014

Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor a (IL7R) or cytokine receptor like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias. Here we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays showed that these are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells in vitro and are transforming in vivo. Protein fragment complementation assays suggest that despite the absence of cysteines, the mechanism of activation is through ligand-independent dimerization. Mutagenesis experiments and ConSurf calculations suggest that the mutations stabilize the homodimeric conformation, positioning the cytosolic kinases in predefined orientation to each other, thereby inducing spontaneous receptor activation independently of external signals. Hence, type I cytokine receptors may be activated in leukemia through 2 types of transmembrane somatic dimerizing mutations. © 2014 by The American Society of Hematology. Source

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