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Tel Aviv, Israel

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.

Goldberg Y.,Hebrew University of Jerusalem | Kedar I.,Raphael Recanati Genetics Institute | Kariiv R.,TASMC | Halpern N.,Hebrew University of Jerusalem | And 18 more authors.
Familial Cancer | Year: 2014

Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68 %) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73 %) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6 %) were large deletions. Only 20/51 (39 %) families were Amsterdam Criteria positive; 42 (82 %) were positive for the Bethesda guidelines and 9 (18 %) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73 % families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling. © 2013 Springer Science+Business Media.

Melchert C.,University of Lubeck | Gez E.,TASMC | Bohlen G.,University of Lubeck | Koziol I.,VA Urology Richmond | And 10 more authors.
Radiotherapy and Oncology | Year: 2013

Purpose: To evaluate dose reduction caused by the implantation of an interstitial inflatable and biodegradable balloon device aiming to achieve lower rectal doses with virtual 3D conformal external beam radiation treatment. Materials and methods: An inflatable balloon device was placed, interstitially and under transrectal ultrasound guidance, into the rectal-prostate interspace prior treatment initiation of 26 patients with localized prostate cancer, who elected to be treated with radiotherapy (3D CRT or IMRT). The pre- and post-implant CT imaging data of twenty two patients were collected (44 images) for the purpose of the 3D conformal virtual planning presented herein. Results: The dorsal prostate-ventral rectal wall separation resulted in an average reduction of the rectal V70% by 55.3% (±16.8%), V80% by 64.0% (±17.7%), V90% by 72.0% (±17.1%), and V100% by 82.3% (±24.1%). In parallel, rectal D2 ml and D0.1 ml were reduced by 15.8% (±11.4%) and 3.9% (±6.4%), respectively. Conclusions: Insertion of the biodegradable balloon into the prostate-rectum interspace is similar to other published invasive procedures. In this virtual dose distribution analysis, the balloon insertion resulted in a remarkable reduction of rectal volume exposed to high radiation doses. This effect has the potential to keep the rectal dose lower especially when higher than usual prostate dose escalation protocols or hypo-fractionated regimes are used. Further prospective clinical investigations on larger cohorts and more conformal radiation techniques will be necessary to define the clinical advantage of the biodegradable interstitial tissue separation device. © 2012 Elsevier Ireland Ltd. All rights reserved.

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