Search results for "germline"
showing 10 items of 154 documents
Multicenter Phase II Study of Lurbinectedin in BRCA-Mutated and Unselected Metastatic Advanced Breast Cancer and Biomarker Assessment Substudy
2018
Purpose This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. Patients and Methods Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resist…
Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.
2011
Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p…
Determination of somatic oncogenic mutations linked to target-based therapies using MassARRAY technology
2016
Somatic mutation analysis represents a useful tool in selecting personalized therapy. The aim of our study was to determine the presence of common genetic events affecting actionable oncogenes using a MassARRAY technology in patients with advanced solid tumors who were potential candidates for target-based therapies. The analysis of 238 mutations across 19 oncogenes was performed in 197 formalin-fixed paraffin-embedded samples of different tumors using the OncoCarta Panel v1.0 (Sequenom Hamburg, Germany). Of the 197 specimens, 97 (49.2%) presented at least one mutation. Forty-nine different oncogenic mutations in 16 genes were detected. Mutations in KRAS and PIK3CA were detected in 40/97 (4…
BRCA1 genetic testing in 106 breast and ovarian cancer families from Southern Italy (Sicily): a mutation analyses.
2007
PURPOSE: To evaluate the contribution of germline BRCA1 mutations in the incidence of hereditary and familial Breast Cancer (BC) and/or Ovarian Cancer (OC) in patients from Southern Italy (in the region of Sicily) and to identify a possible association between the higher frequency of BRCA1 mutations and a specific familial profile. EXPERIMENTAL DESIGN: A consecutive series of 650 patients with BC and/or OC diagnosed between 1999 and 2005 were recruited from the Southern Italian region of Sicily, after interview at the "Regional Reference Centre for the Characterization and Genetic Screening of Hereditary Tumors" at the University of Palermo. Genetic counselling allowed us to recruit a total…
Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.
2021
Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of p…
Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.
1998
Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of b…
A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation.
2007
X-linked mental retardation has been traditionally divided into syndromic (S-XLMR) and non-syndromic forms (NS-XLMR), although the borderlines between these phenotypes begin to vanish and mutations in a single gene, for example PQBP1, can cause S-XLMR as well as NS-XLMR. Here, we report two maternal cousins with an apparently X-linked phenotype of mental retardation (MR), microphthalmia, choroid coloboma, microcephaly, renal hypoplasia, and spastic paraplegia. By multipoint linkage analysis with markers spanning the entire X-chromosome we mapped the disease locus to a 28-Mb interval between Xp11.4 and Xq12, including the BCOR gene. A missense mutation in BCOR was described in a family with …
Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia
2004
In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was co…
High prevalence of BRCA1 deletions in BRCAPRO-positive patients with high carrier probability.
2007
Mutation screening of the BRCA1 and BRCA2 genes in probands with familial breast/ovarian cancer has been greatly improved by the multiplex ligation-dependent probe amplification (MLPA) assay able to evidence gene rearrangements not detectable by standard screening methods. However, no criteria for selection of cases to be submitted to the MLPA test have been reported yet. We used the BRCAPro software for the selection of familial breast/ovarian cancer probands investigated with the MLPA approach after negative BRCA1/2 conventional mutation screening. One hundred and seventy-seven probands were investigated for germline BRCA1/2 mutations after assessment of genetic risk using BRCAPro. Proban…
Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas
2015
Multiple osteochondromas (MO) is an autosomal-dominant skeletal disorder caused by mutations in the exostosin-1 ( EXT1 ) or exostosin-2 ( EXT2 ) genes. In this study, we report the analysis of the mutational status of the EXT2 gene in tumor samples derived from a patient affected by hereditary MO, documenting the somatic loss of the germline mutation in a giant chondrosarcoma and in a rapidly growing osteochondroma. The sequencing of all exons and exon–intron junctions of the EXT1 and EXT2 genes from blood DNA of the proband did not reveal any mutation in the EXT1 gene but did demonstrate the presence of the transition point mutation c.67C > T in the EXT2 gene, determining the introduction …