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From germline towards somatic mutations in the pathophysiology of vascular anomalies.

ABSTRACT: The localized structural abnormalities that arise during vasculogenesis, angiogenesis and lymphangiogenesis, the developmental processes which give rise to the adult vasculature, are collectively termed vascular anomalies. The last 2 years have seen an explosion of studies that underscore paradominant inheritance, the combination of inherited changes with somatic second-hits to the same genes, as underlying rare familial forms. Moreover, local, somatic genetic defects that cause some of the common sporadic forms of these malformations have been unraveled. This highlights the importance of assessing for tissue-based genetic changes, especially acquired genetic changes, as possible pathophysiological causes, which have been largely overlooked except in the area of cancer research. Large-scale somatic screens will therefore be essential in uncovering the nature and prevalence of such changes, and their downstream effects. The identification of disease genes combined with exhaustive, precise clinical delineations of the entire spectra of associated phenotypes guides better management and genetic counseling. Such a synthesis of information on functional and phenotypic effects will enable us to make and use animal models to test less invasive, targeted, perhaps locally administered, biological therapies.

SUBMITTER: Limaye N

PROVIDER: S-EPMC2657941 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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From germline towards somatic mutations in the pathophysiology of vascular anomalies.

Limaye Nisha N Boon Laurence M LM Vikkula Miikka M

Human molecular genetics 20090401 R1

The localized structural abnormalities that arise during vasculogenesis, angiogenesis and lymphangiogenesis, the developmental processes which give rise to the adult vasculature, are collectively termed vascular anomalies. The last 2 years have seen an explosion of studies that underscore paradominant inheritance, the combination of inherited changes with somatic second-hits to the same genes, as underlying rare familial forms. Moreover, local, somatic genetic defects that cause some of the comm ...[more]

PMID: 19297403

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Project description:ObjectivesIn breast cancer (BC) patients, the frequency of germline BRCA mutations (gBRCA) may vary according to the ethnic background, age, and family history of cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the second most common somatic mutated gene in BC; however, the association of mutations in both genes with cancer has not been thoroughly investigated. Thus, our aims were to investigate gBRCA mutation frequency in a cohort of postmenopausal Brazilian BC patients and the association of gBRCA1/BRCA2 and PIK3CA somatic mutations.MethodsForty-nine postmenopausal (>55 years) and forty-one young (≤35 years) BC patients were included in this study. The postmenopausal group included patients who reported a positive family history of cancer. For these patients, gBRCA1/BRCA2 were sequenced using next-generation sequencing (NGS) or Sanger sequencing. Data for gBRCA in young patients were already available from a previous study. DNA from formalin-fixed, paraffin-embedded (FFPE) tumors was obtained from 27 postmenopausal and 41 young patients for analyzing exons 9 and 20 of PIK3CA. The association between gBRCA1/BRCA2 and somatic mutations in PIK3CA was investigated.ResultsThe overall frequency of gBRCA1/BRCA2 among the 49 postmenopausal patients was 10.2%. The frequencies of somatic mutations in PIK3CA in the postmenopausal and young patients were 37% and 17%, respectively (ns). The most common PIK3CA mutation was found to be E454A. Nonsense and frameshift mutations, which may counteract the oncogenic potential of PIK3CA were also detected. Regardless of age, 25% of BRCA1/BRCA2 mutation carriers and non-carriers , each, had PIK3CA somatic mutations.ConclusionsData obtained indicate that BRCA1/BRCA2 gene testing may be considered for postmenopausal patients with BC who have a family history of cancer. Although some of them are not considered pathogenic, somatic variants of PIK3CA are frequently observed in BC patients, especially in postmenopausal patients.

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From germline towards somatic mutations in the pathophysiology of vascular anomalies.

Publications

From germline towards somatic mutations in the pathophysiology of vascular anomalies.

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