Low incidence ofBRCA1 mutations among Italian families with breast and ovarian cancer

Santarosa, Manuela; Viel, Alessandra; Dolcetti, Riccardo; Crivellari, Diana; Magri, M. D.; Pizzichetta, Maria Antonietta; Tibiletti, Maria Grazia; Gallo, Angelo; Tumolo, Salvatore; Tin, Laura Del; Boiocchi, Mauro

doi:10.1002/(sici)1097-0215(19981123)78:5<581::aid-ijc9>3.0.co;2-g

Cited by 22 publications

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References 23 publications

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“…In the time frame of 19 years (1996–2014), 1114 breast and/or ovarian cancer patients complying with the eligibility criteria for BRCA testing [ 16 ], were screened for BRCA1 or BRCA2 mutations. The updated criteria in use at the Centro di Riferimento Oncologico (CRO, National Cancer Institute, Aviano) were (a) three or more cases of breast and/or ovarian cancer at any age, with one case being a first-degree relative of the other two; (b) two first-degree relatives with breast cancer diagnosed before 50 years of age or at any age but with one case of bilateral breast cancer; (c) two first-degree relatives with ovarian cancer at any age or one ovarian cancer at any age and one breast cancer before the age of 50; and (d) one case of breast cancer before the age of 36 or breast cancer in male or breast and ovarian cancer in the same woman.…”

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confidence: 99%

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

et al. 2016

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BackgroundAbout 20 % of hereditary breast cancers are caused by mutations in BRCA1 and BRCA2 genes. Since BRCA1 and BRCA2 mutations may be spread throughout the gene, genetic testing is usually performed by direct sequencing of entire coding regions. In some populations, especially if relatively isolated, a few number of recurrent mutations is reported, sometimes caused by founder effect.MethodsBRCA1 and BRCA2 screening for mutations was carried out on 1114 breast and/or ovarian cancer patients complying with the eligibility criteria for BRCA testing. Haplotype analysis was performed on the probands carrying recurrent mutations and their relatives, using two sets of microsatellite markers covering the BRCA1 (D17S588, D17S806, D17S902, D17S1325, D17S855, D17S1328, D17S800, and D17S250) and BRCA2 (D13S220, D13S267, D13S171, D13S1701, D13S1698, D13S260, D13S290, D13S1246) loci. The DMLE + 2.2 software was used to estimate the age of BRCA1 c.676delT and BRCA2 c.7806-2A > G. A multiplex PCR and two different primer extension assays were optimized and used for genotyping the recurrent mutations of the two genes.ResultsIn the time frame of almost 20 years of genetic testing, we have found that five BRCA1 and three BRCA2 mutations are recurrent in a substantial subset of carriers from North-East Italy and neighboring Istria, where they represent more than 50 % of all mutations. Microsatellite analyses identified a common haplotype of different length for each mutation. Age estimation of BRCA1 c.676delT and BRCA2 c.7806-2A > G mutations revealed that they arose in the Friuli Venezia Giulia area about 86 and 94 generations ago, respectively. Suggestion of an association between BRCA2 c.7806-2A > G and risk of breast cancer in males has emerged. Finally, we developed a simple and efficient pre-screeening test, performing an in-house primer extension SNaPshot® assay for the rapid identification of the eight recurrent mutations.ConclusionsProofs of common ancestry has been obtained for the eight recurrent mutations. The observed genotype-phenotype correlation and the proposed rapid mutation detection strategy could improve the clinical management of breast and ovarian patients in North-East of Italy and neighboring geographic areas.

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Section: Methodsmentioning

confidence: 99%

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

et al. 2016

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BRCA1 andBRCA2 genes: Role in hereditary breast and ovarian cancer in Italy

et al. 1999

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The heritable defects of BRCA1 and BRCA2 genes have been shown to predispose to breast and ovarian cancers. In a previous report, we analyzed 46 Italian families with breast and/or ovarian cancer for BRCA1 mutations. In the present study, those families and 11 others were screened for BRCA2 mutations; the newly enrolled families were also analyzed for the BRCA1 gene. The coding region and splice boundaries of BRCA2 and BRCA1 genes were assessed by the protein‐truncation test and single‐strand conformational polymorphism. A total of 20 different mutations were found in 21 families (37%). A total of 9 families (16%) showed mutations in the BRCA1 gene, including the one new mutation identified in this study (5382insC), and 12 families (21%) presented mutations in the BRCA2 gene. BRCA2‐mutated families presented breast and ovarian cancers or breast cancers only, whereas most BRCA1‐mutated families presented ovarian cancer alone or in association with breast cancer. All the BRCA2 mutations led to a truncated protein: 6 were frameshift mutations, 4 were non‐sense mutations and 2 involved the intronic invariant region leading to splice variants. Therefore, in the Italian population, the cumulative proportion of BRCA1 and BRCA2 mutations was within the range observed in other studies (37%), with higher involvement of BRCA2 than of BRCA1. Many families in which no mutations were found presented a very high incidence of breast and/or ovarian cancer. Among the 36 BRCA1 and BRCA2 wild‐type families, 24 presented at least 4 cancer cases, indicating the existence of other important predisposing genes. Int. J. Cancer 83:5–9, 1999. © 1999 Wiley‐Liss, Inc.

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RINGDomain Proteins

Dominguez¹,

Folkers²,

Boelens³

2004

Handbook of Metalloproteins

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The RING domain is a cysteine‐rich sequence motif that can bind two zinc atoms. In the canonical RING motif, also called the C3HC4 motif, one zinc ion is bound to four cysteines, and the other ion to three cysteines and a histidine. The tetrahedral coordination is atypical and referred to as a ‘cross‐brace’ motif. There are now more than 380 RING motifs identified in the human genome. The RING domain has been shown to mediate a crucial step in the ubiquitination pathway that targets protein substrates for degradation by the 26 S proteasome. This pathway involves three enzymes, and the RING finger proteins have been classified in this scheme as ubiquitin ligases. There are actually nine structures of RING domains solved by X‐ray and NMR. The βαβ fold of the RING domain is conserved among all structures. The structures of RING domains in complex with other proteins involved in the ubiquitination pathway provide considerable insight into the molecular basis of ubiquitination. Recently, ubiquitination has been shown to be not only a simple protein removal system but also an indispensable regulatory process. This is underscored by the observation that many diseases, such as cancer and Parkinson's disease, are due to mutations in RING domains that prevent an efficient ubiquitination and degradation process. In this review, we compare the different structures of RING domains, analyze their functional aspects through structural information of RING domains in complex with other proteins, and describe medical aspects of RING finger proteins involved in cancer and Parkinson's disease.

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Low incidence ofBRCA1 mutations among Italian families with breast and ovarian cancer

Cited by 22 publications

References 23 publications

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

Tracking of the origin of recurrent mutations of the BRCA1 and BRCA2 genes in the North-East of Italy and improved mutation analysis strategy

BRCA1 andBRCA2 genes: Role in hereditary breast and ovarian cancer in Italy

RINGDomain Proteins

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