Two founder BRCA2 mutations predispose to breast cancer in young women

Infante, Mar; Durán, Mercedes; Lasa, Adriana; Acedo, Alberto; Hoya, Miguel de la; Esteban-Cardeñosa, Eva; Sanz, David J.; Pérez-Cabornero, Lucía; Lastra, Enrique; Miner, Cristina; Velasco, Eladio A.

doi:10.1007/s10549-009-0661-1

Cited by 8 publications

(5 citation statements)

References 18 publications

(27 reference statements)

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“…These two frameshift variants are prevalent, representing 10.6% of BRCA2 positive families and have been linked to early-onset breast cancer. 30 In another study, four distinct BRCA1 mutations accounted for 72.7% of BRCA1-attributable breastovarian cancer in 104 families originated from the Centraleastern part of Tuscany. 31 Furthermore, BRCA2 c.7806-2A>T is a novel variant predicted to cause abnormal splicing 24 and is probably representing a specific settlement of colonists, 32 occurring as a single genomic event in Crete, approximately 800 years ago.…”

Section: Discussionmentioning

confidence: 96%

“…In addition to this, haplotype analysis revealed that the recurrent BRCA2 c.5146_5149delTATG and c.9310_9311delAA pathogenic variants are Spanish founders and all families originated from Castilla‐Leon. These two frameshift variants are prevalent, representing 10.6% of BRCA2 positive families and have been linked to early‐onset breast cancer . In another study, four distinct BRCA1 mutations accounted for 72.7% of BRCA1 ‐attributable breast‐ovarian cancer in 104 families originated from the Central‐eastern part of Tuscany …”

Section: Discussionmentioning

confidence: 99%

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BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects

Apostolou

Fostira

Kouroussis

et al. 2020

Intl Journal of Cancer

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Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost-and timeefficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects

Apostolou

Fostira

Kouroussis

et al. 2020

Intl Journal of Cancer

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“…It was detected for the first time in northwestern Spain in Castilla y León [ 52 ] and has been described as a recurrent founder mutation in this region. Interestingly, it has been associated with EOBC (mean age 37.4 years; p = 0.033) [ 53 ]. Overall, this mutation has been identified in a group of eight independent Spanish families [ 53 – 55 ], and also in two Korean patients [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco

et al. 2020

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Background To date, the contribution of BRCA1/2 mutations in Moroccan early onset breast cancer patients remains unknown. Here we assess these genetic alterations for the first time in a cohort from North of Morocco. Methods Thirty-three patients diagnosed with breast cancer at the age of ≤40 years were recruited irrespective of breast and/or ovarian cancer family history. Coding regions and intron-exon boundaries of BRCA1 and BRCA2 genes were sequenced from peripheral blood DNA using Ion Proton (Thermo Fisher Scientific) next generation sequencing platform. Results Overall, five BRCA germline mutations were identified (15.1%). The frequency of mutations among patients with family history of breast cancer was 16.7%. Three mutations were found in BRCA1 (9%) and two within the BRCA2 gene (6%). These are three frameshift mutations (c.798_799del, c.2125_2126insA, c.5116_5119delAATA), one missense (c.116G > A) and one nonsense mutation (c.289G > T). The mutation c.5116_5119delAATA has a founder effect in North Africa. Moreover, one variant of unknown significance was identified in BRCA2 (c.4090A > G). Most BRCA mutations carriers (80%) had no family history of breast cancer. Conclusion Our data do not support the hypothesis that BRCA mutations alone explain the higher frequency of breast cancer in Moroccan young women. The young age (≤40 years) for breast cancer diagnosis seems to be strongly predictive of BRCA mutation status in Moroccan patients. These results will help in decision making with regard to genetic counseling and testing in the national scale.

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“…The response rate was even higher (64%) when the plasma concentrations of INCB7839 were above the IC 50 for HER2 cleavage. [104] INC7839 also improved progression-free survival in a subset of the patients expressing the p95 fragment of HER2. [105] The p95 fragment is a constitutively active portion of HER2 left (Right) Overlay of ADAM17 (magenta), ADAMTS-5 (blue) and MMP-9 (cyan), and ADAM22 (gray) structures shows sIVa-sIVb loop does not align with structures of other metzincins suggesting its uniqueness.…”

Section: Adam17mentioning

confidence: 99%

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

2017

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Remodeling of the extracellular matrix (ECM) is crucial in development and homeostasis, but also has a significant role in disease progression. Two metalloproteinase families, the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs), participate in the remodeling of the ECM, either directly or through the liberation of growth factors and cell surface receptors. The correlation of MMP and ADAM activity to a variety of diseases has instigated numerous drug development programs. However, broad-based and Zn -chelating MMP and ADAM inhibitors have fared poorly in the clinic. Selective MMP and ADAM inhibitors have been described recently based on (a) antibodies or antibody fragments or (b) small molecules designed to take advantage of protease secondary binding sites (exosites) or allosteric sites. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages.

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Two founder BRCA2 mutations predispose to breast cancer in young women

Cited by 8 publications

References 18 publications

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects

BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects

Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

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