Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients

Park, Boyoung; Sohn, Ji Yeon; Yoon, Kyong–Ah; Lee, Keun Seok; Cho, Eun Hae; Lim, Myong Cheol; Yang, Moon Jung; Park, Soo‐Jin; Lee, Moo Hyun; Lee, See Youn; Chang, Yoon Jung; Lee, Dong Ock; Kong, Sun‐Young; Lee, Eun Sook

doi:10.1007/s10549-017-4142-7

Cited by 15 publications

(11 citation statements)

References 32 publications

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“…Other variants that also lead to skipping of exon 23 have been published as pathogenic, e.g. c.5407-2A>G [11,26], c.5407-10G>A [27], c.5467+1G>A [28] and c.5434C>G (p.Pro1812Ala) [11,29]. Although a wide range of alternative transcripts have been described for the BRCA1 locus [12], there were no signs of aberrant splicing of exon 23 among the 30 normal controls in our study.…”

Section: Discussioncontrasting

confidence: 56%

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23—a likely pathogenic variant with reduced penetrance?

et al. 2020

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Rare sequence variants in the non-coding part of the BRCA genes are often reported as variants of uncertain significance (VUS), which leave patients and doctors in a challenging position. The aim of this study was to determine the pathogenicity of the BRCA1 c.5407-25T>A variant found in 20 families from Norway, France and United States with suspected hereditary breast and ovarian cancer. This was done by combining clinical and family information with allele frequency data, and assessment of the variant's effect on mRNA splicing. Mean age at breast (n = 12) and ovarian (n = 11) cancer diagnosis in female carriers was 49.9 and 60.4 years, respectively. The mean Manchester score in the 20 families was 16.4. The allele frequency of BRCA1 c.5407-25T>A was 1/64,566 in non-Finnish Europeans (gnomAD database v2.1.1). We found the variant in 1/400 anonymous Norwegian blood donors and 0/784 in-house exomes. Sequencing of patient-derived cDNA from blood, normal breast and ovarian tissue showed that BRCA1 c.5407-25T>A leads to skipping of exon 23, resulting in frameshift and protein truncation: p.(Gly1803GlnfsTer11). Western blot analysis of transiently expressed BRCA1 proteins in HeLa cells showed a reduced amount of the truncated protein compared with wild type. Noteworthily, we found that a small amount of full-length transcript was also generated from the c.5407-25T>A allele, potentially explaining the intermediate cancer burden in families carrying this variant. In summary, our results show that BRCA1 c.5407-25T>A leads to partial skipping of exon 23, and could represent a likely pathogenic variant with reduced penetrance.

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Section: Discussioncontrasting

confidence: 56%

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23—a likely pathogenic variant with reduced penetrance?

et al. 2020

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“…For the 4 studies that reported BRCA mutation in patients with HR+/HER2- breast cancer, none was in the same population in terms of criteria used to select patients. One of the studies required patients to fulfill a complex set of selection criteria in accordance with the National Medical Insurance Reimbursement in South Korea,15 and another only included females with early breast cancer 46…”

Section: Resultsmentioning

confidence: 99%

<p>A systematic review of the international prevalence of <em>BRCA </em>mutation in breast cancer</p>

Armstrong

Ryder

Forbes

et al. 2019

CLEP

187

122

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A systematic review was conducted, summarizing international BRCA 1 or 2 ( BRCA1/2 ) mutation prevalence in breast cancer. Databases (eg, Medline and Embase; N=7) and conferences were searched (January 2012 to December 2017). From 17,872 records, 70 studies were included. In 58 large (N>100) studies, BRCA1/2 mutation prevalence varied widely from 1.8% (Spain) in sporadic breast cancer to 36.9% (United States) in estrogen receptor/progesterone receptor low+ (1–9% on immunohistochemistry/human epidermal growth factor receptor 2–negative [HER2-]) breast cancer. In 2 large studies unselected for family history, ethnicity, sex, or age and no/unclear selection by breast cancer stage or hormone receptor (HR) status, germline BRCA (g BRCA ) mutation prevalence was 2.9% (Italy) to 3.0% (South Korea). In the 4 large unselected triple-negative breast cancer studies, g BRCA mutation prevalence varied from 9.3% (Australia) to 15.4% (United States). g BRCA mutation prevalence in 1 large unselected HR positive/HER2- early breast cancer study was 5% (United States). In 2 large unselected metastatic breast cancer studies, g BRCA mutation prevalence was 2.7% (France) and 4.3% (Germany). Locally advanced breast cancer studies were small and not in unselected populations. Poor reporting of g BRCA status and basis of selection implies a need for further large well-reported BRCA mutation prevalence studies in breast cancer.

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“…“Basal-like” tumors are characterized by overexpression of genes associated with basal epithelium and proliferation and minimal to no expression of genes associated with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). This gene expression profile is reflected in the immunohistochemical expression of basal markers including cytokeratin 5/6 and epidermal growth factor receptor (EGFR), in addition to lack of expression of ER and progesterone receptor (PR) as well as HER2 ( 27 , 32 – 35 ). Metaplastic carcinomas have also been reported in BRCA1 mutations carriers ( 36 , 37 ).…”

Section: Hboc-associated Breast Cancermentioning

confidence: 99%

Pathology of Hereditary Breast and Ovarian Cancer

Hodgson

Turashvili

2020

Front. Oncol.

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Hereditary breast and ovarian cancer (HBOC) syndrome is most commonly characterized by deleterious germline mutations in BRCA1 and BRCA2. HBOC patients are prone to the development of malignant neoplasms in multiple organs including the breast, ovary, and fallopian tube. From a pathological perspective, a number of morphological features have been described in BRCA-associated breast and tuboovarian cancers. For example, breast cancers diagnosed in BRCA1-mutation carriers are frequently of a high Nottingham grade and display medullary morphology and a triple-negative and/or a basal-like immunophenotype. In contrast, breast cancers in BRCA2-mutation carriers are similar to sporadic luminal-type tumors that are positive for hormone receptors and lack expression of human epidermal growth factor receptor 2. Cancers arising in the fallopian tube and ovary are almost exclusively of a highgrade serous histotype with frequent Solid, pseudo-Endometrioid, and Transitional cell carcinoma-like morphology ("SET features"), marked nuclear atypia, high mitotic index, abundant tumor infiltrating lymphocytes, and necrosis. In addition, pushing or infiltrative micropapillary patterns of invasion have been described in BRCA-associated metastases of tubo-ovarian high-grade serous carcinomas. Besides BRCA1 and BRCA2 mutations, alterations in a number of other homologous recombination genes with moderate penetrance, including PALB2, RAD51C, RAD51D, BRIP1, and others, have also been described in HBOC patients with varying frequency; however, distinct morphological characteristics of these tumors have not been well characterized to date. In this review, the above pathological features are discussed in detail and a focus is placed on how accurate pathologic interpretation plays an important role in allowing HBOC patients to receive the best possible management.

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Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients

Cited by 15 publications

References 32 publications

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23—a likely pathogenic variant with reduced penetrance?

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23—a likely pathogenic variant with reduced penetrance?

<p>A systematic review of the international prevalence of <em>BRCA </em>mutation in breast cancer</p>

Pathology of Hereditary Breast and Ovarian Cancer

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