The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1510-1510
Author(s):  
Kara Noelle Maxwell ◽  
Daniel De Sloover ◽  
Lyndsey Emery ◽  
Bradley Wubbenhorst ◽  
Kurt P D'Andrea ◽  
...  
Keyword(s):  
Ovarian Tumor ◽  
Tp53 Mutation ◽  
Single Gene ◽  
Breast Tumors ◽  
Ovarian Tumors ◽  
Deleterious Mutations ◽  
Brca1 And Brca2 ◽  
Tp53 Mutations ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance

1510 Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.

Somatic BRCA status in ovarian tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5528-5528
Author(s):  
B. Hennessy ◽  
K. Timms ◽  
M. S. Carey ◽  
A. Gutin ◽  
R. Broaddus ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Ovarian Tumor ◽  
Tumor Tissue ◽  
Deleterious Mutation ◽  
Brca Mutation ◽  
Ovarian Tumors ◽  
Deleterious Mutations ◽  
Base Pair Deletion

5528 Background: The combined prevalence of BRCA1/2 mutations in germline DNA derived from a population of invasive ovarian cancer patients is up to 15.3%. PARP inhibitor trials are ongoing in patients who carry germline BRCA1/2 mutations. It is important to know whether somatic (non-germline) BRCA changes are present in ovarian tumors, given the predicted sensitivity of BRCA mutation-carrying tumors to PARP inhibitors and other DNA damaging agents. However, a large cohort of ovarian tumor tissues has not been studied to determine the frequency of BRCA deficiency due to additional somatic changes. Methods: BRCA1/2 exons/flanking regions were sequenced in 235 high-grade ovarian cancers and 38 ovarian cancer cell lines. In 112 tumors, we also performed gene expression analysis and copy number arrays with ultradense probe tiling throughout both BRCA genes. Results: For BRCA1, 31 tumors (13.2%) harbored mutations: 23 known deleterious mutations, 1 suspected deleterious mutation, 3 novel indels, 1 novel mis-sense and 3 novel nonsense mutations. For BRCA2, 12/178 sequenced tumors (6.7%) harbored mutations: 8 known deleterious mutations, 1 suspected deleterious mutation and 3 novel indels. Only 3 BRCA1 mutations were detected in 2 cell lines, two known deleterious and 1 a novel 29 base pair deletion. One cell line thus appears to have both a germline and a somatic mutation. BRCA mutation status was associated with a trend to improved progression-free survival (PFS) in univariate analysis (p = 0.17). However, BRCA deficiency (defined by BRCA1/2 gene expression loss (4 tumors) and homozygous deletion (1 tumor) in addition to mutations) was associated with improved PFS in univariate (p = 0.04) and multivariate (p = 0.03) analyses. Conclusions: The frequency of BRCA1/2 mutations in ovarian tumors detected by sequencing regardless of family history is ≈20%, higher than the expected prevalence of germline mutations. In both BRCA1/2 genes, almost 25% of mutations in tumor tissue were novel and not previously seen in germline DNA. We are now sequencing corresponding germline DNA to determine the exact number of these novel mutations that are somatic. Direct analysis of ovarian tumor tissue is likely to expand the number of women with BRCA-deficient tumors beyond that detectable by germline sequencing. [Table: see text]

scholarly journals Clinically Applicable Models to Characterize BRCA1 and BRCA2 Variants of Uncertain Significance

2008 ◽  
Vol 26 (33) ◽  
pp. 5393-5400 ◽  
Author(s):  
Andrew D. Spearman ◽  
Kevin Sweet ◽  
Xiao-Ping Zhou ◽  
Jane McLennan ◽  
Fergus J. Couch ◽  
...  
Keyword(s):  
Segregation Analysis ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Variant Of Uncertain Significance ◽  
Reduction Strategies ◽  
Uncertain Significance ◽  
History Of ◽  
Risk Reduction Strategies ◽  
Study Participants ◽  
Sporadic Tumors

Purpose Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components. Methods To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants. Results We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21. Conclusion Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.

TUMOR GANAS OVARIUM RESIDIF METASTASIS KARSINOMA MUSIN KE UMBILIKUS, PERITONEUM, DAN CAIRAN ASITES TANPA DITEMUKAN TANDA KEGANASAN PADA PEMERIKSAAN HISTOPATOLOGIS PASCA OPERATIF SEBELUMNYA

2019 ◽  
Vol 3 (2) ◽  
pp. 130-136
Author(s):  
Arif Fadillah ◽  
Andi Friadi
Keyword(s):  
Ovarian Carcinoma ◽  
Ovarian Tumor ◽  
Malignant Tumors ◽  
Histopathological Examination ◽  
Ovarian Tumors ◽  
Postoperative Chemotherapy ◽  
Definitive Treatment ◽  
Malignant Ovarian Tumor ◽  
Patient Will ◽  
Optimal Debulking

Background : Malignant ovarian tumor are still the number one cause of death and the second most  of incidents for gynecological malignant tumors. The principles of management of ovarian cancer are the same as the principles of handling other malignant diseases, for the treatment of primary lesions operatively and the handling of potential sites of tumor metastases with chemotherapy. Histopathological examination is still considered a gold standard for diagnosis and definitive treatment of malignant ovarian tumors. If histopathologic results are obtained, then the patient will be planned to undergo postoperative chemotherapy. The mismatch between the preoperative and intraoperative clinical features, and the results of postoperative histopathological examination is a problem in managing cases of ovarian malignant tumors.Objective : Report a case of residive ovarian carcinoma with no appearance of malignancy marker in the previous postoperative histopathological examination.Method : Case reportCase : We report the case of a 45-year-old woman with a history of two previous laparotomy. The first operation was carried out in February 2014 on the indication of an extra ovarian cyst, resulting in the impression of a "Follicular Cysts" based on histopathological examination. The second operation was performed in March 2015, performed surgical staging tumors with an indication of malignant ovarian tumors with clinical metastases, but from histopathological examination it was found that "Cystadenoma Ovarii Muscinosum Multiloculare" and "no visible signs of malignancy", so the patient was not managed with postoperative chemotherapy. In April 2019 patients came with complaints of new mass growth, from CT-Scan and USG investigations there was a suspicious impression of a residive ovarian tumor with metastases into the omentum and massive ascites. On May 16, 2019 an optimal debulking was performed with the findings of residive mass, ascites, and mass metastases in the intra operative peritoneum. From the results of histopathological examination, it was found that "Muscinous Carcinoma with metastases to the umbilicus, peritoneum, and ascitic fluidKeywords: Malignant residive ovarian tumor, mucinous ovarian carcinoma

scholarly journals Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up

2021 ◽  
Vol 7 (2) ◽  
pp. 22
Author(s):  
Jamie Matteson ◽  
Stanley Sciortino ◽  
Lisa Feuchtbaum ◽  
Tracey Bishop ◽  
Richard S. Olney ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Program Implementation ◽  
Screening Program ◽  
Birth Prevalence ◽  
Variant Of Uncertain Significance ◽  
Implementation Challenges ◽  
Screening Programs ◽  
Uncertain Significance ◽  
Long Term Follow Up

X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California’s experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.

scholarly journals First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Mario Tumminello ◽  
Antonella Gangemi ◽  
Federico Matina ◽  
Melania Guardino ◽  
Bianca Lea Giuffrè ◽  
...  
Keyword(s):  
Ectodermal Dysplasia ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Hypohidrotic Ectodermal Dysplasia ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Clinical Potential ◽  
Genomic Variant ◽  
Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

scholarly journals P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii32-iii32
Author(s):  
H Noor ◽  
R Rapkins ◽  
K McDonald
Keyword(s):  
Overall Survival ◽  
Tp53 Mutation ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Wild Type ◽  
Mutation Status ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3322-3329 ◽  
Author(s):  
Thorsten Zenz ◽  
Alexander Kröber ◽  
Katrin Scherer ◽  
Sonja Häbe ◽  
Andreas Bühler ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Clone Size ◽  
Tp53 Mutations ◽  
Long Term Follow Up ◽  
Serial Samples

AbstractThe exact prognostic role of TP53 mutations (without 17p deletion) and any impact of the deletion without TP53 mutation in CLL are unclear. We studied 126 well-characterized CLL patients by direct sequencing and DHPLC to detect TP53 mutations (exons 2-11). Most patients with 17p deletions also had TP53 mutations (81%). Mutations in the absence of 17p deletions were found in 4.5%. We found a shorter survival for patients with TP53 mutation (n = 18; P = .002), which was more pronounced when analyzed from the time point of mutation detection (6.8 vs 69 months, P < .001). The survival was equally poor for patients with deletion 17p plus TP53 mutation (7.6 months, n = 13), TP53 mutation only (5.5 months, n = 5), and 17p deletion only (5.4 months, n = 3). The prognostic impact of TP53 mutation (HR 3.71) was shown to be independent of stage, VH status, and 11q and 17p deletion in multivariate analysis. Serial samples showed evidence of clonal evolution and increasing clone size during chemotherapy, suggesting that there may be patients where this treatment is potentially harmful. TP53 mutations are associated with poor sur-vival once they occur in CLL. The de-monstration of clonal evolution under selective pressure supports the biologic significance of TP53 mutations in CLL.

53. Clinical utility of single-gene ultra-deep coverage NGS assay for TP53 mutations for detection of low-level mutations

2018 ◽  
Vol 226-227 ◽  
pp. 56
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Meenakshi Mehrotra ◽  
Bedia Barkoh ◽  
Saradhi Mallampati ◽  
Ana Maria Bolivar ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Single Gene ◽  
Tp53 Mutations ◽  
Low Level

scholarly journals Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis

2022 ◽  
Vol 8 (1) ◽  
pp. e654
Author(s):  
Melissa Nel ◽  
Amokelani C. Mahungu ◽  
Nomakhosazana Monnakgotla ◽  
Gerrit R. Botha ◽  
Nicola J. Mulder ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Population Group ◽  
Genetic Ancestry ◽  
Familial Case ◽  
Data Sets ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Sporadic Als ◽  
Uncertain Significance ◽  
Lateral Sclerosis

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

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