Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10–30%), compared to 35% (95% confidence interval 22–48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32–39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.

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Impact of Postoperative Radiotherapy on Survival of Patients With de novo Stage IV Breast Cancer: A Population-Based Study From the SEER Database

Frontiers in Oncology ◽

10.3389/fonc.2021.625628 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jie Zhang ◽

Shiping Luo ◽

Zhaozhen Qiu ◽

Yuxiang Lin ◽

Chuangui Song

Keyword(s):

Breast Cancer ◽

Confidence Interval ◽

De Novo ◽

Postoperative Radiotherapy ◽

Stage Iv ◽

Seer Database ◽

Radiotherapy Group ◽

Kaplan Meier ◽

Stage Iv Breast Cancer ◽

Subgroup Analyses

Purpose: In our study, we aimed to evaluate the role of postoperative radiotherapy for patents with de novo stage IV breast cancer.Patients and Methods: Patients diagnosed with stage IV breast cancer from 2010 to 2016 were selected from the Surveillance, Epidemiology, and End Result (SEER) database. Those patients who received both chemotherapy and surgery and lived longer than 6 months were divided into radiotherapy and non-radiotherapy groups. Kaplan-Meier analysis and multivariate Cox proportional hazards models were used to estimate the survival outcomes before and after being 1:1 propensity score matched (PSM). Subgroup analyses stratified by age, subtype, status of distant metastasis, and surgery type were also performed.Results: Among 1,935 patients, 52% (1006) underwent radiotherapy while the non-radiotherapy group contained 48% (929). After PSM, a total of 1,520 patients in two groups of 760 patients were enrolled in this analysis. Kaplan-Meier and the multivariate survival analysis demonstrated that the radiotherapy group presented with a better prognosis compared to the non-radiotherapy group (after PSM, BCSS: Hazard Ratio, 0.697; 95% confidence interval, 0.59–0.823; P < 0.001; OS: Hazard Ratio, 0.707; 95% confidence interval, 0.601–0.831; P < 0.001). Further subgroup analyses showed the Luminal subtype (HR+/HER2–), triple-negative breast cancer (TNBC), and bone-only metastasis patients presented with the most promising survival in the radiotherapy group.Conclusions: Postoperative radiotherapy is associated with a significant survival advantages in BCSS and OS. It can be an optimal supplementary treatment for stage IV patients after surgery, especially for Luminal subtype, TNBC, and patients with a low metastatic burden.

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Novel de novo BRCA1 mutation in a woman with early onset breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22143 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22143-e22143

Author(s):

E. Tang ◽

A. Kwong ◽

C. Wong ◽

F. Law ◽

C. Wong ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Early Onset ◽

De Novo ◽

Family Members ◽

Gene Sequencing ◽

Large Deletion ◽

Early Onset Breast Cancer ◽

De Novo Mutations ◽

History Of

e22143 Background: Germline mutations in BRCA1/2 account for a significant portion of hereditary breast/ovarian cancer. Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease. Rarely, germline mutations are found only in the probands but not in any family members. Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familial adenomatous polyposis. De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2. Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient. Methods: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA). Family members were analyzed for the same mutation. Paternity was determined by a set of highly polymorphic short tandem repeat (STR) markers. Results: Full gene sequencing found no deleterious mutation. MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband. MLPA performed on 5 family members: proband's mother and father (who were 1st degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion. By using a set of highly polymorphic STR markers, the proband's father and mother were confirmed to be her biological parents. Conclusions: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history. Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion. The mutation found in this study is de novo. This may simply be a random mutation event which occurred in the parents' germ cells during their lifetime which passed onto one of their offspring or maybe a result of gene inversion or splicing deficiency. The relations of such mutations with consanguineous marriage cannot be ruled out. Mutation screening is important in early onset breast cancer patients even if there is no family history. No significant financial relationships to disclose.

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Correction: Møller, P.; et al. Causes for Frequent Pathogenic BRCA1 Variants Include Low Penetrance in Fertile Ages, Recurrent De-Novo Mutations and Genetic Drift. Cancers 2019, 11, 132

Cancers ◽

10.3390/cancers12020410 ◽

2020 ◽

Vol 12 (2) ◽

pp. 410

Author(s):

Møller ◽

Dominguez-Valentin ◽

Rødland ◽

Hovig

Keyword(s):

Genetic Drift ◽

De Novo ◽

De Novo Mutations

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. [...]

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Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

Journal of Clinical Medicine ◽

10.3390/jcm9020370 ◽

2020 ◽

Vol 9 (2) ◽

pp. 370 ◽

Cited By ~ 4

Author(s):

Maria Franaszczyk ◽

Grazyna Truszkowska ◽

Przemyslaw Chmielewski ◽

Malgorzata Rydzanicz ◽

Joanna Kosinska ◽

...

Keyword(s):

Candidate Genes ◽

De Novo ◽

Positive Family History ◽

Disease Onset ◽

De Novo Mutation ◽

De Novo Mutations ◽

Whole Exome ◽

The Family ◽

High Prevalence ◽

Generation Sequencing

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.

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Multiple Perspectives on the Barriers to Identification and Management of Pediatric Voice Disorders

Perspectives of the ASHA Special Interest Groups ◽

10.1044/persp2.sig3.49 ◽

2017 ◽

Vol 2 (3) ◽

pp. 49-56

Author(s):

Jana Childes ◽

Alissa Acker ◽

Dana Collins

Keyword(s):

Academic Success ◽

Voice Disorders ◽

School Personnel ◽

Voice Disorder ◽

Multiple Perspectives ◽

Vocal Qualities ◽

High Prevalence ◽

Pediatric Populations ◽

Low Incidence ◽

University Settings

Pediatric voice disorders are typically a low-incidence population in the average caseload of clinicians working within school and general clinic settings. This occurs despite evidence of a fairly high prevalence of childhood voice disorders and the multiple impacts the voice disorder may have on a child's social development, the perception of the child by others, and the child's academic success. There are multiple barriers that affect the identification of children with abnormal vocal qualities and their access to services. These include: the reliance on school personnel, the ability of parents and caretakers to identify abnormal vocal qualities and signs of misuse, the access to specialized medical services for appropriate diagnosis, and treatment planning and issues related to the Speech-Language Pathologists' perception of their skills and competence regarding voice management for pediatric populations. These barriers and possible solutions to them are discussed with perspectives from the school, clinic and university settings.

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Prophylactic Mastectomy Lowers Risk of Breast Cancer 90%

Ob Gyn News ◽

10.1016/s0029-7437(05)70094-x ◽

2005 ◽

Vol 40 (6) ◽

pp. 17

Author(s):

BRUCE JANCIN

Keyword(s):

Breast Cancer ◽

Prophylactic Mastectomy

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Prophylactic Mastectomy - Evaluation and Treatment of High Risk Patients

Swiss Surgery ◽

10.1024/1023-9332.8.2.45 ◽

2002 ◽

Vol 8 (2) ◽

pp. 45-52 ◽

Cited By ~ 3

Author(s):

Remmel ◽

Harder

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Risk Reduction ◽

Prophylactic Mastectomy ◽

Interdisciplinary Approach ◽

Reconstructive Procedures ◽

Medline Search ◽

Breast Cancer Risk Reduction ◽

Cancer Risk Reduction

Prophylactic mastectomy is an aggressive strategy for breast cancer risk reduction. The indications and efficiency of this procedures are not yet clearly defined. Randomized, prospective studies, comparing different surgical procedures with other modalities of breast cancer risk reduction are lacking. The report evaluates the existing controversy, based on Medline search in the following sequence: risk factors, possibilities of risk reduction, effectiveness of risk reduction, technical considerations and recommendations. Patient selection is difficult and needs an interdisciplinary approach. The women have to be well informed about all treatment alternatives and various reconstructive procedures. An appropriate risk reduction strategy should be selected individually for each patient. Up to now, there exist only recommendations from different institutions but no definitive guidelines.

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