scholarly journals BRCA1andBRCA2Unclassified Variants and Missense Polymorphisms in Algerian Breast/Ovarian Cancer Families

2012 ◽  
Vol 32 (6) ◽  
pp. 343-353 ◽  
Author(s):  
Farid Cherbal ◽  
Nadjet Salhi ◽  
Rabah Bakour ◽  
Saida Adane ◽  
Kada Boualga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Clinical Significance ◽  
Direct Sequencing ◽  
Germline Mutations ◽  
Ovarian Cancer Risk ◽  
In Trans ◽  
Young Breast Cancer ◽  
First Time ◽  
Uv C

Background: BRCA1andBRCA2germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs) (variants with unknown clinical significance) and missense polymorphisms inBRCA1andBRCA2genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously forBRCA1andBRCA2genes germline mutations analysis.Methods: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The approach used is based onBRCA1andBRCA2sequence variants screening by SSCP or High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In silico analyses have been performed using different bioinformatics programs to individualize genetics variations that can disrupt theBRCA1andBRCA2genes function.Results: Among 80 UVs and polymorphisms detected inBRCA1/2genes (33BRCA2and 47BRCA2), 31 were new UVs (10BRCA2and 21BRCA2), 7 were rare UVs (4BRCA2and 3BRCA2) and 42 were polymorphic variants (19BRCA2and 23BRCA2). Moreover, 8 new missense UVs identified in this study: twoBRCA1(c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and sixBRCA2(c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen2 program and could be pathogenic. In addition, 5 newBRCA2missense UVs out of six that were found to be damaging by PolyPhen2 program, also were deleterious according to SIFT program. The rareBRCA2UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleteriousBRCA1mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. Moreover, 10 new identified intronic variants with unknown clinical significance (3BRCA1and 7BRCA2) in the present study, could be considered as benign, because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no splice site alteration for these variants. Several missense polymorphisms ofBRCA1c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly andBRCA2c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who were tested negative forBRCA1andBRCA2mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian breast/ovarian cancer families where pathologicalBRCA1andBRCA2mutations were not present.Conclusions: For the first time, UVs and missense polymorphisms inBRCA1andBRCA2genes have been identified in Algerian breast/ovarian cancer families. Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study.

scholarly journals Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer

2018 ◽  
Vol 10 (2) ◽  
pp. 337-346 ◽  
Author(s):  
Mary Kathleen Ladd ◽  
Beth N Peshkin ◽  
Leigha Senter ◽  
Shari Baldinger ◽  
Claudine Isaacs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Genetic Counseling ◽  
Cancer Risk ◽  
Prophylactic Surgery ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Affective Factors ◽  
Risk Reducing

Abstract Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21–75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20–11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17–1.81), perceived pros (OR = 1.79, 95% CI = 1.38–2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65–0.996), and decision conflict (OR = 0.80, 95% CI = 0.66–0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09–0.89), perceived pros (OR = 1.35, 95% CI = 1.11–1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59–0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65–0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further.

scholarly journals Significant Post-Chemotherapy Decrease of Ovarian Reserve in Iranian Women With Breast Cancer

2020 ◽  
Author(s):  
Bita Eslami ◽  
Amirmohsen Jalaeefar ◽  
Ashraf Moini ◽  
Ramesh Omranipour ◽  
Maryam Haghighi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fertility Preservation ◽  
Ovarian Function ◽  
Newly Diagnosed ◽  
Breast Cancer Patients ◽  
Study Results ◽  
Young Breast Cancer ◽  
Almost All ◽  
First Time

Fertility preservation counseling has a high priority in young breast cancer (BC) patients. Cytotoxic chemicals used for chemotherapy in these patients increased the risk of premature ovarian failure. This study evaluated the anti-mullerian hormone (AMH) level at the time of diagnosis and within a month after the end of chemotherapy, while predicting the time of the return of ovarian function in BC cases (n=46) younger than 46 years for the first time in Iran. Cases were selected from those attending the breast oncology clinic of the two hospitals with a newly diagnosed in situ or invasive BC. The present study results showed AMH levels were significantly decreased in almost all women within a month after chemotherapy. It seems that the need for fertility preservation depends on patient age and baseline AMH level, but counseling should be offered by the clinician in young breast cancer patients.

scholarly journals Clinical Significance of Age at the Time of Diagnosis among Young Breast Cancer Patients

2011 ◽  
Vol 14 (4) ◽  
pp. 314 ◽  
Author(s):  
Im-kyung Kim ◽  
Seho Park ◽  
Hyewon Hwang ◽  
Jun Sang Lee ◽  
Si Mon Ko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Breast Cancer Patients ◽  
Young Breast Cancer

scholarly journals Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

2012 ◽  
Vol 21 (4) ◽  
pp. 645-657 ◽  
Author(s):  
Fergus J. Couch ◽  
Mia M. Gaudet ◽  
Antonis C. Antoniou ◽  
Susan J. Ramus ◽  
Karoline B. Kuchenbaecker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Common Variants ◽  
Brca1 And Brca2 ◽  
Mutation Carriers

scholarly journals Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

2021 ◽  
Author(s):  
Emma R. Woodward ◽  
Elke M. van Veen ◽  
Claire Forde ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Ovarian Cancer Risk ◽  
Breast Cancers ◽  
Breast And Ovarian Cancer ◽  
Cancer Pathology ◽  
Er Positive ◽  
Grade 3 ◽  
Breast Cancer Pathology

Abstract Purpose To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Methods Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Results Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast–ovarian = 5.90 [95% CI: 1.92–18.36], CHEK2 breast–ovarian = 4.46 [95% CI: 1.86–10.46], PALB2 breast = 6.16 [95% CI: 1.98–19.21], CHEK2 breast = 4.89 [95% CI: 2.01–11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P < 0.0001). PALB2_PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20–39 = 11/520, P = 0.04) but not for CHEK2_1100delC (MS < 15 = 29/1,762, MS 20–39 = 4/520). PALB2 PGVs showed perfect segregation in 20/20 first-degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P = 0.002). Conclusion PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors.

scholarly journals Risk reduction strategies for BRCA1/2 hereditary ovarian cancer syndromes: a clinical practice guideline

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Michelle Jacobson ◽  
Nadia Coakley ◽  
Marcus Bernardini ◽  
Kelly-Ann Branco ◽  
Laurie Elit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Risk Reduction ◽  
Hormone Replacement ◽  
Breast Cancer Mortality ◽  
Pathogenic Variant ◽  
Ovarian Cancer Risk ◽  
Eligibility Criteria ◽  
Cancer Risk Reduction

Abstract Objective The purpose of this guideline is to make recommendations regarding the care of women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2. Methods Draft recommendations were formulated based on evidence obtained through a systematic review of RCTs, comparative retrospective studies and guideline endorsement. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners. Results The literature search yielded 1 guideline, 5 systematic reviews, and 15 studies that met the eligibility criteria. Conclusions In women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 screening for ovarian cancer is not recommended. Risk-reducing surgery is recommended to reduce the risk of ovarian cancer. In the absence of contraindications, premenopausal women undergoing RRSO should be offered hormone therapy until menopause. Systemic hormone replacement therapy, is not recommended for women who have had a personal history of breast cancer. RRSO should be considered for breast cancer risk reduction in women younger than 50 years. After a breast cancer diagnosis, RRSO for breast cancer mortality reduction can be considered within two years to women who harbour a pathogenic or likely pathogenic variant in BRCA1 if younger than the recommended age range for ovarian cancer risk reduction. RRSO before the age of 40 and specifically for breast cancer treatment in BRCA2 should be considered only if recommended by their breast cancer oncologist. Following RRSO, it is not recommended to do surveillance for peritoneal cancer.

Clinical significance of gene polymorphisms for hereditary predisposition to breast and ovarian cancer (review of literature)

2021 ◽  
Vol 66 (12) ◽  
pp. 760-767
Author(s):  
D. I. Vodolazhsky ◽  
A. V. Mayakovskaya ◽  
A. V. Kubyshkin ◽  
K. A. Aliev ◽  
I. I. Fomochkina
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Dna Repair ◽  
Clinical Significance ◽  
Hereditary Breast Cancer ◽  
Molecular Genetic ◽  
Breast And Ovarian Cancer ◽  
Hereditary Predisposition ◽  
Oncological Diseases

The review presents classical and modern views on the molecular genetic causes underlying hereditary predisposition to breast and ovarian cancer. A computerized literature search was carried out in the electronic databases MEDLINE, Scopus, and Web of Science, published between January 1994 and May 2021, using the keywords: «hereditary breast and ovarian cancer», «BRCA» and «DNA repair». Current views on the role of germline mutations in genes for susceptibility to breast cancer (BC): BRCA1, BRCA2, PALB2, TP53, CHEK2, PTEN, ATM, and PPM1D are presented. The role of a complex of genes involved in homologous DNA repair and causing other hereditary oncological diseases is considered. The role of the loss of heterozygosity in these genes, which increases the level of chromosomal instability and leads to an increased risk of malignant transformation, is considered. Germinal mutations in the genes under consideration in 90% of clinical cases are the cause of initiation of tissue malignancy and greatly increase the risk of developing hereditary breast cancer and OC. The review emphasizes the complex nature of pathogenesis and significant polymorphism of genetic targets for hereditary breast cancer and OC. It is concluded that it is necessary to use NGS panels for complex screening of genes of hereditary susceptibility to these oncological diseases. The review provides data on the clinical significance of each group of genes of hereditary predisposition in the pathogenesis of breast cancer and OC, and also demonstrates the possible role of methylation of the promoter regions of genes and the state of mitochondrial DNA in the development of these pathologies. The purpose of this review was to broaden the horizons of specialists in the field of oncology and clinical diagnostics in the context of the rapidly expanding spectrum of molecular genetic markers of hereditary breast and ovarian cancers.

Prevalence of CDH1 germline mutations in subjects with early onset or familial lobular breast cancer, a multicenter collaboration

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11042-11042
Author(s):  
S. Masciari ◽  
K. A. Schrader ◽  
J. Senz ◽  
N. Tung ◽  
J. Balmana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Family History ◽  
Early Onset ◽  
Direct Sequencing ◽  
Familial Cancer ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Prophylactic Gastrectomy ◽  
History Of

11042 Background: Invasive lobular breast carcinoma (LBC) is part of the hereditary diffuse gastric cancer (HDGC) syndrome, associated with germline mutations in the E-cadherin (CDH1) gene. CDH1 mutations can be identified in 80% of families ascertained by DGC. The risk of DGC in CDH1 mutation carriers is 67% in males, and 83% in females; the estimated risk of LBC in women is 39–50% to age 80. Management of HDGC includes prophylactic gastrectomy. In this study, we estimated the prevalence of germline CDH1mutations among women with LBC who were either diagnosed at young age or had family history of breast cancer (BC). Methods: Germline DNA was collected from 383 women with LBC or mixed, lobular/ductal, BC from breast cancer programs, familial cancer clinics, and population-based cohorts. Germline BRCA1or BRCA2mutations carriers were excluded. Eligible women had (1) LBC before age 45 or (2) LBC at any age with at least two 1st or 2nd degree relatives with BC of any type. Denaturing high pressure liquid chromatography was undertaken, followed by direct sequencing of exons displaying changes. Results: At the time of submission 310 of 383 samples have been fully sequenced. One previously characterized missense mutation and four novel non-synonymous variants (1.6%) were found. Three of these women had LBC before 45 years and no family history of BC; two had BC family history. No gastric cancers were reported in these families. Functional assays to assess the pathogenicity of the variants are in process. Conclusions: These results confirm that CDH1 is responsible for a small proportion of familial and early onset LBC. Given the difficulty of identifying CDH1 mutations from BC history alone and the importance of managing the gastric cancer risk in CDH1carriers, these findings should underscore the need to obtain an accurate abdominal cancer family history from women with LBC. No significant financial relationships to disclose.

scholarly journals Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer

2016 ◽  
Vol 34 (13) ◽  
pp. 1460-1468 ◽  
Author(s):  
Nadine Tung ◽  
Nancy U. Lin ◽  
John Kidd ◽  
Brian A. Allen ◽  
Nanda Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Triple Negative ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Cancer Predisposition ◽  
Ashkenazi Jewish ◽  
Breast Cancer Predisposition ◽  
Cancer Susceptibility Genes ◽  
Predisposition Genes

Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

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