Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening

BackgroundBreast and ovarian cancers are the most prevalent cancers and one of the leading causes of death in Indian women. The healthcare burden of breast and ovarian cancers and the rise in mortality rate are worrying and stress the need for early detection and treatment.MethodsWe performed amplicon sequencing of 144 cases who had breast/ovarian cancer disease (total 137 cases are patients and seven are tested for BRCA1/2 carrier) Using our custom designed gene panel consisting of 14 genes, that are associated with high to moderate risk of breast and ovarian cancers. Variants were called using Torrent Variant Caller and were annotated using ThermoFisher’s Ion Reporter software. Classification of variants and their clinical significance were identified by searching the variants against ClinVar database.ResultsFrom a total of 144 cases, we were able to detect 42 pathogenic mutations in [40/144] cases. Majority of pathogenic mutations (30/41) were detected in BRCA1 gene, while (7/41) pathogenic mutations were detected in BRCA2 gene, whereas, (2/41) pathogenic mutations were detected in TP53 gene and BRIP1, PALB2, and ATM genes respectively. So, BRCA genes contributed 88.09% of pathogenic mutations, whereas non-BRCA genes contributed 11.91% of pathogenic mutations. We were also able to detect 25 VUS which were predicted to be damaging by in silico prediction tools.ConclusionEarly detection of cancers in the Indian population can be done by genetic screening using customized multi-gene panels. Indications of our findings show that in the Indian population, apart from the common BRCA genes, there are other genes that are also responsible for the disease. High frequency mutations detected in the study and variants of uncertain significance predicted to be damaging by in silico pathogenicity prediction tools can be potential biomarkers of hereditary breast and ovarian cancer in Indian HBOC patients.

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A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico

Cancers ◽

10.3390/cancers10110419 ◽

2018 ◽

Vol 10 (11) ◽

pp. 419 ◽

Cited By ~ 8

Author(s):

Hector Diaz-Zabala ◽

Ana Ortiz ◽

Lisa Garland ◽

Kristine Jones ◽

Cynthia Perez ◽

...

Keyword(s):

Ovarian Cancer ◽

Puerto Rico ◽

Puerto Rican ◽

Age Of Onset ◽

Brca2 Mutation ◽

Brca2 Gene ◽

Dna Polymorphisms ◽

Common Mutation ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.

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A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

International Journal of Molecular Sciences ◽

10.3390/ijms22020889 ◽

2021 ◽

Vol 22 (2) ◽

pp. 889

Author(s):

Ava Kwong ◽

Cecilia Y. S. Ho ◽

Vivian Y. Shin ◽

Chun Hang Au ◽

Tsun Leung Chan ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Brca1 Gene ◽

Pathogenic Mutation ◽

Compound Heterozygous ◽

Strong Family History ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations ◽

Increased Risk ◽

History Of

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.

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Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer

Cancers ◽

10.3390/cancers13010118 ◽

2021 ◽

Vol 13 (1) ◽

pp. 118

Author(s):

Louisa Lepkes ◽

Mohamad Kayali ◽

Britta Blümcke ◽

Jonas Weber ◽

Malwina Suszynska ◽

...

Keyword(s):

Ovarian Cancer ◽

In Silico ◽

Copy Number ◽

Gc Content ◽

Copy Number Variations ◽

Cancer Predisposition ◽

Predictive Values ◽

Prediction Tools ◽

Predisposition Genes ◽

Female Index

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.

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Determination of Serum CA125 and evaluate its efficiency as screening tool For Early Detection of Ovarian Tumors

Baghdad Science Journal ◽

10.21123/bsj.12.1.55-62 ◽

2015 ◽

Vol 12 (1) ◽

pp. 55-62

Author(s):

Baghdad Science Journal

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

Screening Tool ◽

Stage I ◽

Ca 125 ◽

Benign Tumors ◽

Cancer Antigen 125 ◽

Ovarian Cancers ◽

Serum Ca125 ◽

Low Sensitivity

Epithelial ovarian cancer is the leading cause of cancer deaths in women. To date, an effective screening tool for ovarian cancer has not been identified Several clinical and biological factors including serum cancer antigen 125 (CA- 125) have been assessed for prognostic and predictive relevance CA-125 is an epithelial marker derived from coelomic epithelium. It is elevated in 90% of advanced ovarian cancers and in 50% of early ovarian cancers while 20% of ovarian cancers have low or no expression of CA- 125 CA-125 concentrations were measured by Mini Vidas test (VIDAS CA125 II / BIOMERIEUX / France). The median CA-125 levels were significantly higher in the sera of ovarian cancer patients than in those with benign tumors and in healthy controls. However in correlation with stages the results showed that Patients with stage II have highly significant differences in level of serum CA125 compare with stage I in and stage III.CA125 showed low sensitivity to detect stage I carcinoma of the ovary which limits its value as an initial screening tool therefore combining of CA125 with other markers might enable improved early detection of ovarian cancer as compared with use of this marker alone.

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A case series of sporadic breast and ovarian cancers in Salentinian families with BRCA mutation-associated Hereditary Breast and Ovarian Cancer (HBOC) syndrome

Annals of Oncology ◽

10.1093/annonc/mdw337.26 ◽

2016 ◽

Vol 27 ◽

pp. iv67

Author(s):

E. De Matteis ◽

M.R. De Giorgio ◽

P. Tarantino ◽

G. Ronzino ◽

M. Ciccarese ◽

...

Keyword(s):

Ovarian Cancer ◽

Brca Mutation ◽

Case Series ◽

Breast And Ovarian Cancer ◽

Ovarian Cancers

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Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.979 ◽

1998 ◽

Vol 16 (3) ◽

pp. 979-985 ◽

Cited By ~ 151

Author(s):

V R Grann ◽

K S Panageas ◽

W Whang ◽

K H Antman ◽

A I Neugut

Keyword(s):

Quality Of Life ◽

Ovarian Cancer ◽

High Risk ◽

Surgical Procedures ◽

Brca2 Gene ◽

Cost Effective ◽

Prophylactic Surgery ◽

Breast And Ovarian Cancer ◽

Prophylactic Surgical Procedures

PURPOSE Young Ashkenazi Jewish women or those from high-risk families who test positive for BRCA1 or BRCA2 mutant genes have a significant risk of developing breast or ovarian cancer by the age of 70 years. Many question whether they should have prophylactic surgical procedures, ie, bilateral mastectomy and/or oophorectomy. METHODS A Markov model was developed to determine the survival, quality of life, and cost-effectiveness of prophylactic surgical procedures. The probabilities of developing breast and ovarian cancer were based on literature review among women with the BRCA1 or BRCA2 gene and mortality rates were determined from Surveillance, Epidemiology, and End Results (SEER) data for 1973 to 1992. The costs for hospital and ambulatory care were estimated from Health Care Financing Administration (HCFA) payments in 1995, supplemented by managed care and fee-for-service data. Utility measures for quality-adjusted life-years (QALYs) were explicitly determined using the time-trade off method. Estimated risks for breast and ovarian cancer after prophylactic surgeries were obtained from the literature. RESULTS For a 30-year-old woman, according to her cancer risks, prophylactic oophorectomy improved survival by 0.4 to 2.6 years; mastectomy, by 2.8 to 3.4 years; and mastectomy and oophorectomy, by 3.3 to 6.0 years over surveillance. The QALYs saved were 0.5 for oophorectomy and 1.9 for the combined procedures in the high-risk model. Prophylactic surgeries were cost-effective compared with surveillance for years of life saved, but not for QALYs. CONCLUSION Among women who test positive for a BRCA1 or BRCA2 gene mutation, prophylactic surgery at a young age substantially improves survival, but unless genetic risk of cancer is high, provides no benefit for quality of life. Prophylactic surgery is cost-effective for years of life saved compared with other medical interventions that are deemed cost-effective.

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Prevalence Rates of Pathogenic Mutations in theBRCA1andBRCA2Genes in Families with Different Disease Histories: Results from the German Consortium for Hereditary Breast and Ovarian Cancer.

10.1158/0008-5472.sabcs-09-4073 ◽

2009 ◽

Cited By ~ 1

Author(s):

K. Kast ◽

R. Schmutzler ◽

W. Distler ◽

N. Arnold ◽

C. Bartram ◽

...

Keyword(s):

Ovarian Cancer ◽

Prevalence Rates ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

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Results of NGS panel of hereditary breast and ovarian cancer in Lebanese women.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13045 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13045-e13045

Author(s):

Joseph Al Ajami ◽

Nadine Jalkh ◽

Ghadi Moubarak ◽

Roland Eid ◽

Fady Haddad ◽

...

Keyword(s):

Ovarian Cancer ◽

High Risk ◽

Mutation Rate ◽

Founder Effect ◽

Familial Cancer ◽

Brca1 Gene ◽

Pathogenic Mutation ◽

Genetic Alterations ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

e13045 Background: Hereditary breast (BC) and ovarian cancer (OC) genetic alterations are considered the most prevalent among familial cancer. To date, four studies have exposed the mutations related to hereditary BC predisposition in the Lebanese population , with percentage of BRCA-related pathogenic mutations ranging between 5 % and 15 %. Methods: Between 2017 and 2019, 117 patients with high risk hereditary breast and ovarian cancer were referred to undergo the testing at the Unité de Génétique médicale (UGM) of Saint-Joseph University of Beirut, Lebanon. The sequencing was accomplished by using the 21-panel Next-Generation Sequencing (NGS) method for all of our patients, to which we also added the MLPA technique followed by the Sanger sequencing for validation whenever a genetic alteration was found. Results: From 117 Lebanese women with high-risk hereditary breast and ovarian cancer predisposition, 19 pathogenic mutations were identified in this study: 11 BRCA1, 1 BRCA2, 2 PALB2, 1 ATM, 1 CDH1, 1 MSH6, 1 RAD51C, and 1 BRIP1. Among those, 13 patients had BC, one had OC and five were healthy individuals. Five similar mutations were found within the BRCA1 gene, the p.C44F mutation, accounting for 45.4 %, thus suggesting a founder effect. Average age at diagnosis in the BC patients carrying a mutation was 41 years and 38.5% had a triple negative BC. Conclusions: The overall pathogenic mutation rate was equal to 16.2% while the BRCA deleterious mutation rate was 10.3% lower to those reported in the literature. The p.C44F mutation appeared five times suggesting a founder effect. [Table: see text]

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