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BRCA1 / BRCA2, Full Gene Analysis with NGS

The BRCA1 / BRCA2 Full Gene Analysis with NGS is a genetic screening test performed using the Next Generation Sequencing (NGS) technique. It aims at detecting a mutation in the sequence coding BRCA1 and BRCA2 genes. This test determines the risk of developing breast and/or ovarian cancer, connected with the specific mutations in BRCA genes.

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Identifying BRCA1 and BRCA2 mutations is crucial for assessing an individual's risk of hereditary breast and ovarian cancer. People with mutations in these genes may consider increased surveillance, preventive measures, or risk-reduction strategies, such as prophylactic surgery. In some cases, knowing about these mutations can also guide treatment decisions, especially in the context of targeted therapies like PARP inhibitors.

Genetic testing can identify BRCA1 and BRCA2 mutations, and genetic counseling is recommended for individuals with a family history of breast or ovarian cancer to assess their risk and discuss appropriate actions.

Not all mutations in these genes have the same impact, and the specific mutation type and location can influence the level of cancer risk. Genetic and environmental factors also contribute to an individual's overall cancer risk.

BRCA1 and BRCA2 are two human genes that play a crucial role in maintaining the stability of the DNA in the cells. Mutations or alterations in these genes can significantly increase the risk of developing breast and ovarian cancers, as well as other cancers.

BRCA1 (Breast Cancer Gene 1)
  • Function: The BRCA1 gene is a tumor suppressor gene that plays a role in DNA repair. It helps repair damaged DNA, preventing the accumulation of mutations that could lead to the development of cancer.
  • Chromosomal Location: BRCA1 is located on the long arm of chromosome 17 (17q21).
  • Associated Cancers: Mutations in BRCA1 are associated with an increased risk of breast cancer, ovarian cancer, and other cancers, such as prostate and pancreatic cancer. The risk of breast and ovarian cancer is particularly high in individuals with BRCA1 mutations.
  • Inheritance Pattern: BRCA1 mutations are typically inherited in an autosomal dominant pattern. This means that an individual with a single mutated BRCA1 allele has an increased risk of developing cancer.
BRCA2 (Breast Cancer Gene 2)
  • Function: Like BRCA1, BRCA2 is also a tumor suppressor gene in DNA repair. It is responsible for repairing double-strand DNA breaks, which are particularly crucial for maintaining genomic stability.
  • Chromosomal Location: BRCA2 is located on the long arm of chromosome 13 (13q13).
  • Associated Cancers: Mutations in BRCA2 are associated with an increased risk of breast cancer, ovarian cancer, and other cancer types, such as pancreatic cancer, prostate cancer, and melanoma. The risk of breast and ovarian cancer is elevated in individuals with BRCA2 mutations.
  • Inheritance Pattern: BRCA2 mutations are also inherited in an autosomal dominant pattern.

Next-generation sequencing (NGS) is a powerful and high-throughput technology used for sequencing DNA, which includes the analysis of BRCA genes. NGS, also known as massively parallel sequencing, is a modern DNA sequencing technology that allows for the rapid and cost-effective analysis of DNA, RNA, or other nucleic acids. It has revolutionized genomics research and clinical diagnostics due to its ability to sequence large amounts of genetic material simultaneously.

NGS is widely used in the analysis of BRCA genes for several purposes:

  • Mutation Detection: NGS can detect mutations, including point mutations and large structural variations, within the BRCA1 and BRCA2 genes.
  • Sequencing Entire Genes: NGS enables the sequencing of the entire BRCA1 and BRCA2 genes, allowing for comprehensive analysis, including both coding and non-coding regions.
  • Identifying Variants: NGS can identify single nucleotide variations (SNVs), small insertions or deletions (indels), and copy number variations (CNVs) within BRCA genes.
  • Tumor Profiling: NGS is used to profile tumors. This information is valuable for guiding treatment decisions, especially in the context of targeted therapies like PARP inhibitors.

NGS analysis of BRCA genes is utilized in both clinical and research settings. In the clinic, it is used for genetic counseling and risk assessment, as well as to guide decisions about preventive measures or treatment options for patients at risk. In research, NGS is essential for understanding the genetics of hereditary cancers, improving risk prediction, and developing new therapies.

While Next-Generation Sequencing (NGS) has revolutionized genetic testing, including the analysis of BRCA1 and BRCA2 genes, it does have some limitations and challenges.

Variant Interpretation Complexity: NGS can identify numerous variations in the BRCA genes, including common polymorphisms and rare, potentially pathogenic mutations. Distinguishing between benign and disease-causing variants can be challenging, requiring extensive databases and sophisticated bioinformatics tools for interpretation.

False Positives and False Negatives: NGS can produce false-positive and false-negative results. False positives may occur when a sequence variation is incorrectly identified as pathogenic, leading to unnecessary anxiety or interventions. False negatives can miss clinically significant mutations, failing to identify individuals at risk.

Uncertain Clinical Significance: Some genetic variations may have uncertain clinical significance, meaning it's unclear whether they contribute to disease risk. These variants are often categorized as "variants of uncertain significance" (VUS), making it challenging for specialists to provide clear guidance to patients with such variants.

Copy Number Variations (CNVs): NGS may have limitations in accurately detecting large CNVs in BRCA genes. Other techniques, such as multiplex ligation-dependent probe amplification (MLPA), may be needed to complement NGS in identifying such variations.

See also: BRCA1 / BRCA2, Full Gene Analysis with NGS and MLPA

Despite these limitations, NGS remains a valuable and powerful tool for BRCA gene analysis and genetic testing. Advances in bioinformatics, data interpretation, and quality control procedures continue to improve the accuracy and reliability of NGS results, making it an essential technology for assessing hereditary cancer risk and guiding clinical decisions.

Detection of pathogenic/potentially pathogenic mutations is confirmed by SANGER sequencing.


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