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Tumor Discovery Haplotype and LD of BRCA genes in GBM

1. Introduction in GBM patients, the impaired DNA compromises
pharmacological methodologies aiming to induce synthetic
Glioblastoma (GBM) is the most prevalent primary lethality that causes cancer cell death. This cell-killing
brain tumor in adults. According to the World Health procedure occurs only when two molecular pathways are
Organization, it is an aggressive, necrosis-prone, and concurrently lacking in a single cell, while an isolated
mitotically vigorous grade IV malignant. It accounts for defect is innocuous. One category of drugs that applied
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45.2% of all malignant primary tumors of the brain and in this cell-killing procedure includes inhibitors of poly
central nervous system (CNS). GBM is considered an (ADP-ribose) polymerase (PARP) enzyme, a significant
inveterate disease with a 15-month median survival rate. DNA damage response constituent. PARP inhibitors
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Only 5.5% of patients survive for 5 years after diagnosis. (PARPis) may induce artificial lethality in tumor cells with
2
GBMs are divided into primary and secondary subtypes pre-existent imperfections in the HR repair pathway, such
that develop through various genetic routes, affecting as lethal mutations of the BRCA1 and BRCA2 suppressor
individuals at different ages with varying outcomes. genes. Most GBM clinical experiments assessing PARPis
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Primary GBMs account for 80% of GBMs and are detected do not assess the BRCA status to correlate outcomes
in people over the age of 62, while secondary GBMs occur among patient assemblies. A plausible explanation for
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in patients under the age of 45 and are triggered by low- this omission could be the predictable low incidence of
grade astrocytomas or oligodendrogliomas. Secondary BRCA mutations in GBM compared to ovarian, breast, and
GBMs are more likely to occur in the frontal lobe, display pancreatic cancer. 16,17
less necrosis, and have a better prognosis than primary
GBMs. At present, the detection of mutations in certain Germline mutations in several types of genes (tumor
cancer cell genes has an extremely high predictive and suppressors, oncogenes, and DNA repair genes) have been
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prognostic value and enables the advancement of targeted widely analyzed in genome-wide association studies.
therapies. The previous studies have reported that genomic variants
linked to cancer often exhibit an ancestry-specific effect,
Existing treatment approaches for GBM are based on a termed “flip-flop,” as the variant associated with cancer in
combination of surgical methods along with radiotherapy an ancestral population might have no association or an
and chemotherapy. Important variations in therapeutic opposite association as a result of linkage and epistatic
techniques include the addition of temozolomide (TMZ) effect. There are few studies worldwide implicating local
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(alkylating chemotherapeutics) to the treatment regimen. ancestry for cancer-causing alterations or recognizing
Fractionated radiotherapy and six cycles of TMZ-based novel ancestry-associated molecular characteristics. 20,21
4,5
chemotherapy have been used in GBM patients. Several
clinical trials have demonstrated that long-term adjuvant This research aims to investigate the frequency of
TMZ chemotherapy improves progression-free survival BRCA mutations in GBM patients compared to healthy
(PFS) and 2-year survival rates in GBM patients and individuals, using sequencing technology to detect single
enhances their quality of life, but does not improve the nucleotide polymorphisms (SNPs) as well as insertions
overall survival (OS) significantly. A recent randomized and deletions (InDels) that serve as the foundation for
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trial compared the results obtained from using TMZ allele differentiation. Haplotype analysis, which contains a
in combination with interferon alpha and TMZ alone collection of linked SNPs, proves to be more informative
to evaluate the therapeutic efficacy and assess toxic than the analysis of single SNPs in determining associations
consequences in high-grade glioma (grades 3 and 4). with phenotypes.
The study reported that the combination of TMZ with 2. Methods
interferon alpha extended the survival time while
maintaining tolerable toxicities compared to using TMZ 2.1. Sample selection and inclusion criteria
alone. 7 On obtaining ethical approval from the Medical Ethical
The breast cancer susceptibility genes (BRCAs) are Committee of the National Research Centre (ID #17111)
a group of tumor suppressor genes, which includes for this prospective study, 44 individuals were enrolled,
BRCA1 (125,951bp) and BRCA2 (85,405bp). BRCA genes divided into patients with GBM (n = 15) and healthy,
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are involved in cellular resistance to alkylating chemicals normal individuals as controls. The inclusion criteria for
and are responsible for homologous recombination (HR) the recruited groups were as follows: for GBM patients,
(a double-strand break repair process). 8-11 Mutations in they were above 18 years old, newly diagnosed using
these genes have been identified in several cancers, the magnetic resonance imaging (MRI) and pathological
most common of which are breast and ovarian cancer. examination, and their presentation was ≤2 according to
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Although genomic instability may lead to a poor prognosis the Ester Clinical Oncology Group, while for the normal

Volume 3 Issue 1 (2024) 2 https://doi.org/10.36922/td.1480