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Tumor Discovery Haplotype and LD of BRCA genes in GBM

(PRAPi) to improve efficacy through synergistic activity 5. Conclusion
and potentially sensitize naturally PARPi-resistant tumors
to PARPi. Initial combinations of PARPi and chemotherapy We build on our earlier finding that haplotype analysis
were delayed by major overlapping hematologic toxicity, among GBM patients can help predict patients who may
but the latest combinations with lower toxicities and more benefit from TMZ treatment and that analyzing BRCA1
targeted approaches are currently undergoing assessments. haplotypes may identify those who are at low risk of
28
developing cancer.
In preclinical studies, the combination of TMZ with PRAPi
has an enhanced cytotoxic effect, independent of HR, as Acknowledgments
29
TMZ stimulates base damage, leading to the development
of PARP-DNA complexes, which, in combination with None.
effective PARP-trapping agents, enhance cytotoxicity.
This has encouraged research into trials assessing this Funding
combination over different tumor histologies such as The study was supported by the Science and Technology
GBM, colorectal cancer, and breast cancer. In general, Development Fund (STDF) through Capacity Building
31
32
30
the combination of TMZ and PARP inhibition was found Grant Fund (CBG) (Grant No. 4940).
to be well-tolerated, although efficacy was modest in most
tumor subtypes. 33 Conflict of interest
One of the assumed haplotypes includes haplotype The authors declare that they have no competing interests.
[B], detected in homo- or heterozygous forms, which was
associated with a familial history of breast cancer in the Author contributions
control individuals studied. This outcome was in agreement Conceptualization: Mohamed K. Khalifa, Amira M Nageeb,
with the study of Tuazon et al. Therefore, it will be Menha Swellam
34
important to carry out a future prospective study to confirm Formal Analysis: Mohamed K. Khalifa MS, Amira M
this finding in a large group of Egyptian individuals. Nageeb
This paper is the first to report on the three identified Investigation: Mohamed K. Khalifa LRE, Amira M Nageeb,
haplotypes, termed haplotypes [C], [D], and [H], and all Lobna R. Ezz El Arab
were in heterozygous form. GBM patients with haplotypes Methodology: Mohamed K. Khalifa, Amira M Nageeb,
[C] and [D] responded to treatment with either CR or PR. Menha Swellam
Hence, it could be of great value to investigate the BRCA1 Writing – original draft: Mohamed K. Khalifa, Amira M
haplotype among GBM patients before their treatment, as Nageeb, Menha Swellam
it was previously confirmed that BRCA1 protein expression Writing – review & editing: All authors
may as well predict GBM survival. Moreover, the newly Ethics approval and consent to participate
35
reported haplotype [H] was only detected in healthy
individuals (n = 25), which may indicate that this type of Ethical approval of the study was obtained from the
haplotype reports a lack of risk for cancer predisposition. Medical Ethical Committee of the National Research
A prospective study is currently underway to confirm this Center (ID#17111), Egypt, and all participants signed
finding in a large Egyptian population. informed consent.
Although GBM haplotype analysis is of great importance Consent for publication
and the present study sheds light on this type of analysis in Participants have signed their informed consent for
relation to GBM as one of the cancers worldwide, the small publishing their data in this study.
number of cases is one of the limitations of the study. This
small number could be due to the fact that the incidence Availability of data
of cancer among Egyptians is not as high as breast or
liver cancer. As this study is in the preliminary stage, the Data used in this work are available from the corresponding
enrollment of a large number of cases will be considered author on reasonable request.
in ongoing prospective research. Another limitation is References
the lack of some data for GBM patients, such as Isocitrate
dehydrogenase1 (IDH1) and O6-methylguanine-DNA- 1. Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic
methyltransferase (MGMT) status, so a comparison of and molecular prognostic review of glioblastoma. Cancer
haplotype variance regarding mutant IDH1 and MGMT Epidemiol Biomarkers Prev. 2014;23(10):1985-1996.
methylation was not reported. doi: 10.1158/1055-9965.EPI-14-0275

Volume 3 Issue 1 (2024) 7 https://doi.org/10.36922/td.1480