BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents

Darabi, Sourat; Braxton, David R.; Xiu, Joanne; Carneiro, Benedito A.; Swensen, Jeff; Antonarakis, Emmanuel S.; Liu, Stephen V.; McKay, Rana R.; Spetzler, David; El‐Deiry, Wafik S.; Demeure, Michael J.

doi:10.3390/medicina58121818

Cited by 8 publications

(9 citation statements)

References 18 publications

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“…Notably, these variants were prominently located in exon 10 for BRCA1 and exon 11 for BRCA2, mirroring the distribution pattern observed for BRCA1/2 somatic PVs. This underscores the susceptibility of the relatively larger exon 10 and exon 11 in both genes to heightened mutational activity, as previously suggested by Darabi et al [ 35 ].…”

Section: Discussionsupporting

confidence: 80%

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

Youssef,

Zekri,

Mohanad

et al. 2023

Clin Exp Med

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This study aimed to identify BRCA1/2 mutational patterns in the tissue and blood of Egyptian colorectal cancer (CRC) patients and to study the possible correlation of this mutational pattern with Human papillomavirus (HPV) infection. Eighty-two colonoscopic biopsies and forty-six blood samples were collected from Egyptian CRC patients, as well as blood samples of age and sex-matched healthy controls (n = 43) were enrolled. The libraries were performed using Qiaseq Human BRCA1 and BRCA2 targeted DNA panel and sequenced via Ion proton sequencer. Also, the CRC tissues were subjected to conventional PCR targeting the HPV Late 1 (L1) region. Our analysis revealed that the BRCA-DNA damage pathway had been altered in more than 65% of the CRC patients. Comparing tissue and blood samples from CRC patients, 25 somatic mutations were found exclusively in tissue, while 41 germline mutations were found exclusively in blood. Additionally, we identified 23 shared BRCA1/2 pathogenic (PVs) mutations in both blood and tissue samples, with a significantly higher frequency in blood samples compared to tissue samples. The most affected exon in BRCA1 was exon 10, while the most affected exons in BRCA2 were 11, 14, 18, 24, and 27 exons. Notably, we revealed an ethnic-related cluster of polymorphism variants in our population closely related to South Asian and African ethnicities. Novel PVs were identified and submitted to the ClinVar database. HPV was found in 23.8% of the CRC tissues, and 54% of HPV-positive cases had somatic BRCA1/2 PVs. The results of this research point to a possible connection between infection with HPV and BRCA1/2 mutations in the occurrence of colorectal cancer in the Egyptian population, which has a mixed ethnic background. Our data also indicate that liquid biopsy (blood samples) may be more representative than tissue samples for detecting BRCA1/2 mutations. These findings may have implications for cancer screening and the development of personalized, targeted therapies, such as PARP inhibitors, which can effectively target BRCA1/2 mutations.

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Section: Discussionsupporting

confidence: 80%

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

Youssef,

Zekri,

Mohanad

et al. 2023

Clin Exp Med

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“…and Yonina et al . [ 12 , 13 ] also presented findings indicating a higher occurrence of reversion mutations in breast and ovarian carcinomas compared with other tumor histologies. Whether this observation can be attributed to the elevated frequency of BRCA mutations in breast and ovarian cancers, or if there exists a tissue-specific context that facilitates a higher likelihood of reversion mutations, remains to be clarified.…”

Section: Discussionmentioning

confidence: 89%

Metastatic lung adenocarcinoma with BRCA2 mutation and longstanding disease control on olaparib, developing triple negative breast adenocarcinoma with additional BRCA2 reversion mutation: a case report

del Giglio,

da Costa Aguiar Alves,

Murad

et al. 2023

J Med Case Reports

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Background The BRCA2 gene is a well-known tumor suppressor gene implicated in breast and ovarian cancers. BRCA1/2 mutations can be sensitive to poly ADP-ribose polymerase (PARP) inhibitors such as olaparib. However, some of these patients develop resistance to this treatment and an essential factor contributing to acquired insensitivity is the occurrence of reversion mutations in the BRCA1/2 genes. Case presentation We report the case of a 65-year-old Brazilian female patient who had previously been diagnosed with metastatic lung carcinoma carrying a BRCA2 mutation that had extended to the central nervous system. Following disease progression, olaparib was administered, resulting in a stabilizing effect on her condition for ~ 30 months. During a routine follow-up, a new triple-negative breast tumor was found. Genetic testing revealed the presence of two distinct BRCA2 gene mutations in the breast tumor. The original mutation (p.Val220Ilefs4) led to a frameshift, culminating in the production of a truncated and non-functional BRCA2 protein; the second mutation, K437fs22, rectified the reading frame of exon 11. Consequently, Rad51 could properly bind to BRCA2—an essential protein crucial for DNA repair. This restoration resulted in a functional BRCA2 protein, effectively elucidating the clinical resistance observed in the new breast tumor in this case. Conclusions This case report highlights the clinical significance of comprehensive next-generation sequencing analyses for lung adenocarcinomas, both at diagnosis and upon progression. Such analyses enable informed decisions regarding targeted therapies and facilitate a deeper comprehension of resistance mechanisms.

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“…In the present study, we explored combining olaparib with ATR/CHK1 pathway inhibitors in the previously developed PEO1-OR cell line with acquired resistance to olaparib and restored BRCA2 9 . Although BRCA2 reversion mutations occur in the minority of OC patients treated with PARPi 26 , 27 , they tend to accumulate upon progression 27 and represent a well-established mechanism of olaparib resistance. Importantly, our cell line serves as a valuable model of olaparib resistance, mirroring reversion mutations in BRCA2 in PARPi-treated HGSOC patients 28 .…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells

Biegała,

Gajek,

Szymczak-Pajor

et al. 2023

Sci Rep

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Olaparib is a PARP inhibitor (PARPi) approved for targeted treatment of ovarian cancer (OC). However, its efficacy is impeded by the inevitable occurrence of resistance. Here, we investigated whether the cytotoxic activity of olaparib could be synergistically enhanced in olaparib-resistant OC cells with BRCA2 reversion mutation by the addition of inhibitors of the ATR/CHK1 pathway. Moreover, we provide insights into alterations in the DNA damage response (DDR) pathway induced by combination treatments. Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Antibody microarrays were used to explore changes in expression of 27 DDR-related proteins. Olaparib in combination with ATR/CHK1 inhibitors synergistically induced a decrease in viability and clonogenic survival and an increase in apoptosis mediated by caspase-3/7 in all OC cells. Combination treatments induced cumulative alterations in expression of DDR-related proteins mediating distinct DNA repair pathways and cell cycle control. In the presence of ATRi and CHK1i, olaparib-induced upregulation of proteins determining cell fate after DNA damage (PARP1, CHK1, c-Abl, Ku70, Ku80, MDM2, and p21) was abrogated in PEO1-OR cells. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2MUT olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC.

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BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents

Cited by 8 publications

References 18 publications

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

Metastatic lung adenocarcinoma with BRCA2 mutation and longstanding disease control on olaparib, developing triple negative breast adenocarcinoma with additional BRCA2 reversion mutation: a case report

Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells

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