Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay

Baert, Annelot; Depuydt, Julie; Maerken, Tom Van; Poppe, Bruce; Malfait, Fransiska; Damme, Tim Van; Nobele, Sylvia De; Perletti, Gianpaolo; Leeneer, Kim De; Claes, Kathleen; Vral, Anne

doi:10.3892/or.2017.5407

Cited by 29 publications

(21 citation statements)

References 39 publications

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“…Loss of such DNA-damage "recognition and signaling" genes have often been described to promote radio-resistance (10)(11)(12)31,32). In contrast, the protein product of the BRCA2 gene plays a key role in the effector downstream of DNA-repair and deficiency at this point of the cascade commonly translates into increased radio-sensitivity (12,13,33,34).…”

Section: Next-generation-sequencingmentioning

confidence: 99%

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

et al. 2019

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Prostate-specific membrane antigen (PSMA) targeting alpha-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT nonresponding lesions by targeted next-generation sequencing (tNGS). Methods: Out of 60 patients treated with 225 Ac-PSMA-617, we identified 10 patients that presented with a poor response despite sufficient tumor-uptake in PSMA-PET/CT. We were able to perform CT-guided biopsies with histologic validation of the non-responding lesions in seven of these non-responding patients. Specimens were analyzed by tNGS interrogating 37 DNA damage-repair associated genes. Results: In the seven tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n=3); CHEK2 (n=2), ATM (n=2); BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB and PMS1 (n=1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC-and various FANC-genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA-positivity frequently harbor mutations in DNA-damage-repair and checkpoint genes. While the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA-damage-repair targeting agents such as Poly(ADPribose)-Polymerase inhibitors.

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Section: Next-generation-sequencingmentioning

confidence: 99%

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

et al. 2019

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“…The exclusion criteria was having a medical treatment especially radiation exposure. The ABO blood typing was performed using monoclonal grouping kit (Fortress Diagnostics Ltd, UK) G 2 MN assay G 2 MN assay was conducted based on the Baert et al [22] with modifications. Two cultures were set up in 15 mL centrifuge tube for each blood sample.…”

Section: Blood Samplingmentioning

confidence: 99%

Assessment of Individual Radiosensitivity in Inhabitants of Takandeang Village － A High Background Radiation Area in Indonesia

et al. 2019

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People living in high background radiation areas (HBRAs) possibly develop the radioadaptive response (RAR) phenomenon. The Mamuju area in West Sulawesi Indonesia is known as an HBRA in Indonesia due to its high natural uranium contents. It is possible that RAR has developed in Mamuju inhabitants. To prove this hypothesis, here in this study, evaluation of the individual radiosensitivity in the inhabitants of Takandeang Village, Mamuju, was conducted using G 2 micronucleus (MN) assay. Association between blood groups and TP53 Arg72Pro polymorphism with individual radiosensitivity was also evaluated in this study. Using G 2 MN assay, we assessed the individual radiosensitivity of Takandeang Village inhabitants and control samples. For each sample, three parameters were calculated. The spontaneous (baseline) MN number, MN number after 0.5 Gy in vitro irradiation, and radiation-induced MN were calculated to predict the individual radiosensitivity. The radiation-induced MN was defined by subtracting the spontaneous MN number from the MN number after irradiation. The mean and SD of the number of micronuclei induced by radiation found in control group (CG) was set as the cutoff value to determine the individual radiosensitivity in all samples. The occurrence of a radiation-induced MN value higher than the mean CG + 1SD CG was scored as 1, indicating a milder radiosensitive phenotype, whereas a result higher than the mean CG + 2SD CG was scored as 2, and indicated a more severe radiosensitive phenotype. When the individual value was lower than the mean CG + 1SD CG, a score of 0 was attributed to the tested subject. The results showed that four individuals in Takandeang Village inhabitants had a milder radiosensitive phenotype, while the others were categorized as normal radiosensitive. A similar finding was also found in control samples. Our study failed to find any correlation between radiosensitivity and either blood group or the TP53 Arg72Pro polymorphism. Overall, our study revealed the possibility of RAR phenomena in Takandeang Village inhabitants. Further investigation using a different point of radiation dose value and larger sample number should be performed to validate this study results.Journal homepage: http://aij.batan.go.id

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“…Mutation of BRCA1 5'ss 41222944 is known to activate a css at +69 (13)(14)(15) or at +65 (16) These two css exactly match the bss with the most supporting reads ( Figure 1B, red shading). The background splicing information is therefore a good match to the slightly different experimental results of both groups.…”

Section: Brca1mentioning

confidence: 93%

Background splicing and genetic disease

Alexieva

Sarkar

et al. 2020

Preprint

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We report that low level background splicing by normal genes can be used to predict the likely effect of splicing mutations upon cryptic splice site activation and exon skipping, with emphasis on the DBASS databases, BRCA1, BRCA2 and DMD. In addition we show that background RNA splice sites are also involved in pseudoexon formation, recursive splicing and aberrant splicing in cancer. We discuss how background splicing information might inform splicing therapy.

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Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay

Cited by 29 publications

References 39 publications

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Assessment of Individual Radiosensitivity in Inhabitants of Takandeang Village － A High Background Radiation Area in Indonesia

Background splicing and genetic disease

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