BRCA deletion

Our findings suggest that MCU alterations may be linked to BRCA progression, unveiling new diagnostic and prognostic implications for MCU in BRCA. The study underscores MCU's role in the tumor immune microenvironment and cell cycle progression, positioning it as a potential tool for BRCA precision medicine and drug screening.

The patient received docetaxel chemotherapy and pelvic radiotherapy. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

P2, N=150, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2022 --> Dec 2025

We were able to establish IDCP cases from past high-grade PIN cases. As a number of HRR gene mutations of unknown pathological significance were detected, IDCP cases could be retrieved from past cases and genetic abnormalities could be identified efficiently. The findings of the study provide a possible approach to diagnose prostate cancer cases with genetic mutations at an early stage.

No abstract available

Conclusions Patients with the Mexican founder BRCA1 mutation treated with first line platinum-based chemotherapy have better survival compared with patients with other BRCA1/2 mutations. Legal entity responsible for the study J.A. Bahena.

In general, in our population ovarian cancer associated to BRCA mutation has worse prognosis than sporadic ovarian cancer (BRCA negative). In the other hand, the cases with the large deletion in exons 9-12 in BRCA1 gene has almost the double risk of primary resistance to platinum treatment versus any other pathogenic variant.

Conversely, TP53 alterations were less common for men with rPFS ≥12 months vs <2 months (2/16 vs 14/27; P=0.02 Fisher's exact test, 2-tails), potentially reflecting negative prognosis or a subgroup less sensitive to PARP inhibition. Conclusions Based on these retrospective, exploratory analyses of TALAPRO-1, men exhibiting prolonged benefit typically exhibited BRCA2 copy number loss or homozygous alterations, and lacked TP53 alterations.

Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.

Poly (ADP‑ribose) polymerase (PARP)‑inhibitors (PARPi) such as olaparib and niraparib are currently used as a treatment option for BRCA‑deficient tumors and also show efficacy in platinum‑sensitive tumors...In the present study, it was investigated whether stepwise exposure of ovarian cancer cells to escalating concentrations of olaparib produced subcells with acquired resistance to PARPi and/or acquired cross‑resistance to platinum compounds, paclitaxel, and doxorubicin...Moreover, PARPi sensitivity associated with cross‑sensitivity not only to platinum compounds but also to anthracylines, paclitaxel, and inhibitors of histone deacetylases. These in vitro data indicated that olaparib exposure is unlikely to produce an acquired resistance phenotype and that PARPi‑sensitive ovarian cancer cells are also cross‑sensitive to non‑platinum and even to compounds not directly interacting with the DNA.

Of the 42 BRCA-negative cases, 4 (9.5%) carried a PV in a cancer susceptibility gene. The negative results obtained with MLPA in cases negative for BRCA and the extended genetic panel suggest that large deletions of BRCA are not a relevant cause of cancer susceptibility in this cohort. Otherwise, whole exome sequencing of 22 cases negatives for the previous genetic test showed pathogenic or probably PV in genes with no current evidence of association with breast and ovarian cancer.

Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing DNA damage repair, thus suggesting that SET8 potentiated radiotherapy of carcinomas. As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings, combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated.

Additionally, patients with reversions trended to have longer median radiographic progression-free survival compared to those without or low reversions (8.1 vs 5.5 mo, p=0.12). In conclusion, the high prevalence of patients with BRCA reversion mutations and the displayed longer benefit from niraparib underscores the dependence of these tumors on BRCA mutation as an oncogenic driver and reversion mutations as a marker of secondary resistance to niraparib treatment.

P2, N=150, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

More importantly, these somatic indels in cancer genomes tend to locate in sequences with important functions, which can affect the core secondary structures of proteins and have a bigger overlap with predicted TFBSs in coding regions than the germline indels. The somatic CDS indels are also enriched in highly conserved nucleotides when compared with germline CDS indels.

Conclusions Analysis of serially biopsied BRCA m breast cases revealed frequent acquisition of BRCA1/2 reversion mutations and CREBBP alterations that are not frequently observed in BRCA wt samples. Additional studies are warranted to investigate the possible role of CREBBP in PARPi therapy resistance.

If confirmed in larger series, it might have a relevant clinical impact, leading to a more tailored approach for risk-reducing surgery strategies for OC prevention. Moreover, as we initially include only advanced stages in our analysis, further investigation on the time of onset of early BRCA mutated OC is currently ongoing.

P2, N=150, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2020 --> Dec 2023 | Trial primary completion date: Dec 2020 --> Dec 2022

BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA deletion...RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alteration while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM immunohistochemical expression associated with clinical benefit.

Conclusion  The BRCA MASTR Plus assay on the MiSeq platform is accurate and reproducible for germline BRCA genetic testing, making it suitable for use in a clinical diagnostic laboratory. However, Sanger sequencing may still serve as a confirmatory method to improve diagnostic capability of the MPS assay.

Our findings showed that even though the use of BAP1 and p16 are important tools in the diagnosis of mesothelioma, a proportion of cases still remains negative with approximately 30 % of the cases in which the concordance of BAP1 loss and p16 homozygous deletion will not be present. We consider that the final diagnosis of mesothelioma is best accomplished by a global interpretation of clinical, radiographic, and pathological features including immunohistochemistry and molecular studies.

Among the mutations detected in our study, TP53 (p.R81X), VHL (p.E52X), and BRCA2 (p.K3326X) mutations, which lead to an aberrant transcript with a premature stop codon, were reported for the first time in breast cancer patients from Saudi Arabia. Our study will help in identifying the damaging mutations and predisposing genes in Saudi breast cancer patients.

The study is currently open and enrolling patients. Research Funding: Pfizer, Internal funding

Long-term responders to rucaparib include OC with BRCA mutation, particularly homozygous deletion or rearrangements, which would not be susceptible to somatic reversion mutations, as well as BRCA1 hypermethylation, and RAD51C/D mutations. Research Funding: Clovis Oncology, Inc.

P2, N=150, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2019 --> Dec 2020

P=N/A, N=40, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed