MCM9 (Minichromosome Maintenance 9 Homologous Recombination Repair Factor)

In the follow-up gene combination double-knockout experiment among 65 genes selected from cell death pathways, 242 synthetic lethal gene pairs were discovered to overcome chemoresistance in TNBC. In this study, we identified synthetic lethal targets in treating TNBC with cisplatin and doxorubicin through a genome-wide CRISPR-Cas9 screening and gene combination double-knockout screening.

Collectively, our data indicates that biallelic MCM9 variants are associated with polyposis, gastric cancer, and early-onset CRC, while both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of including MCM8/MCM9 in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance.

In vivo, ASO 8-3419 inhibited the expression of MCM8 in xenografted tumors of colon cancer-derived HCT116 cells in nude mice and increased tumor sensitivity to cisplatin with minimal toxicity. These findings suggest that AmNA-modified, MCM8-specific ASOs hold promise as novel anti-cancer agents.

Additionally, the procedure developed based on expression levels of TMEM182, MCM9, LRRFIP1, LAMP1, FAM161A, KLHL36, ETV5, RNF168, SRSF11, NCKAP5, CRTAP, VAMP2, ZBTB49 and RIMBP2 proved to be capable in predicting FOLFOX therapy response. In conclusion, our approach can give a unique insight into clinical decision-making regarding therapy scheme administration, potentially increasing patients' survival and, consequently, medical futility due to incorrect therapy application.

Finally, cell-based assays revealed that this HORMA-closure motif interaction pattern contributes to DNA mismatch repair and is required for HORMAD1-dependent HR repair. Together, our results provide structural and biochemical insights into the common theme and functional plasticity of the HORMA domain-containing protein family, and also reveal a universal regulation mechanism for HORMAD1.

In the homozygous females studied, the clinical, hormonal, and gonadal phenotypes revealed ovarian dysgenesis consistent with previous reports. Active screening for potential colorectal and other cancer risks in the homozygotic MCM9 subjects has been instigated.

Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response...In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials.