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In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation‐wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0–10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety‐one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety‐eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7–10. The major reason for choosing 0–6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy. In Japan, where comprehensive genomic profiling tests are given as part of the national healthcare system, patient satisfaction of the test process was high. More patients need to be treated with genomically matched therapy.

Integrins are transmembrane receptors that facilitate cell adhesion to the extracellular matrix and neighboring cells. Aberrant expression of integrins has been associated with tumor progression and metastasis in various cancer types. Integrin alpha‐5 (ITGA5) is an integrin subtype that serves as a receptor for fibronectin, fibrinogen, and fibrillin‐1. The purpose of this study was to elucidate how ITGA5 expression plays a role in human non‐small cell lung cancer (NSCLC). Our clinical data, along with data retrieved from The Cancer Genome Database (TCGA), revealed that high ITGA5 expression in NSCLC patients was associated with a lower recurrence‐free survival and overall survival. In our in vitro functional assays, ITGA5 overexpression in human NSCLC cell lines resulted in increased cell size, adhesion, and migration properties, while knockdown of ITGA5 restored the phenotypes. Correspondingly, knockdown and inhibition of ITGA5 in endogenously high‐expressing NSCLC cell lines resulted in decreased cell size, adhesion, migration, and proliferation. The antiproliferative effect was also confirmed by a reduction in Ki‐67 without discernible changes in apoptosis. Collectively, these findings reveal the significant role of ITGA5 in various functional behaviors in NSCLC, providing a potential therapeutic target for NSCLC patients with high ITGA5 expression. Our overexpression, knockdown, and inhibitor studies showed that ITGA5 may play a significant role in NSCLC by affecting cellular adhesion, migration, and proliferation. These findings imply a potential therapeutic target for NSCLC patients with elevated ITGA5 expression.

High-grade serous ovarian cancer (HGSOC) is a poor prognostic disease, especially in BRCA1 / 2 wild-type (BRCA-WT) patients with homologous recombination (HR) proficiency. These patients often show limited response to both platinum-based chemotherapy and PARP inhibitors. HR and non-homologous end joining (NHEJ) are the two major DNA double-strand break (DSB) repair pathways. HR is a precise repair mechanism for DSBs but is limited to S and G2 phases. In contrast, NHEJ functions more broadly throughout the cell cycle, including G1. We investigated whether inhibiting the G2/M checkpoint kinases PLK1 or WEE1 individually could disrupt mitotic control and expose therapeutic vulnerabilities in BRCA-WT/HR-proficient HGSOC cells. We evaluated cell cycle–targeted strategies to overcome HR-proficient chemoresistance using either volasertib (a selective PLK1 inhibitor) or adavosertib (a potent WEE1 inhibitor) in BRCA-WT/HR-proficient and BRCA-mutant/HR-deficient HGSOC models. Both agents induced DNA damage, impaired HR repair (reduced RAD51 foci), and triggered mitotic catastrophe—a form of cell death caused by defective mitosis and unresolved DNA damage—in BRCA-WT cells. Volasertib caused polyploidy and abnormal spindle formation, indicating mitotic slippage and cytokinesis failure, whereas adavosertib abrogated the G2/M checkpoint, forcing premature mitotic entry. In contrast, BRCA-mutant cells were resistant to either volasertib or adavosertib, consistent with sustained and functional NHEJ activity. This resistance was restored by the pharmacological or genetic inhibition of DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), a prominent component of NHEJ. Functional and xenograft models confirmed selective vulnerability of BRCA-WT tumors to either PLK1 or WEE1 inhibition. Our work highlights a mechanistic framework linking cell cycle checkpoint inhibition to DNA repair pathway selectivity, providing a rationale for targeting mitotic regulators in HR-proficient ovarian cancer—a subgroup with high clinical unmet need.

Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including an Alu insertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk. MEGAnE is a new tool to detect and genotype mobile element variants (MEVs) from short-read whole-genome sequencing datasets. Genetic analyses implicate MEVs as population-specific drivers of gene expression variation and disease risk.

Mobile genetic elements (MEs) are heritable mutagens that contribute to divergence between lineages by recursively generating structural variants. ME variants (MEVs) are difficult to genotype, obscuring their impact on recent genome and trait diversification. We developed a tool that uses short-read sequence data to accurately genotype MEVs, enabling us to study them using statistical genetics methods in global human genomes. We observe population-specific differences in the distribution of Alu insertions that distinguish Japanese from other populations. We integrated MEVs with epigenomic and expression quantitative trait loci (eQTL) maps to determine how they impact traits. This reveals coherent patterns by which specific MEs regulate tissue-specific gene expression, including creating or attenuating enhancers and recruiting post-transcriptional regulators. We pinpoint MEVs as genetic causes of disease risk, including a LINE-1 insertion linked to keloid and other diseases of fibroblast inflammation, by introducing MEVs into the genome-wide association study (GWAS) framework. In addition to nominating previously-hidden MEVs as causes of human diseases, this work highlights MEs as accelerators of human population divergence and begins to decipher the semantics of MEs. Competing Interest Statement The authors have declared no competing interest.