Zhu, Xudong

Background: Integrin family are known as key gears in focal adhesion for triple-negative breast cancer (TNBC) metastasis. However, the integrin independent factor TLN1 remains vague in TNBC. Methods: Bioinformatics analysis was performed based on TCGA database and Shengjing Hospital cohort. Western blot and RT-PCR were used to detect the expression of TLN1 and integrin pathway in cells. A small-molecule C67399 was screened for blocking TLN1 and integrin β1 through a novel computational screening approach by targeting the protein-protein binding interface. Drug pharmacodynamics were determined through xenograft assay. Results: Upregulation of TLN1 in TNBC samples correlates with metastasis and worse prognosis. Silencing TLN1 in TNBC cells significantly attenuated the migration of tumour cells through interfering the dynamic formation of focal adhesion with integrin β1, thus regulating FAK-AKT signal pathway and epithelial-mesenchymal transformation. Targeting the binding between TLN1 and integrin β1 by C67399 could repress metastasis of TNBC. Conclusions: TLN1 overexpression contributes to TNBC metastasis and C67399 targeting TLN1 may hold promise for TNBC treatment. Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81872159, 81902607, 81874301), Liaoning Colleges Innovative Talent Support Program (Name: Cancer Stem Cell Origin and Biological Behaviour), Outstanding Scientific Fund of Shengjing Hospital (201803), and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

Objectives To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC‐P). Patients and Methods We performed targeted sequencing of plasma cell‐free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC‐P and 84 without IDC‐P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients’ survival outcomes was also explored. Results We identified that 29.8% (48/161) and 21.4% (18/84) of patients with and without IDC‐P harboured genomic alterations in DNA repair pathways, respectively ( P = 0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC‐P carriers compared to IDC‐P non‐carriers (11.8% [19/161] vs 2.4% [two of 84], P = 0.024). Germline BReast CAncer type 2 susceptibility protein ( BRCA2 ) and somatic cyclin‐dependent kinase 12 ( CDK12 ) defects were specifically identified in IDC‐P carriers relative to PAC ( BRCA2 : 8.7% [14/161] vs 0% and CDK12 : 6.8% [11/161] vs 1.2% [one of 84]). Patients with IDC‐P had a distinct androgen receptor (AR) pathway alteration, characterised by an enrichment of nuclear receptor corepressor 2 ( NCOR2 ) mutations compared with patients with pure PAC (21.1% [34/161] vs 6.0% [five of 84], P = 0.004). Increased AR alterations were detected in patients harbouring tumours with an IDC‐P proportion of ≥10% vs those with an IDC‐P proportion of <10% (6.4% [five of 78] vs 18.1% [15/83], P = 0.045). For IDC‐P carriers, tumour protein p53 ( TP53 ) mutation was associated with shorter castration‐resistant‐free survival (median 10.9 vs 28.9 months, P = 0.026), and BRCA2 alteration was related to rapid prostate‐specific antigen progression for those receiving abiraterone treatment (median 9.1 vs 11.9 months, P = 0.036). Conclusion Our findings provide genomic evidence explaining the aggressive phenotype of tumours with IDC‐P, highlighting the potential therapeutic strategies for this patient population.

AbstractPurpose:Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.Experimental Design:Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded.Results:We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade–based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03).Conclusions:These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.