The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection.

Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. This prospective cohort study enrolled 46 patients with stage I–III gastric cancer that underwent resection with curative intent. Sixty resected tumor samples and 296 plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. ctDNA detection was correlated with clinicopathologic features and post-operative disease-free (DFS) and overall survival (OS). ctDNA was detected in 45% of treatment-naïve plasma samples. Primary tumor extent (T stage) was independently associated with pre-operative ctDNA positivity (p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 95%CI, 7.991–61.29, p < 0.0001 and HR = 7.664, 95% CI, 2.916–21.06, p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.

Abnormalities in epigenetic modifiers are emerging as driving events in prostate cancer (PCa). The histone methyltransferase KMT2D, a frequently aberrant epigenetic modifier in various tumors, has an undefined role in PCa. Moreover, little is known regarding KMT2D’s mutation in Chinese patients or its downstream signaling pathways and targets. Here, we profiled the mutational spectrum of 32 significantly PCa-associated genes by using disease-targeted sequencing, and found that KMT2D was highly mutated (63.04%, 29/46) in Chinese patients. Moreover, high KMT2D transcription was also associated with poor prognosis in an independent cohort (n = 51). In KMT2D-knockdown PC-3 and DU145 cells, cell proliferation (P < 0.01), invasion (P < 0.001), and migration (P < 0.01) were consequently suppressed. KMT2D depletion effectively suppressed tumor growth by 92.21% in vivo. Notably, integrative analyses of RNAseq and ChIPseq characterized two crucial genes downregulated by KMT2D, leukemia inhibitory factor receptor (LIFR) and Kruppel-like factor-4 (KLF4), which are regulators in PI3K/Akt and EMT, respectively. Our present study revealed that KMT2D epigenetically activates PI3K/Akt pathway and EMT by targeting LIFR and KLF4 and thus serves as a putative epigenetic-based target for treating PCa.

BackgroundTo better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC.MethodsWe performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis.ResultsMutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2 and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs.ConclusionOur results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.

Infection by chronic hepatitis B virus (HBV) is one of the major causes of liver cirrhosis and primary hepatocellular carcinoma (HCC). Viral DNA integration into the host cell genome is a key mechanism of hepatocarcinogenesis. However, the molecular characterization and the potential clinical implications of HBV DNA integration into patients suffering from different hepatitis and HCC remain unclear. In this study, we analyzed HBV integrations in patients with hepatitis B and HCC using HBV probe-based capturing and next-generation sequencing. The results revealed that the sizes of the HBV integrations ranged from 28 bp to 3215 bp, including the full-length HBV DNA sequence. The integration breakpoints were preferentially distributed in the viral enhancer, X protein, and core protein regions of the HBV genome. The number of HBV integrations followed an increasing trend from hepatitis to HCC, which was positively correlated with the HBV virus load in patients with hepatitis. The number of HBV integrations in the HBeAg positive chronic hepatitis B group was significantly greater than that in the other hepatitis B groups (P < 0.05). However, the relative abundance of HBV integrations was significantly higher in HCC tissues than in the adjacent liver tissues. Interestingly, 61.6% (8/13) of HBV-human DNA integration fragments could be detected at the RNA level. Our results also showed that HBV integration-targeted genes (ITGs) were significantly enriched in many cancer-related pathways, such as MAPK, extracellular matrix (ECM)-receptor interaction, and the hedgehog signaling pathway. Individuals with HBV integrations exhibited shorter disease-free survival (DFS) and overall survival (OS) than those without HBV integrations in some ITGs including LINC00293 (long intergenic non-protein coding RNA 293; DFS P = 0.008, OS P = 0.009), FSHB (follicle stimulating hormone beta subunit; DFS P = 0.05, OS P = 0.186), and LPHN3 (latrophilin-3; DFS P = 0.493, OS P = 0.033). This study determined the underlying mechanism of HBV DNA integration in liver diseases and laid the foundation for future studies on the pathogenesis of liver cancer.

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Connexin 43 (Cx43), a vital gap junction protein in tumor microenvironment (TME), is a novel molecular target for melanoma chemotherapeutics due to its tumor suppressive function. Dioscin, an herbal steroidal saponin, exerts anti-tumor effects while the underlying mechanism is unclear. Using WB, FACS, and immunofluorescence methodologies, we found dioscin significantly activated the transcription and translation of Cx43 via the retinoid acid signaling pathway and simultaneously enhanced the transporting function of Cx43. Through stimulating Cx43, dioscin remarkably suppressed the migratory and invasive capacities of B16 cells, and notably decreased pluripotency markers of cancer stem cells and epithelial-to-mesenchymal transition in B16 cells and animal tumor tissues. Conversely, dioscin improved the secretion of pro-inflammatory cytokines (IL-6, TNFα, and IL-1β), and the phagocytic capacity of tumor-associated macrophages by increasing M2-to-M1 phenotype transition. More strikingly, even in Cx43 functional deficient B16 and RAW264.7 cells, dioscin still dramatically reversed the aggravated tumor malignancy and reduced macrophage phagocytic activity. Two classical metastasis animal models were utilized in vivo and results showed that dioscin showed significant anti-metastatic effects, which is closely related to the expression of Cx43 either in in situ tumor or metastatic lung nodes. In conclusion, dioscin targets Cx43 to suppress the tumor cell malignancy and activate macrophage sensitivity, thereby targeting melanoma microenvironment.

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