Genomic alterations dissection revealed MUC4 mutation as a potential driver in lung adenocarcinoma local recurrence.

Background: Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, of which genomic alterations play a major role in tumorigenesis. The prognosis of LUAD has been improved these years but nearly half of the patients still develop recurrence even after radical resection. The underlying mechanism driving LUAD recurrence especially genomic alterations is complicated and worth exploring. Methods: Forty-one primary tumors and 43 recurrent tumors were collected from 41 LUAD patients who received surgery resection after recurrence. Whole exon sequencing (WES) was performed to make genomic landscapes. WES data were aligned to genome and further analyzed for somatic mutation, copy number variation and structure variation. MutsigCV was used to identify significantly mutated genes and recurrence specific genes. Results: Significantly mutated genes including EGFR, MUC4 and TP53 were identified in primary and recurrent tumors. Some were found to be more specifically mutated in recurrent tumors, such as the MUC17, KRAS and ZNF families. In recurrent tumors, ErbB signaling pathway, MAPK pathway and cell cycle pathway were highly activated, which maybe the mechanism driving recurrence. The adjuvant therapy would affect tumor evolution and molecular features during recurrence. MUC4 was highly mutated in this study cohort, and it was a potential driver gene in LUAD recurrence by activating ErbB signaling pathway as a ligand of ERBB2. Conclusions: Genomic alteration landscape was changing during LUAD recurrence to construct a more suitable environment for the survival of tumor cells. Several potential driver mutations and targets during LUAD recurrence were identified, such as MUC4, and more investigation was needed to verify the specific functions and roles.

Comparison of perioperative and survival outcomes between sublobar resection and lobectomy of patients who underwent a second pulmonary resection.

BACKGROUND: Repeat pulmonary resection is widely accepted in clinical practice. This study aimed to compare sublobar resection (segmentectomy or wedge resection) with lobectomy in the treatment of patients who underwent a second pulmonary resection. METHODS: This study retrospectively included patients who underwent lobectomy or sublobar resection for second pulmonary resection. 1:1 propensity score matching (PSM) was performed to balance selection bias. Clinicopathological features, perioperative and survival outcomes of lobectomy and sublobar resection were compared. RESULTS: A total of 308 patients who underwent second pulmonary resection were identified: 71 (23.1%) who underwent lobectomy and 237 (76.9%) who underwent sublobar resection. After PSM, 58 patients for each group were selected with well-balanced clinicopathological characteristics. In patients who underwent sublobar resection, significantly shorter chest tube duration (days) (median, 4 vs. 2, p < 0.001) and postoperative hospital stay (days) (median, 6 vs. 4, p < 0.001) were observed. There was no significant difference in overall survival between these two groups after the second and first surgery (p = 0.65, p = 0.98), respectively. Subgroup analysis according to the type of the first resection showed consistent results. CONCLUSIONS: Sublobar resection may be considered as an alternative option for second pulmonary resection due to its perioperative advantages and similar survival outcomes compared with lobectomy.

Efficacy and safety of neoadjuvant chemotherapy and immunotherapy in locally resectable advanced esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell cancer (ESCC) patients with the potentially resectable disease most would experience relapse after surgery. Immunotherapy has been reported to improve the prognosis of advanced esophageal cancer and may be a new strategy to prevent this urgent condition's recurrence. We first evaluated the efficacy and safety of neoadjuvant chemotherapy combined with immunotherapy in patients with resectable ESCC. METHODS: All patients with resectable locally advanced ESCC (clinical stage III-IVB). Received at least 1 cycle of neoadjuvant chemotherapy combined with immunotherapy (NACI), and the interval between each cycle and the operation should be at least 3 weeks. All patients were treated with standard surgery. The tumor imaginations were obtained at baseline and within a week before surgery. The efficacy endpoint was the rate of major pathologic response (MPR, 10% viable tumor cells). Expression of immunohistochemical-related molecules was investigated in surgical samples. RESULTS: A total of 38 patients with ESCC were included (36 males, median age 61 years), and most of them used Pembrolizumab (55.26%) and Camrelizumab (31.58%). We analyzed 19 patients and found that 13 patients (68.42%) achieved radiological partial response (PR) by CT images. R0 resection was performed in 35 patients (92.11%), and 10 patients (26.32%) developed postoperative complications. Through postoperative pathology, we found 13 (34.21%) patients had complete pathologic response (cPR), and 16 (42.11%) patients achieved MPR. We also found that none of the factors had a statistically significant impact on MPR. Still, the regression rate of Sum of lesion diameter (SLD) was significantly positively correlated with the pathological remission rate (P=0.012, r=0.565). CONCLUSIONS: The rate of MPR in ESCC patients reached 42.11%. The use of the NACI regimen did not increase the occurrence of complications in neoadjuvant treatment and operation, and the SLD regression rate has a certain guiding significance for the effect of immunotherapy.

A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks.

BACKGROUND: Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. RESULTS: A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. CONCLUSIONS: Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.

Integrated analysis of optical mapping and whole-genome sequencing reveals intratumoral genetic heterogeneity in metastatic lung squamous cell carcinoma.

BACKGROUND: Intratumoral heterogeneity is a crucial factor to the outcome of patients and resistance to therapies, in which structural variants play an indispensable but undiscovered role. METHODS: We performed an integrated analysis of optical mapping and whole-genome sequencing on a primary tumor (PT) and matched metastases including lymph node metastasis (LNM) and tumor thrombus in the pulmonary vein (TPV). Single nucleotide variants, indels and structural variants were analyzed to reveal intratumoral genetic heterogeneity among tumor cells in different sites. RESULTS: Our results demonstrated there were less nonsynonymous somatic variants shared with PT in LNM than in TPV, while there were more structural variants shared with PT in LNM than in TPV. More private variants and its affected genes associated with tumorigenesis and progression were identified in TPV than in LNM. It should be noticed that optical mapping detected an average of 77.1% (74.5-78.5%) large structural variants (>5,000 bp) not detected by whole-genome sequencing and identified several structural variants private to metastases. CONCLUSIONS: Our study does demonstrate structural variants, especially large structural variants play a crucial role in intratumoral genetic heterogeneity and optical mapping could make up for the deficiency of whole-genome sequencing to identify structural variants.