Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.

OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

Tumor mutation burden and recurrent tumors in hereditary lung cancer.

Lung cancer is the leading cause of cancer death worldwide and cancer relapse accounts for the majority of cancer mortality. The mechanism is still unknown, especially in hereditary lung cancer without known actionable mutations. To identify genetic alternations involved in hereditary lung cancer and relapse is urgently needed. We collected genetic materials from a unique hereditary lung cancer patient's blood, first cancer tissue (T1), adjacent normal tissue (N1), relapse cancer tissue (T2), and adjacent normal tissue (N2) for whole genome sequencing. We identified specific mutations in T1 and T2, and attributed them to tumorigenesis and recurrence. These tumor specific variants were enriched in antigen presentation pathway. In addition, a lung adenocarcinoma cohort from the TCGA dataset was used to confirm our findings. Patients with high mutation burdens in tumor specific genes had decreased relapse-free survival (P = 0.017, n = 186). Our study may provide important insight for designing immunotherapeutic treatment for hereditary lung cancer.

Association of Bone Metastasis With Early-Stage Breast Cancer in Women With and Without Precancer Osteoporosis According to Osteoporosis Therapy Status.

Importance: Deaths from cancer are attributed more to secondary than primary tumors, but the pathogenesis of organ-specific cancer metastasis has not been determined. Objective: To investigate whether precancer osteoporosis and osteoporosis therapy are associated with alteration of bone metastasis patterns. Design, Setting, and Participants: This nationwide retrospective cohort study was performed from January 1, 2002, to December 31, 2013, using 2 cohorts from the Taiwan National Health Insurance Research Database: a random sample of 1 million beneficiaries from the Longitudinal Health Insurance Database who were enrolled in 2005 (LHID2005) and a specific data set of all the patients with osteoporosis. Patients diagnosed with breast cancer and precancer osteoporosis from January 1, 2002, to December 31, 2011, were included in the study, and their records were examined through December 31, 2013. From LHID2005, we selected 9104 women with early-stage breast cancer, of whom 705 had precancer osteoporosis. We identified 29 183 patients from the cohort of patients with breast cancer and osteoporosis, 14 020 of whom had precancer osteoporosis. Data analysis was performed from December 31, 2016, to August 31, 2018. Exposures: Precancer osteoporosis and osteoporosis therapy. Main Outcomes and Measures: The risk of bone metastasis in patients with and without precancer osteoporosis and patients receiving and not receiving osteoporosis therapy as well as time to bone metastasis development. Results: Among 9104 patients with breast cancer from the Longitudinal Health Insurance Database (mean [SD] age, 46.7 [14.0] years), precancer osteoporosis was not associated with a difference in risk of bone metastasis (adjusted hazard ratio [aHR], 0.87; 95% CI, 0.58-1.30; P = .49). Among 14 020 patients with precancer osteoporosis from the other cohort (mean [SD] age, 58.9 [11.6] years), osteoporosis therapy had no association with the risk of bone metastasis (bisphosphonates: aHR, 1.47; 95% CI, 1.00-2.17; P = .05; nonbisphosphonate drugs: aHR, 1.00; 95% CI, 0.72-1.39; P > .99). Compared with those without precancer osteoporosis (median time to bone metastasis development, 2.87 years; interquartile range [IQR], 1.34-4.86 years), among those with precancer osteoporosis, the median time to develop bone metastasis was shorter in those who did not receive treatment (1.74 years; IQR, 0.58-3.60 years; P < .001), whereas this time was the same for those who received treatment (bisphosphonates: 2.34 years; IQR, 1.23-3.13 years; nonbisphosphonate drugs: 2.08 years; IQR, 0.92-4.95 years). Conclusions and Relevance: Precancer osteoporosis was not associated with risk of bone metastasis, but untreated osteoporosis was associated with accelerated progression of bone metastasis when it occurred. Organ microenvironments interact with disseminated cancer mostly after the specific organ has been predetermined to be the designated location. Because recurrences and metastases are major obstacles to cancer treatments, determining which organs may be at risk for metastases may be crucial to treating the disease.

Serum Glutamine Levels as a Potential Diagnostic Biomarker in Sepsis following Surgery for Peritonitis.

Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available to clinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure. We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsis in individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013, patients who had peritonitis diagnosed at the emergency department and underwent emergency surgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative, post-operative and recovery time points. The average level of pre-operation serum glutamine was significantly different from that on the recovery day (0.317 ± 0.168 vs. 0.532 ± 0.155 mM, P < 0.001); moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantly lower on the day of surgery than they were at recovery (106.6 ± 36.39 vs. 130.68 ± 56.98 ng/mL, P = 0.013); no significant difference was found between pre-operation and recovery selenium levels. Unlike selenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommend including glutamine as a biomarker for sepsis severity assessment in addition to the commonly used clinical indicators.

Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling.

Cancer stem cells (CSCs) are a promising target for treating cancer, yet how CSC plasticity is maintained in vivo is unclear and is difficult to study in vitro. Here we establish a sustainable primary culture of Oct3/4(+)/Nanog(+) lung CSCs fed with CD90(+) cancer-associated fibroblasts (CAFs) to further advance our knowledge of preserving stem cells in the tumour microenvironment. Using transcriptomics we identify the paracrine network by which CAFs enrich CSCs through de-differentiation and reacquisition of stem cell-like properties. Specifically, we find that IGF1R signalling activation in cancer cells in the presence of CAFs expressing IGF-II can induce Nanog expression and promote stemness. Moreover, this paracrine signalling predicts overall and relapse-free survival in stage I non-small cell lung cancer (NSCLC) patients. IGF-II/IGF1R signalling blockade inhibits Nanog expression and attenuates cancer stem cell features. Our data demonstrate that CAFs constitute a supporting niche for cancer stemness, and targeting this paracrine signalling may present a new therapeutic strategy for NSCLC.

Focal amplification of HOXD-harboring chromosome region is implicated in multiple-walled carbon nanotubes-induced carcinogenicity.

Multiple-walled carbon nanotubes (MWCNTs) may cause carcinogenesis. We found that long-term exposure to MWCNTs can induce irreversible oncogenic transformation of human bronchial epithelial cells and tumorigenicity in vivo. A genome-wide array-comparative genomic hybridization (aCGH) analysis revealed global chromosomal aberration in MWCNTs-treated clones, predominantly at chromosome 2q31-32, where the potential oncogenes HOXD9 and HOXD13 are located. Functional assays confirmed that this variation can modulate oncogenic signaling and plays a part in MWCNTs-induced tumorigenesis, suggesting that MWCNTs are carcinogens that act by altering genomic stability and oncogenic copy numbers.