The genome-wide landscape of C:G > T:A polymorphism at the CpG contexts in the human population.

BACKGROUND: The C:G > T:A substitution at the CpG dinucleotide contexts is the most frequent substitution type in genome evolution. The mutational process is obviously ongoing in the human germline; however, its impact on common and rare genomic polymorphisms has not been comprehensively investigated yet. Here we observed the landscape and dynamics of C:G > T:A substitutions from population-scale human genome sequencing datasets including ~ 4300 whole-genomes from the 1000 Genomes and the pan-cancer analysis of whole genomes (PCAWG) Project and ~ 60,000 whole-exomes from the Exome Aggregation Consortium (ExAC) database. RESULTS: Of the 28,084,558 CpG sites in the human reference genome, 26.0% show C:G > T:A substitution in the dataset. Remarkably, CpGs in CpG islands (CGIs) have a much lower frequency of such mutations (5.6%). Interestingly, the mutation frequency of CGIs is not uniform with a significantly higher C:G > T:A substitution rate for intragenic CGIs compared to other types. For non-CGI CpGs, the mutation rate was positively correlated with the distance from the nearest CGI up to 2 kb. Finally, we found the impact of negative selection for coding CpG mutations resulting in amino acid change. CONCLUSIONS: This study provides the first unbiased rate of C:G > T:A substitution at the CpG dinucleotide contexts, using population-scale human genome sequencing data. Our findings provide insights into the dynamics of the mutation acquisition in the human genome.

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study.

BACKGROUND: NUT carcinoma is a rare aggressive disease caused by BRD4/3-NUT fusion, and C-MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines. MATERIALS AND METHODS: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907). RESULTS: Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC50 of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7-8.2 nmol/L), also showed remarkable efficacies. CONCLUSION: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment. IMPLICATIONS FOR PRACTICE: NUT carcinoma (NC) is a disease caused by BRD-NUT fusion leading to C-MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.

Human glioblastoma arises from subventricular zone cells with low-level driver mutations.

Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months1,2. Identifying the cell of origin that harbours mutations that drive GBM could provide a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates3-5. However, there is a lack of direct genetic evidence from human patients with GBM4,6-10. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumour mass, (ii) tumour tissue, and (iii) normal cortical tissue (or blood), from 28 patients with isocitrate dehydrogenase (IDH) wild-type GBM or other types of brain tumour. We found that normal SVZ tissue away from the tumour in 56.3% of patients with wild-type IDH GBM contained low-level GBM driver mutations (down to approximately 1% of the mutational burden) that were observed at high levels in their matching tumours. Moreover, by single-cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we found that astrocyte-like NSCs that carry driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Together, our results show that NSCs in human SVZ tissue are the cells of origin that contain the driver mutations of GBM.

Mutalisk: a web-based somatic MUTation AnaLyIS toolKit for genomic, transcriptional and epigenomic signatures.

Somatic genome mutations occur due to combinations of various intrinsic/extrinsic mutational processes and DNA repair mechanisms. Different molecular processes frequently generate different signatures of somatic mutations in their own favored contexts. As a result, the regional somatic mutation rate is dependent on the local DNA sequence, the DNA replication/RNA transcription dynamics and epigenomic chromatin organization landscape in the genome. Here, we propose an online computational framework, termed Mutalisk, which correlates somatic mutations with various genomic, transcriptional and epigenomic features in order to understand mutational processes that contribute to the generation of the mutations. This user-friendly tool explores the presence of localized hypermutations (kataegis), dissects the spectrum of mutations into the maximum likelihood combination of known mutational signatures and associates the mutation density with numerous regulatory elements in the genome. As a result, global patterns of somatic mutations in any query sample can be efficiently screened, thus enabling a deeper understanding of various mutagenic factors. This tool will facilitate more effective downstream analyses of cancer genome sequences to elucidate the diversity of mutational processes underlying the development and clonal evolution of cancer cells. Mutalisk is freely available at http://mutalisk.org.

Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas.

Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI-resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues. Results We identified that EGFR TKI-resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell-transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 43× greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced hypermutation was frequent in the branches toward small-cell transformation. Conclusion EGFR TKI-resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI-treated LADCs is informative in predicting small-cell transformation.

A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

BACKGROUND: A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. RESULTS: In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. MATERIALS AND METHODS: 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. CONCLUSIONS: In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.

Mechanisms and Consequences of Cancer Genome Instability: Lessons from Genome Sequencing Studies.

During tumor evolution, cancer cells can accumulate numerous genetic alterations, ranging from single nucleotide mutations to whole-chromosomal changes. Although a great deal of progress has been made in the past decades in characterizing genomic alterations, recent cancer genome sequencing studies have provided a wealth of information on the detailed molecular profiles of such alterations in various types of cancers. Here, we review our current understanding of the mechanisms and consequences of cancer genome instability, focusing on the findings uncovered through analysis of exome and whole-genome sequencing data. These analyses have shown that most cancers have evidence of genome instability, and the degree of instability is variable within and between cancer types. Importantly, we describe some recent evidence supporting the idea that chromosomal instability could be a major driving force in tumorigenesis and cancer evolution, actively shaping the genomes of cancer cells to maximize their survival advantage.

Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation.

The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.

The Impact of Molecularly Targeted Treatment on Direct Medical Costs in Patients with Advanced Non-small Cell Lung Cancer.

PURPOSE: To investigate the impact of targeted treatment on direct medical costs of patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Medical records of 108 stage IIIB/IV NSCLC patients treated in Seoul National University Hospital between 2003 and 2009, were reviewed to collect medical resources utilization data from the diagnosis of stage IIIB/IV NSCLC to the end of active anti-cancer treatment. The direct medical costs were calculated by multiplying the number of medical resources used by the unit price. All costs were expressed in US dollars for each patient. RESULTS: The mean total direct medical costs were $34,732 (standard deviation, 21,168) in the study cohort. The mean total direct medical costs were higher in epidermal growth factor receptor ( EGFR ) mutation (EGFR MT)-positive patients than EGFR wild-type (EGFR WT) patients ($41,403 vs. $30,146, p=0.005). However, the mean monthly direct medical costs did not differ significantly between EGFR MT-positive patients and EGFR WT patients ($2,120 vs. $2,702, p=0.119) because of the longer duration of active anti-cancer treatment in EGFR MT-positive patients. This discrepancy was mainly attributable to EGFR MT-positive patients' lower non-chemotherapy costs ($948 vs. $1,522, p=0.007). The total and monthly direct medical costs of ALK fusion-positive patients who did not receive ALK inhibitors did not differ from WT/WT patients. CONCLUSION: This study suggests that the availability of targeted agents for EGFR MT-positive patients lowers the mean monthly medical costs by prolonging survival and diminishing the use of other medical resources, despite the considerable drug costs.

Terminal cancer patients' and their primary caregivers' attitudes toward hospice/palliative care and their effects on actual utilization: A prospective cohort study.

BACKGROUND: Previous studies on hospice/palliative care indicated that patients' socio-demographic factors, disease status, and availability of health-care resources were associated with hospice/palliative care utilization. However, the impact of family caregivers on hospice/palliative care utilization has not been thoroughly investigated. AIM: To evaluate the association between attitudes toward hospice/palliative care of both patients with terminal cancer (defined as progressive, advanced cancer in which the patient will die within months) and their family caregivers and utilization of inpatient hospice/palliative care facilities. DESIGN: A prospective observational cohort study was performed in 12 hospitals in South Korea. Attitude toward hospice/palliative care was assessed immediately after terminal cancer diagnosis. After the patient's death, caregivers were interviewed whether they utilized hospice/palliative care facilities. PARTICIPANTS: A total of 359 patient-caregiver dyads completed baseline questionnaires. After the patients' death, 257 caregivers were interviewed. RESULTS: At the baseline questionnaire, 137/359 (38.2%) patients and 185/359 (51.5%) of caregivers preferred hospice/palliative care. Preference for hospice/palliative care was associated with awareness of terminal status among both patients (adjusted odds ratio: 1.87, 95% confidence interval: 1.16-3.03) and caregivers (adjusted odds ratio: 2.14, 95% confidence interval: 1.20-3.81). Religion, metastasis, and poor performance status were also independently associated with patient preference for hospice/palliative care. At the post-bereavement interview, 104/257 (40.5%) caregivers responded that they utilized hospice/palliative care facilities. Caregiver's preferences for hospice/palliative care were significantly associated with actual utilization (adjusted odds ratio: 2.67, 95% confidence interval: 1.53-4.67). No patient-related factors were associated with hospice/palliative care utilization. CONCLUSION: Promoting awareness of prognosis and to improve communication between doctors and families is important for facilitating the use of hospice/palliative care.

Prediction of survival in terminally ill cancer patients at the time of terminal cancer diagnosis.

PURPOSE: We aimed to investigate the prognostic factors that can predict terminal stage survival (TSS) at the time of terminal cancer diagnosis. METHODS: We prospectively evaluated 141 patients immediately after the diagnosis of terminal cancer by their attending oncologists. A total of 32 factors, including performance status, clinical prediction of survival, time to terminal cancer (TTC), clinical symptoms, signs, and laboratory tests including the neutrophil-lymphocyte ratio (NLR), were analyzed. TSS was defined as the time from the diagnosis of terminal cancer to death. RESULTS: The mean age of the 141 patients studied was 58.7 years, and 53 were female (38 %). The median TSS was 1.7 months (95 % confidence interval [CI] 1.43-1.97). In the univariate analyses, the TSS was significantly associated with 16 of the 32 factors tested. In the multivariate analysis, a lower Karnofsky performance status (KPS), a shorter TTC (<24 months), a high NLR (≥5), and a high C-reactive protein (CRP) level (≥10 mg/dL) were independently associated with a poorer prognosis. A scoring system (scale, 0-6) developed based on the multivariate analysis could be used to classify terminal cancer patients into better (0-2 points; TSS 3.9 months), intermediate (3-4 points; TSS 1.7 months), or worse (5-6 points; TSS 0.9 month, P < 0.001) prognosis. CONCLUSION: The median TSS after the diagnosis of terminal cancer in advanced cancer patients was 1.7 months. The scoring system using KPS, TTC, NLR, and CRP could predict TSS in these patients.

Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis.

IMPORTANCE: Current guidelines recommend both epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic chemotherapy drugs as standard treatment options for patients with wild-type (WT) EGFR who were previously treated for non-small cell lung cancer (NSCLC). However, it is not clear that EGFR TKIs are as efficacious as chemotherapy in patients with WT EGFR. OBJECTIVE: To determine the association between first-generation EGFR TKI vs chemotherapy and survival in advanced NSCLC patients with WT EGFR. DATA SOURCES: PubMed, EMBASE, Cochrane database, and meeting abstracts of the American Society of Clinical Oncology and European Society of Medical Oncology through December 2013. STUDY SELECTION: Eligible studies were randomized controlled trials comparing EGFR TKI with conventional chemotherapy in patients with advanced NSCLC. Out of 1947 retrieved articles, 11 trials incorporating 1605 patients with WT EGFR were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted trial characteristics and outcomes. The risk of bias was evaluated using the Cochrane tool. All measures were pooled using random-effects models and 95% CIs were calculated. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS), measured as hazard ratios (HRs). The secondary outcomes were objective response rate and overall survival, expressed as relative risks and HRs, respectively. RESULTS: Among patients with WT EGFR tumors, chemotherapy was associated with improvement of PFS, compared with TKI (HR for TKI, 1.41; 95% CI, 1.10-1.81). No statistically significant subgroup difference was identified in terms of line of treatment (first-line vs second- or later-line), experimental drug, dominant ethnicity, or EGFR mutation analysis method. Trials using more sensitive platforms than direct sequencing were associated with a significant PFS benefit with chemotherapy (HR for TKI, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy with improvement in PFS was also significant in second- or later-line trials (HR, 1.34; 95% CI, 1.09-1.65). The objective response rate was higher with chemotherapy (92/549, 16.8%, vs 39/540, 7.2%, for TKI; relative risk for TKI, 1.11; 95% CI, 1.02-1.21); however, no statistically significant difference was observed with respect to overall survival (HR for TKI, 1.08; 95% CI, 0.96-1.22). CONCLUSIONS AND RELEVANCE: Among patients with advanced NSCLC harboring WT EGFR, conventional chemotherapy, compared with first-generation EGFR TKI, was associated with improvement in PFS but not overall survival.

The Understanding of Terminal Cancer and Its Relationship with Attitudes toward End-of-Life Care Issues.

BACKGROUND: Although terminal cancer is a widely used term, its meaning varies, which may lead to different attitudes toward end-of-life issues. The study was conducted to investigate differences in the understanding of terminal cancer and determine the relationship between this understanding and attitudes toward end-of-life issues. METHODS: A questionnaire survey was performed between 2008 and 2009. A total of 1242 cancer patients, 1289 family caregivers, 303 oncologists from 17 hospitals, and 1006 participants from the general population responded. RESULTS: A "6-month life expectancy" was the most common understanding of terminal cancer (45.6%), followed by "treatment refractoriness" (21.1%), "metastatic/recurrent disease" (19.4%), "survival of a few days/weeks" (11.4%), and "locally advanced disease" (2.5%). The combined proportion of "treatment refractoriness" and "6-month life expectancy" differed significantly between oncologists and the other groups combined (76.0% v. 65.9%, P = 0.0003). Multivariate analyses showed that patients and caregivers who understood terminal cancer as "survival of a few days/weeks" showed more negative attitudes toward disclosure of terminal status compared with participants who chose "treatment refractoriness" (adjusted odds ratio [aOR] 0.42, 95% confidence interval [CI] 0.22-0.79 for patients; aOR 0.34, 95% CI 0.18-0.63 for caregivers). Caregivers who understood terminal cancer as "locally advanced" or "metastatic/recurrent disease" showed a significantly lower percentage of agreement with withdrawal of futile life-sustaining treatment compared with those who chose "treatment refractoriness" (aOR 0.19, 95% CI 0.07-0.54 for locally advanced; aOR 0.39, 95% CI 0.21-0.72 for metastatic/recurrent). CONCLUSIONS: The understanding of terminal cancer varied among the 4 participant groups. It was associated with different preferences regarding end-of-life issues. Standardization of these terms is needed to better understand end-of-life care.

Efficacy of exemestane in korean patients with metastatic breast cancer after failure of nonsteroidal aromatase inhibitors.

PURPOSE: Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. METHODS: Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). RESULTS: The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. CONCLUSION: Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment.

Surrogate decision-making in Korean patients with advanced cancer: a longitudinal study.

PURPOSE: Although surrogate decision-making in cancer patients is well-known, few studies investigating the prevalence of surrogate decision-making over time have been reported. The objectives of this study were to investigate the level of surrogate decision-making in advanced cancer patients over time and the impact of demographic and clinical variables on surrogate decision-making. METHODS: The level of surrogate decision-making was measured in 572 consecutive cancer patients who died between January 1 and December 31, 2009. We reviewed 8,639 informed consent forms of these patients, calculated the proportion of decisions made by a surrogate (PDS) for each patient, and analyzed the association of PDS with demographic and clinical variables. RESULTS: Surrogates completed 40.3 % of all consent forms. The prevalence of surrogate decision-making was higher in the end-of-life period (death <7 days, OR = 29.05; reference, >365 days). Surrogates signed consent forms more frequently for do-not-resuscitate directives, intensive care unit admission, emergency hemodialysis, surgery and invasive interventions compared with chemotherapy, radiotherapy, and diagnostic tests (OR = 3.88, P < 0.001). Patients of older age (P = 0.036) and those with a shorter duration of management (P < 0.001) were independently associated with greater PDS. CONCLUSIONS: Surrogate decision-making was frequently observed among Korean cancer patients in this study, especially when the patient's death was imminent, and for decisions related to end-of-life care. Surrogates were also frequently involved in decisions for elderly or rapidly deteriorating patients. Healthcare professionals should consider the significant role of familial surrogates in the end-of-life period; comprehensive approaches are needed to preserve the best interest of the patients.

Metabolic and metastatic characteristics of ALK-rearranged lung adenocarcinoma on FDG PET/CT.

INTRODUCTION: ALK rearrangement in lung cancer has been identified as a novel molecular target in lung adenocarcinoma. In this study, we evaluated metabolic and metastatic features of lung adenocarcinoma by using FDG PET/CT, with regard to specific genotypes of ALK and EGFR mutation. METHODS: Patients with lung adenocarcinoma initially diagnosed and examined with FDG PET/CT and molecular genotyping with biopsy specimen, from September 2009 to September 2011, were selected retrospectively. ALK fluorescence in situ hybridization and EGFR mutations were tested. Maximum standardized uptake value (SUVmax) and metastatic characteristics on FDG PET/CT were analyzed with regard to ALK and EGFR status. RESULTS: Of the 331 lung adenocarcinoma patients, 18 were ALK positive (ALK(+)), 156 were EGFR mutation positive (EGFR(+)), and 157 were wild type (WT) for both ALK and EGFR mutation. The ALK(+) tumor showed significantly higher SUVmax and more common metastasis to lymph nodes and distant organs than those of other genotypes in overall patients (P<0.01). In a subgroup analysis of advanced stage (stage IIIb and IV), ALK(+) lung cancer showed significantly higher SUVmax (P<0.05) than EGFR(+) tumors. In another subgroup analysis of size matched groups, ALK(+) tumors showed significant difference in SUVmax, lymph node and distant metastasis (P<0.01), particularly in the moderate-sized tumors (1.5-3cm). CONCLUSION: ALK-rearranged lung adenocarcinoma represents higher glucose metabolism and more rapid metastasis to lymph nodes or distant sites compared with those with EGFR mutation and wild type, which suggests more aggressive features of ALK rearrangement.

The transcriptional landscape and mutational profile of lung adenocarcinoma.

All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.

Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation.

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer (NSCLC) are mutually exclusive. However, several exceptional cases harboring both genetic alterations have been reported. In this study, a total of 444 patients with lung adenocarcinoma were examined for their EGFR and ALK status at Seoul National University Hospital between July 2008 and September 2011. EGFR mutations and ALK translocations were detected in 228 (51.4%) and 34 (7.7%) patients, respectively. Four patients (0.9%) had both genetic alterations and three underwent curative surgery. One patient who received both EGFR tyrosine kinase and ALK inhibitors, separately showed an objective response to the ALK inhibitor alone. Considering our and previous studies, patients harboring both EGFR mutation and ALK translocation showed differential sensitivities to both targeted therapies, suggesting a variable dependence on EGFR and ALK oncogenes.

Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients.

Fluorescence in situ hybridization (FISH) is currently used to detect non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) gene rearrangement, who are candidates for ALK inhibitor therapy. However, FISH may not be a practical method for screening for ALK-positive patients in a large population due to its cost and difficulty in interpretation. We investigated the role of immunohistochemistry (IHC) to screen for ALK rearrangement in advanced NSCLC. We identified 1,166 stage IIIB or IV NSCLC patients with non-squamous histology from the Seoul National University Hospital NSCLC database. To enrich ALK-positive cases, we selected 262 patients who were either EGFR wild-type or non-responders to previous EGFR tyrosine kinase inhibitors (TKI). ALK IHC and ALK FISH were performed on formalin-fixed, paraffin-embedded tissue. ALK protein was expressed in 28 (10.7%) tumors in 262 patients. ALK FISH was positive in 25 (9.5%) cases. All patients with IHC score of 3 (n=9) were FISH-positive and all patients with score of 0 (n=234) were FISH-negative. Among patients with IHC scores of 1 and 2, five (83.3%, 5/6) and eleven (84.6%, 11/13) were FISH-positive, respectively. The sensitivity and specificity of ALK IHC with intensity score of 1 or more were 100% and 98.7%, respectively. IHC can be a useful test for screening ALK FISH-positive cases in advanced NSCLC. FISH testing should be considered for advanced NSCLC patients with tumors showing mild to moderate staining for ALK by IHC to confirm ALK translocation.