Aberrant DNA methylation of some tumor suppressor genes in lung cancers from workers with chromate exposure

Our previous studies revealed a variety of genetic changes in lung cancers from chromate‐exposed workers (chromate lung cancer). In the present study, we examined epigenetic changes in chromate lung cancers. Nested‐methylation‐specific PCR was employed in studying the methylation of CpG islands in the APC, MGMT, hMLH1 genes in 36 chromate lung cancers and 25 nonchromate lung cancers. Methylation in chromate lung cancers was detected at 86% for APC, 20% for MGMT, and 28% for hMLH1. Whereas, it occurred at lower frequencies in nonchromate lung cancers, particularly in APC (44%) and hMLH1 (0%) genes. Our previous study showed that methylation of p16 gene in chromate lung cancer and nonchromate lung cancer was 33% and 26%, respectively. The mean methylation index (MI), a reflection of the overall methylation status, was significantly higher in chromate lung cancers than nonchromate lung cancers (0.41 vs. 0.21, P = 0.001). Methylation of multiple genes (particularly hMLH1, p16, and APC genes) had experienced more than 15 yr of chromate exposure in chromate lung cancer (MI: <15 yr; 0.19, ≥15 yr, 0.42). There is a significant correlation of p16 and hMLH1 methylation with the expressional decrease or loss of the corresponding gene products (P = 0.037 and 0.024) respectively, and an inverse correlation between APC and MGMT methylation (P = 0.014). This study provides a novel evidence for the chromium carcinogenesis that chromate lung cancer is linked to the progressive methylation of some tumor suppressor genes, which may be related to genomic instability. © 2010 Wiley‐Liss, Inc.     

Frequent microsatellite instability in lung cancer from chromate-exposed workers

Although chromium has been the most extensively investigated metal with respect to mutagenicity and carcinogenicity, its genetic effects in humans are only partly understood. Our previous study demonstrated that lung cancer from chromate-exposed workers infrequently (20%) displayed p53 gene mutations as well as a particular mutation pattern. In the present study, we examined the replication error (RER) and loss of heterozygosity (LOH) in 38 lung cancers from 28 chromate-exposed workers (chromate lung cancer group) and in 26 lung cancer patients without chromate exposure (non-chromate lung cancer group), using six microsatellite markers containing CA repeats: D3S647 (3p23), D3S966 (3p21.3), D3S1289 (3p21.1), D5S346 (5q21-q22), D9S161 (9p21), and TP53 (17p13.1). The RER phenotype was defined as the presence of microsatellite instability (MSI) at two or more loci. Thirty (78.9%) of 38 tumors in the chromate lung cancer group exhibited RER. In contrast, only four (15.4%) of 26 tumors in the non-chromate lung cancer group exhibited RER. The frequency of RER in the chromate lung cancer group was significantly higher than that in the non-chromate lung cancer group (P < 0.0001). By contrast, the frequency of LOH at 3p, 5q, 9p, and 17p loci in tumors with chromate exposure was not significantly different from that in tumors without chromate exposure. In the chromate lung cancer group, the period of chromate exposure in workers with RER (24.5 +/- 6.7 yr) was significantly longer than that in workers without RER (17.0 +/- 3.5 yr) (P = 0.0046). In addition, a longer period of chromate exposure was associated with a tendency toward a higher frequency of MSI. This finding suggests that MSI may play a role in chromium-induced carcinogenesis. In addition to our previous study of p53 mutations, the present findings suggest that the carcinogenic mechanism of chromate lung cancer may differ from that of non-chromate lung cancer.     

Use of stereotactic body radiation therapy for medically inoperable multiple primary lung cancer

Introduction: To review outcomes of medically inoperable patients treated with stereotactic body radiation therapy (SBRT) for multiple primary lung cancer (MPLC). Methods: We retrospectively reviewed the charts of 10 patients (21 lesions) treated with SBRT for synchronous (seven), metachronous (one) or synchronous/metachronous lung cancers. All patients were male, medically inoperable and had a median age of 66 years. Eight patients had bilateral disease and two had unilateral disease. All patients had a histological diagnosis in at least one of the two lesions and four patients (44.4%) had both lesions biopsied. There were 18 T1 lesions and three T2 lesions. SBRT was in three fractions of 20 Gy or five fractions of 11–12 Gy to each lesion. Results: Mean and median follow up were 18.8 and 15.5 months, respectively. At analysis, six patients (60.0%) are alive, and five of these living patients (83.3%) have no evidence of disease recurrence or progression. Four patients (44.4%) developed distant metastatic disease. Twenty lesions (95.2%) achieved in‐field local control. No patients experienced acute pulmonary complications and only two patients (22.2%) experienced late grade I lung toxicity as per the Radiation Therapy Oncology Group toxicity criteria. Conclusion: SBRT for MPLC in medically inoperable patients is a safe, feasible and effective treatment approach.     

肺癌筛查和早期诊断研究进展

在我国肺癌已居肿瘤相关死亡的首位,虽然进展期肺癌患者预后很差,但大部分早期肺癌是可以治愈的.早期诊断、外科治疗仍是提高肺癌治愈率的主要手段.本文复习有关胸片(CXR)、痰细胞学、荧光纤支镜、低剂量CT(LDCT)以及分子生物学技术等在肺癌筛查和早期诊断中应用的相关文献,并对它们的效果加以评估.LDCT是目前对高危人群筛查最有效的方法,荧光纤支镜、痰液基细胞学、分子生物学技术的进展则对早期诊断有重要作用.     

Finding needles in a haystack: annual low-dose computed tomography screening reduces lung cancer mortality in a high-risk group

Evaluation of: Aberle DR, Adams AM, Berg CD et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365(5), 395–409 (2011).

Lung cancer is a global health issue. Compared with other common malignancies, the prognosis is poor as many patients present with advanced disease. The National Lung Screening Trial (NLST) aimed to identify and treat early lung cancers using annual low-dose computed tomography (CT) screening in a high-risk group. When compared with chest x-ray screening, low-dose CT screening reduced lung cancer mortality by 20%; the NLST is the first lung cancer screening trial to demonstrate such a mortality benefit. However, we must wait for cost–effectiveness data from the NLST, as well as the results of ongoing European studies comparing low-dose CT with observation alone, before firm conclusions can be drawn regarding the overall benefits of introducing a CT screening program to clinical practice.     

多层螺旋CT对同时多原发肺癌的诊断价值

目的探讨多层螺旋CT对同时多原发肺癌的诊断价值及其误诊原因。方法回顾性分析40例83个病灶同时多原发肺癌的CT征象及组织病理类型;分析X线胸片及CT漏误诊病变原因。结果同时多原发肺癌同侧肺发病率高于双侧肺(34∶6),周围型多见,占94%。组织学类型以腺癌最多见,占79.5%(66/83),腺癌中以女性发病更多见(55.2%)。周围型病灶边缘见毛刺者占76.9%(60/78),胸膜牵拉者占70.5%(55/78)。腺癌组和非腺癌组病灶的密度(非实性结节、部分实性结节、实性结节)、结节形态(圆形或类圆形、不规则形)、边缘分叶差异有统计学意义(P值均0.05)。CT第一诊断非恶性病灶共12个,术后均为腺癌,其中4个病灶随访3～6个月后复查,病灶增大,经手术病理证实。X线胸片漏诊周围型病灶24个(22个直径≤1.5cm;12个为非实性结节),均由胸部CT扫描检出。结论同时多原发肺癌不同癌灶大多具有原发肺癌的典型CT表现,并与其病理类型有一定关系。X线胸片漏诊率高,多层螺旋CT对检出小癌灶和非实性癌灶尤为重要。初次影像表现恶性征象不典型病灶,密切随诊非常重要。     

肺癌早期诊断研究进展

肺癌在世界范围内居癌症死亡率第一位,由于其发生发展的复杂性,多数患者发现时已是中晚期,因此无法进行根治性手术切除,仅能通过化疗或放疗缓解,以至于5年生存率很低。本文简要综述近年肺癌早期诊断的研究进展。     

Lung cancer screening

Lung cancer is the primary cause of cancer mortality in developed countries. First diagnosis only when disease has already reached the metastatic phase is the main reason for failure in treatment. To this regard, although low-dose spiral computed tomography (CT) has proven to be effective in the early detection of lung cancer (providing both higher resectability and higher long-term survival rates), the capacity of annual CT screening to reduce lung cancer mortality in heavy smokers has yet to be demonstrated. Numerous ongoing large-scale randomised trials are under way in high-risk individuals with different study designs. The initial results should be available within the next 2 years.     

Detecting lung cancer in plasma with the use of multiple genetic markers

Recent studies have demonstrated the possibility to detect genetic changes in plasma DNA of cancer patients. The goal of this study was to validate a panel of molecular markers for lung cancer detection in plasma DNA. Three markers, p53, FHIT and microsatellite alterations at loci on chromosome 3, were used to detect mutations in tumor and plasma DNA of 64 stage I-III non small cell lung cancer patients. p53 mutations were studied by direct sequencing of exons 5 through 8 in tumor DNA and by plaque hybridization assay and sequencing in plasma DNA. Allelic losses were evaluated by fluorescent PCR in tumor and plasma DNA. p53 genomic mutations were detected in 26 (40.6%) of 64 tumor DNA samples and the identical mutation was identified in plasma of 19 (73.1%) of them. Microsatellite alterations at FHIT and 3p loci were observed in 40 (62.5%) tumors and in 23 (35.9%) plasma samples. Of the 40 patients showing microsatellite alterations in tumors, 19 (47.5%) displayed the same change in plasma DNA. At least 1 of the 3 genetic markers (p53, FHIT and 3p) was altered in plasma of 51.6% of all patients and 60.7% of stage I patients. Moreover, genetic markers in plasma identified 29 of 45 (64.4%) of all stages and 15 of 22 (68.2%) of stage I patients whose tumors had an alteration. These results provide the proof of principle that plasma DNA alterations are tumor-specific in most cases and support blood testing as a noninvasive strategy for early detection.     

Lung cancer mortality in a cohort of UK cotton workers: an extended follow-up

Background:

A recent systematic review and meta-analysis suggested that occupational exposure to endotoxins protects against lung cancer. To explore this hypothesis further, the follow-up of mortality of a cohort of 3551 workers, who were employed in the British cotton industry during 1966–1971, was extended by 23 years.

Methods:

Subjects had originally been recruited to a survey of respiratory disease, which collected information about occupation and smoking habits. Cumulative exposures to endotoxins were estimated from data on endotoxin levels by work areas in cotton mills. Risks of lung cancer were estimated using survival modelling.

Results:

During follow-up, 2018 deaths were recorded before the age of 90 years, including 128 deaths from lung cancer. After adjustment for smoking, hazard ratios (95% confidence intervals) for cumulative endotoxin exposures of ⩽30 000, >30 000 and ⩽200 000, >200 000 and ⩽400 000, >400 000 and ⩽600 000 and >600 000 endotoxin units (EU) m⁻³ years were 1, 0.8 (0.5–1.6), 0.7 (0.4–1.3), 0.6 (0.3–1.0) and 0.5 (0.3–0.9), respectively (P for trend=0.005).

Conclusion:

Our findings strengthen the evidence that occupational exposure to endotoxins protects against lung cancer, and suggest that the effect depends on cumulative dose and persists after exposure ceases.     

Molecular sputum analysis for the diagnosis of lung cancer

Lung cancer is the leading cause of cancer mortality rate worldwide, mainly because of the presence of metastatic disease at the time of diagnosis. Early detection of lung cancer improves prognosis, and towards this end, large screening trials in high-risk individuals have been conducted since the past century. Despite all efforts, the need for novel (complementary) lung cancer diagnostic and screening methods still exists. In this review, we focus on the assessment of lung cancer-related biomarkers in sputum in the past decennium. Besides cytology, mutation and microRNA analysis, special attention has been paid to DNA promoter hypermethylation, of which all available literature is summarised without time restriction. A model is proposed to aid in the distinction between diagnostic and risk markers. Research on the use of sputum for non-invasive detection of early-stage lung cancer has brought new insights and advanced molecular techniques. The sputum shows a promising potential for routine diagnostic and possibly screening purposes.     

Clinical features and outcomes of patients with stage I multiple primary lung cancers

The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18 978 registered cases, 9689 patients with clinical stage I non-small-cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was carried out within 2 years after the initial surgery; metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Female sex, nonsmoker, low consolidation-tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, whereas patients with metachronous MPLC had higher frequencies of male sex, smoker, chronic obstructive pulmonary disease (COPD), and nonadenocarcinoma. There was no significant difference in survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC. Logistic regression analysis showed that female sex, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings could have major implications regarding MPLC diagnosis and identification of independent prognostic factors, and provide valuable information for postoperative management of patients with MPLC.     

Lung, liver and bone cancer mortality in Mayak workers

Workers at the Mayak nuclear facility in the Russian Federation offer the only adequate human data for evaluating cancer risks from exposure to plutonium. Risks of mortality from cancers of the lung, liver and bone, the organs receiving the largest doses from plutonium, were evaluated in a cohort of 17,740 workers initially hired 1948-1972 using, for the first time, recently improved individual organ dose estimates. Excess relative risk (ERR) models were used to evaluate risks as functions of internal (plutonium) dose, external (primarily gamma) dose, gender, attained age and smoking. By December 31, 2003, 681 lung cancer deaths, 75 liver cancer deaths and 30 bone cancer deaths had occurred. Of these 786 deaths, 239 (30%) were attributed to plutonium exposure. Significant plutonium dose-response relationships (p < 0.001) were observed for all 3 endpoints, with lung and liver cancer risks reasonably described by linear functions. At attained age 60, the ERRs per Gy for lung cancer were 7.1 for males and 15 for females; the averaged-attained age ERRs for liver cancer were 2.6 and 29 for males and females, respectively; those for bone cancer were 0.76 and 3.4. This study is the first to present and compare dose-response analyses for cancers of all 3 organs. The unique Mayak cohort with its high exposures and well characterized doses has allowed quantification of the plutonium dose-response for lung, liver and bone cancer risks based on direct human data. These results will play an important role in plutonium risk assessment.     

多原发肺癌的再认识

多原发肺癌(multiple primary lung cancer,MPLC)是一种不常见的肺癌,对于多原发肺癌的诊断标准、发病因素、与肺转移癌的鉴别、治疗及长期生存仍存在争议.随着诊断技术的进步和对多原发肺癌认识的提高,多原发肺癌发病率的报道逐渐增多.我们尝试通过回顾多原发肺癌的现况及其最新相关的分子生物标志物加深我们对多原发肺癌的理解.     

Treatment outcomes for patients with synchronous multiple primary non-small cell lung cancer

Introduction

The development of synchronous multiple primary non-small cell lung cancer (NSCLC) is not rare. Nevertheless, the diagnosis, treatment and outcome are controversial. The purposes of this study were to assess the treatment outcomes for patients with synchronous multiple primary NSCLC and to analyze the factors related to this outcome.

Methods

We retrospectively analyzed clinical characteristics and treatment outcomes of 32 patients with synchronous multiple primary NSCLC who underwent surgical resection between 1995 and 2008.

Results

A total of 68 separate tumors were identified in 32 patients. Fifteen (46.9%) patients underwent lobectomy or pneumonectomy with mediastinal lymph node dissection, and 17 (53.1%) patients underwent at least one limited resection or photodynamic therapy. The rate of immediate postoperative mortality was 9.4% (N = 3). The five-year progression-free survival (PFS) and overall survival (OS) rates were 46.0% and 60.9%, respectively. Small tumor size, similar histology, pN0, and pT1 were associated with better PFS in univariable analyses. Female gender, young age, non-smoker, FEV1/FVC ≥70%, small tumor size, similar histology, and highest pT1 were associated with better OS in univariable analyses.

Conclusions

An aggressive surgical approach offers the greatest chance for long-term survival in patient with synchronous multiple primary NSCLC and several clinical factors were associated with survivals. However, the decision of aggressive surgical treatments for synchronous MPLC should be made carefully in the patients with old age and underlying comorbidities due to poor OS and increased surgical mortality.     

合并肺癌的多原发恶性肿瘤70例临床病理特征分析北大核心

目的:探讨合并肺癌的多原发恶性肿瘤(multiple primary malignancies,MPM)患者临床病理特征。方法:收集2017年01月01日至2019年12月31日陕西省肿瘤医院收治的3438例肺癌患者病例资料,回顾性分析其中70例合并肺癌MPM患者的临床病理特征。结果:同时多原发肿瘤(synchronous MPM,SMPM)16例,异时多原发肿瘤(metachronous MPM,MMPM)54例,男女比例为1∶1.06(男34例,女36例);入组病例次原发肿瘤发生的年龄为(61.37±11.22)岁;初原发肿瘤和次原发肿瘤发生平均时间间隔77.09月;肺癌先发组(lung cancer first,LCF)和其他器官肿瘤先发组(other cancer first,OCF)中肺癌病理类型均以肺腺癌最为多见,共42例(60.00%);肺癌分期为Ⅳ期患者共38例(54.29%);62.86%(44/70)患者伴有肺门或纵隔淋巴结转移;吸烟患者更容易出现SMPM。男性OCF组的初原发肿瘤中胃癌比例最高(31.82%,7/22),而原发性乳腺癌在女性中OCF组比例最高(32.26%,10/31)。结论:无病生存期超过5年的肿瘤患者应长期随访监测多原发肿瘤的发生;初原发乳腺癌、宫颈癌、胃癌患者应加强次原发肺癌的筛查,初原发肺癌患者应加强双原发肺癌及次原发胃癌、食管癌的筛查,以尽早发现MPM的发生,规范治疗,争取治愈机会。     

Swedish lung cancer radiation study group: predictive value of histology for radiotherapy response in patients with non-small cell lung cancer

The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (?50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded (n = 141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma (n = 323) or squamous cell carcinoma (n = 596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma (p = 0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA–IIB (p < 0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis (p = 0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables (p = 0.037 and p = 0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA–IIB.     

Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research

Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials'' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.