Driver mutations determine survival in smokers and never‐smokers with stage IIIB/IV lung adenocarcinomas

BACKGROUND:

The authors previously demonstrated that never‐smokers with stage IIIB/IV nonsmall cell lung cancer (NSCLC) lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and sex. In this study, the authors hypothesized that smoking‐dependent differences in the distribution of driver mutations may explain differences in prognosis between these subgroups.

METHODS:

In total, 293 never‐smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for epidermal growth factor receptor (EGFR) mutations and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and rearrangements in anaplastic lymphoma kinase (ALK) between 2009 and 2010 were investigated. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan‐Meier method. Group comparison was performed with log‐rank tests and Cox proportional hazards methods.

RESULTS:

Although the overall incidence of these mutations was nearly identical (55% never‐smokers vs 57% current/former smokers; P = .48), there were significant differences in the distribution of mutations between these groups for EGFR mutations (37% never‐smokers vs 14% former/current smokers; P < .0001), KRAS mutations (4% never‐smokers vs 43% former/current smokers; P < .0001), and ALK rearrangements (12% never‐smokers vs 2% former/current smokers; P < .0001). Among never‐smokers and former/current smokers, the prognosis differed significantly by genotype. Patients who had KRAS mutations had the poorest survival. Smoking status, however, had no influence on survival within each genotype.

CONCLUSIONS:

Never‐smokers and former/current smokers with lung adenocarcinomas were not homogeneous subgroups. Each was made up of individuals whose tumors had a unique distribution of driver mutations, which were associated with different prognoses, irrespective of smoking history. Cancer 2012. © 2012 American Cancer Society.     

槲皮素抑制乳腺癌发生及增殖的实验研究

目的 探讨槲皮素抑制乳腺癌发生及增殖的作用。方法 建立三甲基苯丙蒽（DMBA）诱导的乳腺癌动物模型。79只雌性SD大鼠随机分为A组（DMBA）、B组[DMBA 三苯氰胺（TAMC)],C组（DMBA＋槲皮素）及D组（空白对照）。持续喂养28周,经光镜、电镜观察,抗PCNA及H－ras免疫组化分析。结果 （1）A组大鼠乳腺肿瘤发生率为76．2％,明显高于B组（40．9％）、C组（45．5％）及D组（0％）,P＜0．05;B组与C组相比差异无显著性意义（P＞0．05）。（2）A组大鼠乳腺癌平均直径2．37cm,明显大于B组（1．82cm)及C组（1．71cm),P＜0．05;B组和C组相比差异无显著性意义（P＞0．05）。（3）PCNA免疫组化染色显示;A组和B组和C组相比差异有显著性意义（P＜0．05）;B组和C组相比差异无显著性意义（P＞0．05）。（5）H－ras免疫化染色显示;A组与B组和C组比较差异有显著性意义（P＜0．05）,B组和C组相比差异无显著性意义（P＞0．05）。结论 槲皮素有降低DMBA诱导的SD大鼠乳腺癌发生率及抑制肿瘤生长的作用,其机理可能与抑制ras基因活性、阻抑细胞增殖有关。     

ONCOPROTEINS AND TUMOR SUPPRESSOR PROTEINS IN CONGENITAL SACROCOCCYGEAL TERATOMAS

Congenital sacrococcygeal teratoma SCT is the most common germ cell tumor of infancy and childhood with a female preponderance. Most SCTs are diagnosed at birth, are benign, and consist of fully differentiated, mature tissues. Tumorigenesis of SCTs remains poorly understood. Almost nothing is known about possible oncogene activation or tumor suppressor inactivation in these rare tumors. We describe the presence of various oncoproteins and tumor suppressor proteins in eight cases of congenital SCT. The following oncogenes were examined: ras family c-H-, c-N-, and c-K-ras , early genes fos, jun , and tumor suppressor genes p53 and nm23-H-1 . There was no relationship between the intensity of expression of these oncoproteins and tumor suppressor genes and the following parameters: tumor size, age, and survival of the patients. We did not observe any difference, however, between the expression of the examined oncogenes and tumor suppressor genes nm23 and p53 in immature and mature teratomas. Our findings suggest that the ras family of oncogenes, fos and jun oncogenes, and nm23 and p53 tumor suppressor genes are present in congenital SCT, indicating a possible role in genesis and development of these tumors.     

RAS AND p53 EXPRESSION IN HUMAN THYROID CARCINOMA

Both benign and malignant nodular disorder of the thyroid gland may give rise to similar symptomatology. Even though clinical background and pathologic criteria may predict prognosis, there are still patients without these adverse prognosis indicators who develop subsequent local invasion or distant metastasis after surgical intervention and eventually succumb to the disease.[1] In recent years it has become apparent that malignant transformation is a result of the accumulation of genetic abno…     

Distribution of p21ras during primary palate formation of non-cleft and cleft strains of mice

Cleft lip, with or without cleft palate, is one of the most common defects in craniofacial formation. The primary palatogenesis of mice is similar to that of humans and spontaneous cleft lip is associated with genotype in both mice and humans. To investigate the temporal and spatial expression of ras genes in cleft (A/WySn) and non-cleft strains of mice (BALB/cBy), a broad spectrum ras antibody was used. Positive staining was found in ectodermal, mesenchymal, and neuroepithelial cells of facial prominences before the primary palate formation stage (10 d 20 hr) in both strains. During the primary palate formation stage (11 d 20 hr), positive staining was found in the ectodermal and mesenchymal cells of the facial prominences of the non-cleft strain but not in those of the cleft strain. These results suggest ras genes may play a role in the primary palatogenesis of mice. Cleft lip could be associated with the deficiency of ras gene expression during primary palate formation of mice.     

乳腺癌细胞rasP21基因表达水平检测的临床意义

应用免疫组化方法检测了３７例乳腺癌、２５例良性乳腺疾病和１０例正常乳腺组织ｒａｓ癌基因产物Ｐ２１的表达水平。结果显示：乳腺癌Ｐ２１的阳性反应率（７０．３％）远高于良性乳腺疾病（８％）及正常乳腺（０％），且Ｐ２１表达水平随肿瘤体积、局部浸润和淋巴结转移的扩展而升高（Ｐ＜０．０１）。癌组织分化低者Ｐ２１表达水平亦较高（Ｐ＜０．０５）。提示Ｐ２１过度表达是乳腺癌预后不良的征象。     

FREQUENCY AND CLINICO-PATHOLOGICAL ASSOCIATIONS OF RAS MUTATIONS IN COLORECTAL CANCER IN THE VICTORIAN POPULATION

Background : Mutations in the oncogene ras occur in 20–50% of colorectal cancers. The presence of these mutations allows screening tests to be developed based on the identification of mutant DNA in cells derived from cancers. A study of the prevalence and clinicopathological associations of ras mutations was undertaken. Methods : The frequency of mutations in codons 12 and 13 of the K-ras gene was investigated in 103 colorectal carcinomas using restriction fragment length polymorphism. Results : Mutations were detected in 32% (33/103) of the tumours, predominantly in codon 12 (25/33). No mutations were detected in normal-appearing mucosa from the same patients. Conclusions : Analysis of the frequency of ras mutations compared with various independent clinical variables revealed a sex-linked relationship between the presence of a ras mutation and nodal status but no correlation with any other clinical parameter was found. The findings suggest that screening tests based on ras mutation detection may lack sensitivity because of the presence of mutations in only 32% of tumours.     

Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice.

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.