Purpose: KRAS mutations are found in f25% of lung adenocarcinomas inWestern countries and, as a group, have been strongly associated with cigarette smoking.These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib. Experimental Design: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas. Results: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G!A) rather than the transversion mutations known to be smokingrelated (G!Tor G!C; P < 0.0001).Conclusions: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile.The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.Since the identification of somatic epidermal growth factor receptor (EGFR) mutations, there has been heightened interest in the molecular basis of lung cancer in patients who never smoked cigarettes (1 -3). Somatic mutations in EGFR have been identified in f15% of all patients with lung adenocarcinoma, with the proportion increasing to 50% in patients who never smoked cigarettes. There is an inverse relationship between cigarette smoking history and frequency of EGFR mutations, with the frequency of EGFR mutations decreasing significantly among patients who smoked more than 15 pack years (4). Such refined understanding of the relationship between smoking history and presence of EGFR mutations has allowed the design of clinical trials which use smoking history to enrich the number of patients with somatic EGFR mutations (5-7).In contrast to EGFR mutations, KRAS mutations were initially identified in patients with lung adenocarcinoma who had a history of heavy cigarette smoking and were thought to be uncommon in patients without a history of smoking cigarettes (8). These mutations are found in f25% of lung adenocarcinomas in western countries but are less common in Asian populations (9, 10). KRAS mutations have been associated with poor prognosis in resected non -small cell lung cancer (NSCLC; refs. 11-13), lack of survival benefit from adjuvant chemotherapy (14), and resistance to erlotinib or gefitinib (15). More than 95% of KRAS ...
Introduction Human epidermal growth factor receptor 2 (HER2, ERBB2) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering and University of Colorado combined their data on HER2 alterations in lung cancers. Methods Tumor specimens from 175 patients with lung adenocarcinomas with no prior targeted therapy were evaluated for the presence of HER2 amplification, mutation, and HER2 protein overexpression. Amplification was assessed by fluorescence in-situ hybridization (FISH) and defined as HER2/CEP17 ratio ≥2.0. Mutation was assessed by fragment analysis, mass spectrometry genotyping and Sanger sequencing. Overexpression was assessed by immunohistochemistry (IHC). The frequencies of HER2 amplification, mutation and HER2 overexpression were calculated and their overlap examined. Results HER2 amplification by FISH was detected in 5 of 175 (3%) cases. HER2 mutation was detected in 4 of 148 (3%) specimens, including 3 identical 12bp insertions (p.A775_G776insYVMA) and a 9bp insertion, all in exon 20. None of the HER2 mutant cases were amplified. HER2 overexpression (2+, 3+) on IHC was not detected in the 25 specimens available for testing and negative IHC correlated with negative results on FISH. Conclusions HER2 mutations are not associated with HER2 amplification suggesting a distinct entity and therapeutic target. “HER2-positive lung cancer” may not be an adequate term and patient cohorts for the study of HER2 targeted agents should be defined by the specific HER2 alteration present.
Elevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Routine measurement of postoperative, rather than preoperative, CEA is warranted. Patients with elevated postoperative CEA are at increased risk for recurrence, especially within the first 12 months after surgery.
Background Previous comparisons of gastric cancer between the West and the East have focused predominantly on Japan and Korea, where early gastric cancer is prevalent, and have not included the Chinese experience, which accounts for approximately half the world’s gastric cancer. Methods Patient characteristics, surgical procedures, pathologic information, and survival were compared among gastric cancer patients who underwent curative intent gastrectomy at two large volume cancer centers in China and the US between 1995 and 2005. Results Median age and body mass index were significantly higher in US patients. The proportion of proximal gastric cancer was comparable. Gastric cancer patients in China had larger tumors and a later stage at presentation. The median number of positive lymph nodes was higher (5 vs 4, p<0.02) despite a lower lymph node retrieval (16 vs 22, p<0.001) in Chinese patients. The probability of death due to gastric cancer in Chinese patients was 1.7 fold of that in the US (p<0.0001) after adjusting for important prognostic factors. Conclusions Even after adjusting for important prognostic factors Chinese gastric cancer patients have a worse outcome than US gastric cancer patients. The differences between Chinese and US gastric cancer are a potential resource for understanding the disease.
Keloids represent a dysregulated response to cutaneous wounding that results in an excessive deposition of extracellular matrix, especially collagen. However, the molecular mechanisms regulating this pathologic collagen deposition still remain to be elucidated. A previous study by this group demonstrated that transforming growth factor (TGF)-beta1 and -beta2 ligands were expressed at greater levels in keloid fibroblasts when compared with normal human dermal fibroblasts (NHDFs), suggesting that TGF-beta may play a fibrosis-promoting role in keloid pathogenesis.To explore the biomolecular mechanisms of TGF-beta in keloid formation, the authors first compared the expression levels of the type I and type II TGF-beta receptors in keloid fibroblasts and NHDFs. Next, they investigated the phosphorylation of Smad 3, an intracellular TGF-beta signaling molecule, in keloid fibroblasts and NHDFs. Finally, they examined the regulation of TGF-beta receptor II by TGF-beta1, TGF-beta2, and TGF-beta3 ligands. Our findings demonstrated an increased expression of TGF-beta receptors (types I and II) and increased phosphorylation of Smad 3 in keloid fibroblasts relative to NHDFs. These data support a possible role of TGF-beta and its receptors as fibrosis-inducing growth factors in keloids. In addition, all three isoforms of recombinant human TGF-beta proteins could further stimulate the expression of TGF-beta receptor II in both keloids and NHDFs. Taken together, these results substantiate the hypothesis that the elevated levels of TGF-beta ligands and receptors present in keloids may support increased signaling and a potential role for TGF-beta in keloid pathogenesis.
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