Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad‐based mutational profiling for patients diagnosed ...with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site‐specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2‐hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
摘要
胆囊和胆管起源的肿瘤目前尚难治愈。通过对胃肠恶性肿瘤标本采用广谱突变谱基因分型技术，我们在一种亚群的胆管癌患者中新发现了基因编码异柠檬酸脱氢酶1（ IDH1）突变。本研究对15个癌基因内130个定点突变进行常规临床评估，共检测了胃肠癌患者的287个肿瘤样本（胆道、结直肠、胃食管、肝脏、胰腺和小肠癌）。在部分基因中发现突变，包括 KRAS （35%）、 TP53 （22%）、 PIK3CA（10%）、BRAF（7%）、 APC （6%）、 NRAS （3%）、 AKT1（1%）、CTNNB1（1%）和 PTEN （1%）。尽管代谢酶IDH1突变在该系列其他常见胃肠道恶性肿瘤中十分罕见（2%），但在该系列最初12个胆道癌中却占3个（25%）。为更好地确定 IDH1 和 IDH2 突变状态，我们追加探寻了75个胆囊和胆管癌。结合这些胆管癌队列来看， IDH1 和 IDH2 突变仅见于肝内起源的胆管癌（9/40例，23%），未见于22例肝外胆管癌和25例胆囊癌。冰冻组织样本分析显示， IDH1 突变与酶产物2‐羟基戊二酸组织水平高度升高关联。因此， IDH1 突变是肝内胆管癌的分子特征。这些结果提示，在此类基本无法治愈的胃肠肿瘤中存在一种可能成为治疗新靶点的特异性代谢异常。
The results of mutational profiling of 287 patients with gastrointestinal cancer are presented, identifying for the first time IDH1 mutations in a significant subset of patients with intrahepatic cholangiocarcinoma.
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3594
Background: Functional SNPs in VEGF-A are prognostic for OS in several malignancies, but not described definitively in mCRC. In bevacizumab-treated patients with advanced breast ...cancer, VEGF -2578AA and -1154A were predictive of OS—the latter SNP reported in a recent mCRC series as well. We examined the association between five functional VEGF-A SNPs and OS in a large cohort of bevacizumab-treated patients with mCRC. Methods: 403 patients with mCRC treated from 2004-2010 were included in a retrospective analysis. DNA extraction, genotyping, and SNP evaluation were performed according to standard protocols. Survival was calculated from the time of Stage IV diagnosis until death. Data were censored as of 12/31/2010. Results: There were 279 deaths in this group of 403 patients (69%). Median age was 55.7 (24-86 y), and 54% of patients were male. Age, sex, race, tumor grade, chemotherapies, and curative surgery (metastatectomy to negative margins) were considered. Significant clinical predictors of OS in univariate Cox modeling were cetuximab treatment HR=1.46; 95% CI 1.13-1.88; p=0.0014, irinotecan treatment HR=2.10; 1.32-3.35; p<0.001, and curative surgery HR=0.36; 0.25-0.75; p<0.001. Significant negative interaction was found between both cetuximab and irinotecan and curative surgery, and in modeling that included this interaction, only surgery remained predictive. In multivariate analysis, no association was found between VEGF-A and OS (Table). Conclusions: There was no association between five functional VEGF-A SNPs and OS in this large bevacizumab-treated mCRC cohort. Table: see text
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4125
Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether ...serum 2HG levels in IDHm ICC pts may 1) serve as a surrogate biomarker for IDH status, 2) correlate with tumor burden, and 3) correlate with circulating proangiogenic biomarkers. Methods: Blood samples from 33 ICC pts 11 IDHm, 22 IDH wild-type (IDHwt) of different AJCC stages from MGH and 39 surgically resected ICC patients (7 IDHm, 32 IDHwt) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry. Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA. Results: In the MGH cohort, median serum 2HG levels were significantly elevated in IDHm (478 ng/ml interquartile range 174–643) versus IDHwt ICC pts (118ng/ml 68–160)(p<0.001). Similarly, in the HKU cohort, the pre-resection median serum 2HG levels were significantly elevated in IDHm (343ng/ml 192–596) versus IDHwt ICC pts (56ng/ml 42–81) (p<0.0001). The area under ROC curve for prediction of an IDH mutation using 2HG was 93%; with a threshold of 2HG≥170ng/ml, the sensitivity was 83% and specificity was 90%. IDH2 mutations were more frequent in the HKU cohort (3/7, 43%) compared with the MGH cohort (0/11, 0%) (p<0.05), but 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. 2HG levels correlated directly with tumor burden (Spearman’s rho=0.89; p<0.05) in the HKU cohort. Median plasma levels of PlGF—a growth factor from the VEGF-family—were higher in IDHm (35pg/ml 33–40) versus IDHwt ICC pts (median 26pg/ml 24–34) from the HKU cohort (p<0.05). No other associations were seen between proangiogenic biomarkers and IDH status. Conclusions: IDHm ICC pts had significantly higher serum 2HG levels compared to IDHwt ICC pts. High serum 2HG correlated with increased tumor burden. Pre-resection circulating PlGF levels were higher in IDHm ICC versus IDHwt pts. These data support further exploration of circulating 2HG as potential surrogate and response biomarker in IDHm ICC.
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