Colorectal serrated pathway cancers and precursors

The serrated pathway (SP) can be viewed as two parallel, but partially overlapping, arrays of colorectal precursor lesions, and their respective endpoint carcinomas, that are distinct from those of the conventional adenoma–carcinoma sequence (APC‐pathway). In this review we focus at the outset on the clinical impact, pathological features, molecular genetics and biological behaviours of the various SP cancers. Then we summarize the clinicopathological features, classification and molecular profiles of the two main precursor lesions that anchor the respective pathways: (i) sessile serrated adenoma/polyp (SSA/P), also called sessile serrated lesion (SSL), and (ii) traditional serrated adenoma (TSA). Activating mutations of the RAS–RAF–MAPK pathway initiate and sustain the lesions of the SP, and CpG island methylation of the promoter regions of tumour suppressor and DNA repair genes play the major role in their neoplastic progression. The SP includes microsatellite stable (MSS) carcinomas that are among the most biologically aggressive colorectal carcinomas (CRC), and also accounts for the great preponderance of sporadic hypermutated, mismatch repair (MMR)‐deficient or microsatellite instable (MSI) CRC. The identification, removal and appropriate classification of at‐risk SP precursors and surveillance of individuals who harbour these lesions present a challenge and opportunity for CRC prevention and mortality reduction.     

沉默circROBO1通过下调KRAS抑制鼻咽癌CNE2细胞侵袭与肺转移

目的探讨沉默环状RNA hsa_circ_0124696(circROBO1)对鼻咽癌CNE2细胞侵袭与肺转移的影响机制。 方法qRT-PCR检测鼻咽癌及癌旁组织中circROBO1表达。采用干扰小RNA(siRNA)沉默鼻咽癌CNE2细胞中circROBO1的表达,Transwell及HE染色检测circROBO1对CNE2细胞迁移能力和体内肺转移的影响。TargetScan在线软件预测circROBO1下游miR-217与下游靶基因KRAS的靶向结合位点,双荧光素酶报告基因实验验证两者之间的靶向调控关系。蛋白免疫印迹检测siRNA沉默CNE2细胞中circROBO1表达对KRAS的影响。 结果鼻咽癌组织中circROBO1表达高于癌旁组织(P＜0.05)。与转染si-circNC的对照组相比,si-circROBO1组鼻咽癌CNE2细胞侵袭与体内肺转移能力均显著降低(P＜0.05)。circROBO1下游miR-217与KRAS之间存在靶向结合位点,并且circROBO1可影响KRAS的蛋白和mRNA表达量。 结论沉默circROBO1通过miR-217下调KRAS抑制鼻咽癌CNE2细胞侵袭与肺转移。     

结直肠癌RAS、BRAF基因状态与临床病理特征的关系

目的分析中国人群结直肠癌患者中KRAS、NRAS及BRAF基因突变状态与临床病理特征之间的关系。方法回顾性分析2018年1月—2020年11月于福建省肿瘤医院接受治疗的370例结直肠癌患者的肿瘤组织标本,检测KRAS、NRAS、BRAF基因突变状态及MMR蛋白表达状态,分析基因突变状态与结直肠癌临床病理特征的关系。结果370例患者中存在KRAS基因突变155例(41.9%),NRAS基因突变19例(5.1%),BRAF基因突变40例(10.8%),其中1例患者突变类型为G469V,其他均为V600E突变。KRAS基因在女性、高中分化患者中突变率高(P<0.05)。NRAS基因突变多见于低分化、浸润型患者(P<0.05)。BRAF V600E突变在右半结肠癌、年龄小于50岁、低分化、浸润型、淋巴结及远处转移患者中的突变率高(P<0.05)。结论KRAS基因突变与性别、分化程度有关,NRAS基因突变与分化程度、肿瘤大体分类有关,BRAF基因V600E突变与肿瘤原发部位、年龄、分化程度、肿瘤大体分类、区域淋巴结及远处转移有关。对结直肠癌患者进行KRAS、NRAS及BRAF基因的检测,为了解中国患者热点基因突变分布情况和临床精准诊疗提供理论依据。     

Phenotypic and genotypic differences in colorectal carcinoma among Caucasians,Asians, and Hispanics lack statistical significance

Colorectal carcinoma (CRC) has been shown to have both genetic and environmental factors that can promote carcinoma development. Previous studies have found ethnic differences in the distribution of molecular phenotypes of CRC. Very little specific data exist regarding Hispanic CRC, and these data primarily focus on epidemiology or location of carcinoma. Our retrospective study analyzed 562 Caucasian, Asian, and Hispanic CRC patients at the UCI Medical Center from 2004 to 2012. The results showed that there were no statistically significant differences with respect to mean age, gender or site of carcinoma among the three ethnic groups. There were no statistically significant differences among the three ethnicities with respect to rates of MSI, mutated BRAF, and mutated KRAS. The Caucasian group had a non-significant higher rate of MSI (15%) and BRAF mutation (12%) than the Asian and Hispanic groups. Hispanics had a non-significant higher rate of KRAS mutation (59%) than Caucasians (38%) and Asians (37%). The results of this study demonstrated a higher rate of MSI and BRAF mutation in the Caucasian group and a higher rate of KRAS mutation in the Hispanic group, however differences were not statistically significant.     

A MEK/PI3K/HDAC inhibitor combination therapy for KRAS mutant pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, metastatic disease with limited treatment options. Factors contributing to the metastatic predisposition and therapy resistance in pancreatic cancer are not well understood. Here, we used a mouse model of KRAS-driven pancreatic carcinogenesis to define distinct subtypes of PDAC metastasis: epithelial, mesenchymal and quasi-mesenchymal. We examined pro-survival signals in these cells and the therapeutic response differences between them. Our data indicate that the initiation and maintenance of the transformed state are separable, and that KRAS dependency is not a fundamental constant of KRAS-initiated tumors. Moreover, some cancer cells can shuttle between the KRAS dependent (drug-sensitive) and independent (drug-tolerant) states and thus escape extinction. We further demonstrate that inhibition of KRAS signaling alone via co-targeting the MAPK and PI3K pathways fails to induce extensive tumor cell death and, therefore, has limited efficacy against PDAC. However, the addition of histone deacetylase (HDAC) inhibitors greatly improves outcomes, reduces the self-renewal of cancer cells, and blocks cancer metastasis in vivo. Our results suggest that targeting HDACs in combination with KRAS or its effector pathways provides an effective strategy for the treatment of PDAC.     

Impact of 3′UTR variation patterns of the KRAS gene on the aggressiveness of pancreatobiliary tumors with the KRAS G13D mutation in a Turkish population

ObjectiveSeveral studies have demonstrated the importance of mutations in codons 12, 13 and 61 and variations in the 3′ untranslated region (3′UTR) of the KRAS gene, frequently observed genetic events in the progression of pancreatobiliary tumors (PBT). However, limited data exist on the clinical effect of these alterations. The aim of the current study was to clarify the frequency of relevant alterations of the 3′UTR regions of the KRAS gene and the effect of KRAS 3′UTR polymorphisms on the prognosis of patients with codon 12, 13 and 61 mutations in a Turkish population with PBT.MethodsCodons 12, 13, and 61 and 3′UTRs of the KRAS gene were screened by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing in 43 patients and 10 controls. Chi-squared and independent sample T tests were used to evaluate the results of the mutation analysis and clinical features of the patients.ResultsWe defined the c.38G > A (rs112445441, p.G13D) (39.54%) mutation and two 3′UTR variations, c.*4066delA (rs560890523) (23.26%) and c.*4065_*4066delAA (rs57698689) (6.98%), in the KRAS gene of Turkish patients. There was a statistically significant relationship between the c.*4066delA (rs560890523) and c.*4065_*4066delAA (rs57698689) variations and invasion and lymph node metastasis status of the patients (p < 0.001). Compared to patients with c.38G > A (rs112445441, p.G13D), patients with c.*4066delA (rs560890523) and c.38G > A (rs112445441, p.G13D) presented more aggressive tumors with highly invasive features. The present study contributes findings regarding the clinical effects of KRAS alterations in PBT. Based on our study, further investigations are required.     

KRAS mutations in tongue squamous cell carcinoma

Background: p16^INK4a (p16) expression in tongue cancer (TC) is reportedly not associated with human papilloma virus (HPV). Mutations of KRAS in cancer cells are most frequently observed within codon 12. However, few reports have investigated the association between KRAS mutations and p16 status in TC.

Objectives: This study aimed to evaluate the influence of KRAS mutations on TC.

Methods: Clinical records and surgically resected specimens of 85?TC patients were analyzed. Tumor samples were analyzed for mutations of KRAS located within codons 12 and 13. p16 staining was performed and considered positive in cases with moderate to strong nuclear and cytoplasmic staining.

Results: Positive p16 staining was observed in 10 cases (11.8%). A KRAS mutation was detected in one case (1.2%). The case with KRAS mutation showed negative p16 staining. Despite being at an early stage, the patient died of lung metastasis at 43 months from initial treatment.

Conclusions and Significance: KRAS mutations are not associated with p16 expression in TC and may predict poor prognosis in TC patients. Further analysis of mutations in regions other than codons 12 and 13 of KRAS will be necessary to determine the relationship between KRAS mutations and prognosis of this disease.