Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma

Aims

No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker.

Methods

We monitored a 15-year-old boy diagnosed to have FLHCC by measuring the common markers alanine aminotransaminase, alkaline phosphatase, lactate dehydrogenase, and bilirubin, as well as vitamin B12 (B12), and the forms of the B12 binding proteins. Tumour biopsies were examined immunohistologically. DNA and RNA were extracted from tumour and normal tissue and examined for content of HC DNA and mRNA.

Results

The only markers indicative of disease progression were HC and (B12), levels of which were markedly elevated to 84 (11) nmol/L at the time of diagnosis and returned to values within the reference interval (0.43 (0.33) nmol/L) after an apparently radical removal of the tumour. The disappearance rate of HC followed a biphasic curve, the unsaturated protein displaying a half-life of 2.8 days and B12 and saturated HC one of 13 days. Before each diagnosed relapse, an increased concentration of HC was observed. We found a strong immunoreaction against HC in tumour tissue and a high mRNA expression of HC supporting the notion that HC was tumour derived.

Conclusions

Plasma HC proved to be a useful tumour marker in a patient with FLHCC, and we suggest the use of this protein as a marker of disease progression in these patients.     

The genomic profile of parathyroid carcinoma based on whole-genome sequencing

Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such as CDC73 have been found in patients, the molecular mechanism of PC still needs extensive data to clarify. Whole-genome sequencing (WGS) was performed with frozen samples from 23 PC patients. Peripheral leukocytes were collected from 14 patients and served as controls. Somatic and germline gene alterations, copy number abnormalities and structural variants were detected. Inactivating CDC73 mutations were identified in 39.1% of patients, but only one germline inactivating mutation was found. Other cancer-related mutations identified in more than one case were MAF (2/23), NEB (6/23), NCOR1 (2/23), TTK (2/23), GRIN3A (4/23), TRIO (2/23), MAP1B (2/23), TJP2 (2/23) and FAM20A (2/23). In the seven wild-type CDC73 samples, the mutated genes were enriched in pathways involving antigen presentation, allograft rejection or autoimmune disease. More copy number variants were found in patients with cancer recurrence (P = .006) and CDC73 mutations (P = .022) than in those without these characteristics. PIK3CA loss was found in one sample, which also harboured a CDC73 mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer-predisposing mutations were PDE4DIP (15/23), MAP3K1 (13/23) and CDC42EP1 (10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC. CDC73 mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild-type CDC73 harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on the CDC73 mutation may help to manage follow-up and therapy for PC patients.     

SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma

Reliable biomarkers are required to predict the response to sorafenib. We investigated genomic variations associated with responsiveness to sorafenib for patients with unresectable hepatocellular carcinoma (HCC). Blood samples from 2 extreme, 2 strong and 3 poor responders to sorafenib were subjected to whole-genome analysis. Then, we validated candidate genomic variations with another 174 HCC patients, and performed in vitro functional analysis and in silico analyses. Genomic data of >96 gigabases/sample was generated at average of ~34X sequencing depth. In total, 1813 genomic variations were matched to sorafenib responses in clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes. From them, 36 variants were within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2). Validation genotyping confirmed sequencing results and revealed patients genotype for rs2257212 in SLC15A2 showed longer progression-free survival (HR = 2.18). In vitro study displayed different response to sorafenib depending on the genotype of SLC15A2. Structural prediction analysis revealed changes of the phosphorylation levels in protein, potentially affecting sorafenib-associated enzymatic activity. Our finding using extreme responder seems to generate robust biomarker to predict the response of sorafenib treatment for HCC.     

A pleomorphic hepatocellular carcinoma with biochemical features of fibrolamellar hepatocellular carcinoma

A case of pleomorphic hepatocellular carcinoma with biochemical characteristics similar to those of fibrolamellar carcinoma is described. During chemotherapy there was a marked disorder of vitamin B12 metabolism.     

Targeted or whole genome sequencing of formalin fixed tissue samples: potential applications in cancer genomics

Current genomic studies are limited by the poor availability of fresh-frozen tissue samples. Although formalin-fixed diagnostic samples are in abundance, they are seldom used in current genomic studies because of the concern of formalin-fixation artifacts. Better characterization of these artifacts will allow the use of archived clinical specimens in translational and clinical research studies. To provide a systematic analysis of formalin-fixation artifacts on Illumina sequencing, we generated 26 DNA sequencing data sets from 13 pairs of matched formalin-fixed paraffin-embedded (FFPE) and fresh-frozen (FF) tissue samples. The results indicate high rate of concordant calls between matched FF/FFPE pairs at reference and variant positions in three commonly used sequencing approaches (whole genome, whole exome, and targeted exon sequencing). Global mismatch rates and C·G > T·A substitutions were comparable between matched FF/FFPE samples, and discordant rates were low (<0.26%) in all samples. Finally, low-pass whole genome sequencing produces similar pattern of copy number alterations between FF/FFPE pairs. The results from our studies suggest the potential use of diagnostic FFPE samples for cancer genomic studies to characterize and catalog variations in cancer genomes.     

The genomic landscape of nonsmall cell lung carcinoma in never smokers

Lung cancer is the number one cause of cancer-related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never-smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole-exome and low-coverage whole-genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53, which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six-substitution type patterns or into 96-substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second-hand smoking is not driving NSCLC pathogenesis in never smokers.     

青年原发性肝癌临床特点分析

目的探讨青年原发性肝癌的临床特点.方法分析86例青年肝癌患者(年龄＜40岁)的临床特点,包括临床症状体征、肝癌家族史、饮酒史、HBV感染率、HCV感染率、ALT异常、AFP阳性、AFU阳性、合并肝硬化、门静脉癌栓以及肝癌类型,并与同期122例老年肝癌患者(年龄＞60岁)进行比较.结果青年肝癌患者占原发性肝癌患者的13.6%,在以下方面比例高于老年组,且有显著性或极其显著性差异:发热(36.0%)、HBV感染(86.0%)、ALT异常(74.4%)、AFP阳性(76.7%)、AFU阳性(81.4%)、门静脉癌栓(29.1%)和弥漫性肝癌(33.7%).结论青年肝癌恶性程度高,对HHBV感染ALT反复异常的青年人要定期进行B超和AFP检查,以便早期发现、早期治疗原发性肝癌.     

Comprehensive genome sequencing of the liver cancer genome

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recently, comprehensive whole genome and exome sequencing analyses for HCC revealed new cancer-associated genes and a variety of genomic alterations. In particular, frequent genetic alterations of the chromatin remodeling genes were observed, suggesting a new potential therapeutic target for HCC. Sequencing analysis has further identified the molecular complexities of multicentric lesions and intratumoral heterogeneity. Detailed analyses of the somatic substitution pattern of the cancer genome and the HBV virus genome integration sites by using whole-genome sequencing will elucidate the molecular basis and diverse etiological factors involved in liver cancer development.     

Identification of hallmarks of lung adenocarcinoma prognosis using whole genome sequencing

In conjunction with clinical characteristics, prognostic biomarkers are essential for choosing optimal therapies to lower the mortality of lung adenocarcinoma. Whole genome sequencing (WGS) of 7 cancerous-noncancerous tissue pairs was performed to explore the comparative copy number variations (CNVs) associated with lung adenocarcinoma. The frequencies of top ranked CNVs were verified in an independent set of 114 patients and then the roles of target CNVs in disease prognosis were assessed in 313 patients. The WGS yielded 2604 CNVs. After frequency validation and biological function screening of top 10 CNVs, 9 mutant driver genes from 7 CNVs were further analyzed for an association with survival. Compared with the PBXIP1 amplified copy number, unamplified carriers had a 0.62-fold (95%CI = 0.43–0.91) decreased risk of death. Compared with an amplified TERT, those with an unamplified TERT had a 35% reduction (95% CI = 3%–56%) in risk of lung adenocarcinoma progression. Cases with both unamplified PBXIP1 and TERT had a median 34.32-month extension of overall survival and 34.55-month delay in disease progression when compared with both amplified CNVs. This study demonstrates that CNVs of TERT and PBXIP1 have the potential to translate into the clinic and be used to improve outcomes for patients with this fatal disease.     

同时发生的肝肉瘤样癌与肝细胞癌一例并文献复习

目的:探讨肝肉瘤样癌患者的临床表现、诊断、治疗方法及预后.方法:结合我院收治的1例同时发生的肝肉瘤样癌与肝细胞癌患者,并复习国内外文献,分析该病的临床特点,实验室检查、影像学及病理学表现,治疗及预后.结果:肝肉瘤样癌临床上较少见,病理学上肿瘤包含上皮样成分及梭形细胞肉瘤样成分,肿瘤生长迅速,恶性程度高,预后差.结论:肝肉瘤样癌与肝细胞癌同时发生的病例临床罕见,病因不明,预后较差.     

Fibrolamellar hepatocellular carcinoma in Mexican patients

The aim of this report is to describe the frequency, clinical, and morphologic characteristics of fibrolamellar hepatocellular carcinoma in Mexican patients. Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma. Although this tumor appears to be predominant among the Caucasian population of the U.S, FLHCC has been described in many other countries. The frequency and characteristics of FLHCC in Latin American population is almost unknown. The clinico-pathologic characteristics of seven (5.8%) Mexican patients with FLHCC, obtained among 121 hepato-cellular carcinomas are described. The frequency of these tumors was compared with the frequency reported in other geographic areas in the international literature between 1980 and 1999. There were four women and three men. Two patients had taken oral contraceptives for six months and a year prior to diagnosis; another patient had positive serology for the hepatitis B virus. Common symptoms included a palpable mass, abdominal pain and weight loss; two patients presented jaundice. In two patients the tumor had been removed eight and three years previously, and they were readmitted when FLHCC recurred. In three patients the diagnosis was suspected in radiological studies (computed tomography and/or magnetic resonance). Laboratory tests were non-specific. In four patients, resection of the tumor was performed, and in the remaining three the neoplasm was diagnosed by percutaneous hepatic biopsy. Two patients had died of disease at the time of the study, and another was alive with recurrent disease. Conclusions: fibrolamellar hepatocarcinoma is an uncommon, but not an exceptional neoplasm in our population and represents 5.8% of all hepatocarcinomas reviewed.     

肝细胞癌起源的研究

肝细胞癌是临床常见的难治的恶性肿瘤之一,发病率逐年升高。大量证据表明肝脏干细胞在肝癌的发生发展中起重要作用。有两个关于肝癌干细胞关键问题值得回答：肝细胞癌是否来源于肝干细胞？肝细胞癌是否有肿瘤干细胞的特点？然而到目前为止,肝癌的干细胞仍未被分离,且可靠的表面标志仍未被确认。     

Multidisciplinary treatment of patients with hepatocellular carcinoma

Hepatocellular carcinoma is one of the most common malignancies in the world. When it is diagnosed, patients can choose from among several potentially curative treatments, such as surgical resection, transplantation, ablation therapy and transcatheter arterial chemoembolization. This review will give an overview of the present management of hepatocellular carcinoma. Liver transplantation is considered the best curative option, achieving a high rate of complete response, especially in patients with small hepatocellular carcinoma and good residual liver function. However, a shortage of donor livers restricts the availability of transplantation. In addition, only a minority of patients with hepatocellular carcinoma can be treated surgically, owing to impaired hepatic reserve, multiple intrahepatic lesions, extrahepatic lesions and the inability to obtain an optimal tumor-free margin. Therefore, for most patients, other types of interventions (transcatheter arterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation) have been developed. Among them, two local ablative modalities, percutaneous ethanol injection and percutaneous radiofrequency ablation, have been accepted as the only potentially curative nonsurgical treatments for hepatocellular carcinoma. Radiofrequency ablation may become a standard nonsurgical treatment option for patients with early hepatocellular carcinoma.