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  1. Mairi H McLean, Education Editor

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Basic science

Mutation signatures in oesophageal adenocarcinoma to direct therapy

▸ Secrier M, Li X, de Silva N, et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet 2016;48:1131–41.

Recent next-generation sequencing studies have revealed few common mutated driver genes in patients with oesophageal adenocarcinoma (OAC), particularly those with a known history of Barrett's oesophagus. Genomic instability is a feature of these cancers, and altogether these data paint a picture of tremendous genetic heterogeneity, making it difficult to develop new therapeutic strategies. Here, a comprehensive analysis of copy number changes versus mutations was performed by whole-genome sequencing in 129 patients with OAC. The results were compatible with previous studies that showed a great deal of intrapatient genetic heterogeneity and that chromosomal changes were more prevalent than mutations. No obvious identifiers of cancer subtypes were initially found. However, an interesting observation was made when correlating receptor tyrosine kinase (RTK) copy number changes. Nearly all OAC cases showed amplifications suggesting RTK inhibitors might be a potential therapeutic avenue in this cancer. To search for OAC mutation signatures ‘hidden’ in the high mutation burden, the authors used a previously published non-negative matrix factorisation method—where a mutational signature is built-up from the sequence context of each mutation: there are a possible six classes of base pair substitutions and recording the 5′ and 3′ base of each substitution generates 96 possible mutations that can be identified, and these have been shown to reflect natural history of the cancer such as ageing, ultraviolet exposure and smoking. OAC specimens revealed six signatures that were significant in three: (1) enrichment for BReast CAncer susceptibility gene (BRCA) signature, (2) high mutation signature and (3) an ageing signature. Importantly, these have therapeutic relevance. This report describes for the first time identifiable subtypes of OAC. The authors were able to procure cell lines that reflect each of the signatures and revealed that each was potentially targetable using therapies that would appear to be relevant to the signature. These data may therefore reveal potential personalised therapies for OAC.

Genes and bugs in IBD

▸ Li D, Achkar J-P, Haritunians T, et al. A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition. Gastroenterology 2016;151:724–32.

Genetic factors and the gut microbiota are involved in the aetiology and pathogenesis of Crohn's disease (CD). Genome-wide association studies have identified >200 IBD-associated loci. The association between these loci and the gut microbiota is now under intense study. Changes in the gut microbiota in IBD include compositional alterations and reduction in bacterial diversity. For example, there is loss of Ruminococcaceae including Faecalibacterium prausnitzii and also increased numbers of certain pathogenic bacteria including Enterobacteriaceae. These bacterial changes, along with the knowledge that a number of IBD susceptibility loci reside in genes associated with recognition and processing of bacteria, highlight the role of the microbiota in CD pathogenesis. To further study this link, a collaborative international group analysed >90 000 functional single-nucleotide polymorphisms using Illumina ExomeChip. This identified a common missense variant rs13107325 that encodes SLC39A8 (Ala)391Thr and was significantly associated with CD. SLC39A8 is located approximately 200 kb centrometric from NFKB1 and 250 kb downstream of BANK1, another CD-associated locus. The association with SLC39A8 Ala391Thr was replicated in two independent cohorts, and significant evidence was provided to demonstrate this association with ileal CD and complicated disease behaviour. The authors tested the microbial composition of lavage samples from caecum and sigmoid colon based on SLC39A8 genotype and showed that subjects with the risk genotype (irrespective of disease status) had an altered colonic microbiota. The most consistent changes seen were depletion of F. prausnitzii and also Ruminococcus gnavus. These findings demonstrate the existence of altered microbial composition prior to disease onset resulting from a genetic influence.

Understanding the mechanisms of chemoresistance in HCC

▸ Azzariti A, Mancarella S, Porcelli L, et al. Hepatic stellate cells induce HCC cell resistance to sorafenib through the Laminin-332/α3 integrin axis recovery of FAK ubiquitination. Hepatology Published Onlilne First: 17 Sep 2016. doi: 10.1002/hep.28835

Chemoresistance is thought to arise intrinsically within tumour cells, and substantial efforts are conducted to achieve highly purified ex vivo cancer cells allowing for their in-depth characterisation. However, complementary studies are increasingly focusing on the role of the tumour extracellular microenvironment in determining cancer development and chemoresistance. The development of hepatocellular carcinoma (HCC) is preceded in most cases by an extensive modification of the microenvironment caused by the progressive deposition of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) eventually leading to liver cirrhosis. In this paper, the authors hypothesised a specific role of the ECM in determining HCC resistance to the chemotherapeutic drug, sorafenib. They focused on a possible role of laminin (Ln)-332, an extracellular protein produced in the liver by HSC and known to be overexpressed along the advancing edge of different tumours. Conditioned medium from HSC, or Ln-332, reduced the effect of sorafenib on HCC cell line viability and apoptosis. By using specific antibodies or siRNA directed against distinct Ln-332 receptors, the authors demonstrated that this effect was specifically mediated by the α3 integrin-subunit. Mechanistically, Ln-332 appeared to counteract the accelerated ubiquitination of the protein tyrosine kinase FAK by sorafenib, possibly by regulating membrane localisation. This study uncovers a new mechanism of resistance to sorafenib and reminds us that the drivers of chemoresistance are not only within the cancer cells, but also in their interaction with their surrounding environment. Activated HSC could become extratumoural targets for the therapy of HCC.

Clinical practice

Identifying resectable pancreatobiliary cancer

▸ Kurita A, Kodama Y, Nakamoto Y, et al. Impact of EUS-FNA for preoperative para-aortic lymph node staging in patients with pancreatobiliary cancer. Gastrointest Endosc 2016;84:467–75.

Preoperative assessment of potentially resectable pancreatobiliary (PB) cancer is challenging, and mistakes made at this stage can lead to inappropriate patient selection for surgery. Disease progression beyond regional lymph nodes to the para-aortic lymph nodes (PALNs) is associated with poor prognosis. However, there are difficulties in accurately diagnosing PALN metastases prior to surgery, and there is no accepted best method for doing this. Kurita and colleagues from Japan performed a prospective nonrandomised trial in 208 consecutive patients with PB cancer without apparent distant metastases, comparing the diagnostic capability of EUS-FNA and 18F-fluorodeoxyglucose positron emission tomography with CT (PET/CT). Each patient underwent standard staging with multidetector-row CT scan and then individuals with PALN enlargement—defined as short-axis size ≥5 mm or long-axis size ≥8 mm—were identified for study recruitment.

In total, 52 patients with 71 enlarged PALNs were identified and enrolled. PET/CT and EUS-FNA were performed sequentially as a single combined procedure to assess PALN metastases. Also, 30 lymph nodes (42.3%) in 21 patients (10.8% of total population) were ultimately confirmed as positive for metastasis. EUS-FNA correctly identified 20/21 patients (95.2%) with PALN metastases and PET/CT diagnosed 12/21 (57.1%). EUS-FNA had better sensitivity, specificity, positive predictive value and negative predictive value (96.7%, 100%, 100% and 97.5%, respectively) compared with PET-CT (53.3%, 97.6%, 94.1% and 74.1%, respectively). Where expertise is available, routine use of EUS-FNA in patients with PB cancer and enlarged PALNs should be considered. This will help ensure that only appropriate patients proceed directly to surgery. It is also important to factor in the development of novel neoadjuvant treatment regimens in PB cancer, which means that accurate disease staging will be ever more important, raising the stakes for patients and clinicians in this condition with a historically poor prognosis.

GM-CSF in CD: ignited interest from two large data sets?

▸ Levine AP, Pontikos N, Schiff ER, et al. Genetic complexity of Crohn's disease in two large Ashkenazi Jewish families. Gastroenterology 2016;151:698–709.

▸ Chuang L-S, Villaverde N, Hui KY, et al. A frameshift in CSF2RB predominant among Ashkenazi Jews increases risk for Crohn's disease and reduces monocyte signaling via GM-CSF. Gastroenterology 2016;151:710–23.

The genetic contribution to the pathogenesis of CD is greater than that for UC. Despite the fact that many therapies for CD are aimed at suppressing the adaptive immune response, the genetic and functional data support that a significant proportion of the susceptibility to CD comes from defective handling of commensal bacteria, representing the innate immune response. Two parallel papers in Gastroenterology have replicated the potential crucial significance of granulocyte-macrophage colony stimulating factor (GM-CSF) in CD. Levine and colleagues studied two large Ashkenazi Jewish families with multiple cases of CD to identify novel genetic determinants. They noted that a frameshift mutation in the GM-CSF receptor gene conferred increased disease susceptibility. Chuang and colleagues have independently replicated these findings in a large cohort of Ashkenazi Jews and controls. Moreover, they undertook functional experiments to elucidate the impact, at a cellular level, of this mutation. With cell line work and monocytes from CD sufferers with this mutation, they showed reduced cellular responses to stimulation by GM-CSF. Thus there is renewed interest in impaired GM-CSF signalling in the pathogenesis of CD, despite the previous negative meta-analysis of this as a therapy for CD. It may well be that patients carrying the mutation are best targeted with GM-CSF therapy. This is an attractive prospect in the era of personalised medicine. Also, the debate as to whether CD is actually an innate immunity disorder is alive and kicking!

Does liraglutide signal the end of the LEAN patch for NASH?

▸ Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non–alcoholic steatohepatitis (LEAN): a multicentre, double–blind, randomised, placebo–controlled phase 2 study. Lancet 2016;387:679–90.

The understanding of the pathogenesis of non-alcoholic steatohepatitis (NASH) has undergone major strides in the last decade. However, there are limited therapeutic interventions for this condition. The only drugs that have undergone randomised trials for this disease are vitamin E, pioglitazone and obeticholic acid, and none has gained universal acceptance. The LEAN study was a randomised trial conducted in four centres in the UK. This compared injection of a glucagon like peptide 1 synthetic analogue (liraglutide at a dose of 1.8 mg administered daily) versus placebo in well-characterised patients with histologically proven NASH. The primary outcome was an unequivocal resolution of NASH with no worsening in fibrosis from baseline to end of treatment (48 weeks) validated by two independent pathologists. A total of 26 patients were randomised to each arm with 23 and 22 patients having end-of-treatment biopsies, respectively. The primary outcome was achieved in 9 (39%) of patients who received liraglutide compared with 2 (9%) of patients in the placebo group (relative risk 4.3 (95% CI 1.0 to 17.7); p=0.019). The relative risk to resolve NASH was slightly lower in non-diabetic patients treated with liraglutide (relative risk 3.4 (95% CI 0.8 to 14.4); p=0.11). Of the histological parameters studied, there was a statistical reduction of steatosis but no change in lobular inflammation, hepatocyte ballooning, fibrosis or the non-alcoholic fatty liver disease (NAFLD) activity score. There was a significant loss of weight noted in treated subjects and better glycaemic control while on liraglutide, which seemed to reverse after stopping the drug. This short-term study underpins the importance of weight loss and glycaemic control in resolution of NASH. However, the transient effect of liraglutide suggests that this subcutaneous drug may need to be taken longer, limiting its attractiveness in clinical practice. Newer innovations towards oral preparations and data from a larger cohort of patients will help to deliver a viable future therapeutic option for the treatment of NASH.

Reviewers

Dr Stuart McDonald, Dr Georgina Hold, Dr Enrico de Toni, Dr Jonathan MacDonald, Dr Dan Gaya, Dr Ashis Mukhopadhya

Journals reviewed

Nature Genetics, Gastroenterology, Hepatology, Gastrointestinal Endoscopy, Lancet

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Footnotes

  • Provenance and peer review Not commissioned; internally peer reviewed.

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