The impact of recent next generation sequencing and the need for a new classification in gastric cancer

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Abstract​

The phenotypical and molecular heterogeneity of gastric cancer has hampered the introduction in clinical practice of a unifying classification of the disease. However, as next generation sequencing (NGS) technologies enhanced the comprehension of the molecular landscape of gastric cancer, novel molecular classification systems have been proposed, allowing the dissection of molecular tumor heterogeneity and paving the way for the development of new targeted therapies. Moreover, the use of NGS analyses in the molecular profilingof formalin-fixed paraffin-embedded (FFPE) specimens will improve patient selection for the enrolment in novel clinical trials. In conclusion, the application of NGS in precision oncologywill revolutionize the diagnosis and clinical management in gastric cancer patients.

 

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Introduction​

Gastric cancer (GC) represents the third leading cause of cancer-related death and the fifth most common malignancy worldwide for both sexes, with over 1 million new diagnoses and nearly 800,000 deaths in 2018 [1].
Low/middle income countries account for more than 70% of GCs cases: Eastern Asia, Eastern Europe, and South America present the highest incidence rates, while North America and Western Europe the lowest [2]. GC patients from East Asia seem to have a better prognosis, despite living in a high incidence geographical area [3]. On the other hand, in Western countries, there has been a decrease in the incidence of GC during the last 50 years, together with a change in the location of the primary tumor. In fact, in countries where distal-arising GCs were more predominant in the past, a progressive reduction of incidence is now observed. This trend is probably due to the success of eradication therapies for Helicobacter pylori infections and the improvement of health and hygiene standards [4]. Conversely, the incidence of tumors of the gastric cardia and gastroesophageal junction (GEJ) has grown [5]. The higher incidence of proximal GC has been linked to the increased incidence of gastroesophageal reflux disease and obesity [6].
GC is a heterogeneous disease from both morphological and molecular perspectives. Dissecting heterogeneity of GC is crucial to understand the true nature of this disease in order to develop new and more efficient diagnostic tools, predictive biomarkers, and targeted therapies.
In the last decade, Next Generation Sequencing (NGS) technologies have played a pivotal role in the identification of genetic aberrations involved in cancer pathogenesis. NGS is more accurate, comprehensive, cost effective, and faster than previous sequencing methods, such as Sanger sequencing [7,8]. Moreover, NGS-based analysis is well suited for the characterization of FFPE-derived DNA, allowing a comprehensive profiling of FFPE blocks retrieved from pathology archives [9]. In fact, several amplicon-based NGS assays have been clinically approved and are currently in use for the detection of the most frequent actionable genomic alterations in tumor samples.
The main NGS-based approaches (i.e., Whole Genome Sequencing [WGS], Whole Exome Sequencing [WES], RNA Sequencing [RNA Seq], and targeted sequencing) have been systematically applied to characterize molecular alterations of GC and other tumor types [10]. This great amount of genomic, transcriptomic, and epigenomic data has significantly improved the comprehension of the molecular landscape of GC, dissecting its molecular heterogeneity and leading the way for a comprehensive molecular classification of this complex disease [11,12], which is essential for the development of new molecular targeted drugs.
There is a considerable difference in the detection of gene mutations among the different studies [[13], [14], [15], [16]]. TP53 appears to be the most commonly mutated gene in GC [15]. The most frequent genetic alterations are summarized in Table 1: mutations, copy number variations [13], defective DNA methylation, hypermethylation, and alterations in the methylation status [[17], [18], [19], [20], [21], [22]].

 

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Section snippets​

Histological classifications of GC​

The most common histotype of GC is gastric adenocarcinoma (GAC), which accounts for more than 90% of GCs [23]. Other rarer gastric epithelial malignancies are squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, gastroblastoma, and neuroendocrine neoplasms [23]. Historically, many classifications of GACs have been proposed that try to correlate morphology with clinical and pathological features.
One of the oldest and most used is Laurén’s classification, which divides……

Molecular GC classification according to NGS analysis​

Genomic data have been used to develop molecular classification systems for many types of cancer including colorectal and pancreatic cancer [37,38]. Although renowned classification criteria for GC have been histologically based, recent use of genomic data has led to the development of novel molecular classification schemes.
In 2014, The Cancer Genome Atlas (TCGA) network characterized 295 localized and previously untreated GACs using six molecular platforms: somatic copy number analysis, Whole….

 

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Current standard therapy in GC and the role of NGS​

Therapeutic opportunities in GC are substantially represented by surgery and chemotherapy, depending on the stage of the disease. Surgery together with neoadjuvant/adjuvant chemotherapy is the current standard in locally advanced disease, and in metastatic GC, chemotherapy becomes crucial in the treatment of patients with good performance status [44]. Despite NGS currently playing no role in standard clinical care, its increasing use allows a better understanding of problems in GCs treatment….

 

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PARP inhibitors​

Mutations in genes involved in homologous DNA repair, including BRCA1/BRCA2 and ATM, are relatively common events in GC [22,43].
Neoplasms with homologous recombination repair deficiencies seem to be sensitive to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, which inhibit this important component of the base excision repair pathway. For example, patients with germline BRCA1/2-mutated pancreas carcinoma presented longer progression-free survival if treated with the PARP inhibitor….

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Liquid biopsy in GC management​

As already discussed, GCs are characterized by high levels of intra- and inter-tumoral heterogeneity. Heterogeneity of genomic alterations is responsible for some differences of molecular characterization across various studies [22,43,105] and could negatively affect the efficacy of target therapies. Moreover, heterogeneity of molecular alterations is not a static concept as new and different molecular alterations can arise with time in different sites and after distinct therapies [44]. In…..

 

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Genomic data as new therapeutic and diagnostic options for GC​

Recent NGS studies have undoubtedly provided an abundance of data to allow a better characterization of the genomic landscape of GC. However, translating this genomic data into more effective treatments for GC remains the major challenge, and there are important points that must be considered.
First, we are still far from a clinical validation of the predictive value of the proposed molecular classification schemes. Several novel biomarkers and pathway alterations have been associated with GC,……

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Conclusions​

Worldwide, GC still represents a deadly neoplasm. Different histological and molecular classifications of this disease have been proposed, but a flawless, unifying classification is still lacking. NGS technologies represent powerful tools to study the complexity of GC, with important implications both for the molecular characterization of these neoplasms and for the therapeutic management of GC patients. In fact, the increasingly frequent integration of NGS in the molecular evaluation of the……