**2. From basic research to clinical needs**

Research efforts have identified several risk factors, including environmental factors as well as epigenetic and genetic aberrations, which could be implicated in the initiation and progres‐ sion of gastric malignancies. Advances in high‐throughput technologies and bioinformatic systematic analyses have been complementing our knowledge of an intricate network of genetic and epigenetic changes associated with stomach carcinogenesis. Unfortunately, only a few of common mutations could be associated with the development of sporadic gastric adenocarcinomas, which is the most common type of GC in the non‐Asian world regions. In addition, breakthroughs in next‐generation sequencing and SNP profiling microarrays have revealed another dimension, contributing to the heterogeneity of cancers. Genetic back‐ ground, which affects the susceptibility for developing GC, could also be responsible for dif‐ ferences in responses to drugs and outcome measures evaluating survival, efficacy and safety of novel biological therapeutics in distinct populations.

Discovery‐oriented research performed in different world populations revealed that molecu‐ lar aberrations found in sporadic GCs do not correlate well with macroscopic and microscopic classifications that are currently used in clinical practice for diagnosis and for rough assess‐ ment of the postoperative therapeutic management protocols [11]. For example, pathohis‐ tological Lauren classification, which is the most widely used diagnostic feature in clinical setting in Western countries, recognizes two main subtypes, intestinal and diffuse types of GC. Intestinal type of gastric adenocarcinoma is associated with intestinal metaplasia and tubular structures, whereas diffuse‐type carcinomas mostly consist of discohesive cells and/or signet ring cells. Two additional subtypes fall into this classification, if the tumors do not fit into two major subtypes clearly. Approximately 14% of tumors, exhibiting characteristics of intes‐ tinal and diffuse morphology, are classified as mixed type, whereas roughly 10% of gastric tumors, which display uncommon features, are allocated into indeterminate category [11–16]. It should also be noted that all adenocarcinomas show heterogeneity at the histological level. For example, even if tumors were histologically classified as intestinal or diffuse type, they are in fact often a mixture of several coexisting tissue types, including more or less well‐ developed tubular structures, poorly cohesive cells and signet ring cells, though one of these cell types usually predominates [17]. In the past, researchers have been focused on determin‐ ing distinct gene aberrations that could have been associated with these subtypes in order to constitute reliable biomarker panels, which would correlate with histological subtypes and indicate the likely course of disease progression. However, accumulating molecular data on GC aberrations revealed immense intertumor and intratumor heterogeneity of GCs [9, 18–21].

it is also important to note that the total incidence of most common gastric malignancy, adeno‐ carcinoma, varies by geographic areas up to 20‐fold between the highest and the lowest risk populations. The high risk areas are in certain Asian regions, such as Japan, China and Korea, followed by Eastern Europe and some countries in South America [3]. Low‐risk populations are located in North America, India, the Philippines, most countries in Africa, some Western European countries and Australia [4]. Up to 10% of GCs arise as a consequence of inherited can‐ cer predisposition syndromes, such as Li‐Fraumeni syndrome, Lynch syndrome, Peutz‐Jeghers syndrome, hereditary breast and ovarian cancer, MUTYH‐associated adenomatous polyposis (MAP), familial adenomatous polyposis (FAP), juvenile polyposis syndrome and PTEN hamar‐ toma tumor syndrome (Cowden syndrome) [5, 6]. Genetic counselling and mutation analyses, regular endoscopic surveillance and screening of the at‐risk family members and risk‐reduc‐ tion surgery of stomach have greatly improved management of patients with hereditary muta‐ tions predisposing to the development of hereditary GC [5, 7]. However, approximately 90% of GCs are sporadic and typically occur in elderly population [6, 8]. Despite improvements in the diagnostic procedures, most cases of sporadic GCs are still detected at advanced stages due to the lack of specific symptoms associated with the early phases of tumor development. Consequently, high mortality rates attributable to advanced GC contribute significantly to the public health burden worldwide. The estimated overall 5‐year relative survival rates of patients with advanced GC in developed countries are still low, around 30% [9]. An additional reason for concern is the demographic transition to the older population accounting for the significant pro‐ portion of population in developed countries [10]. This demographic shift will have an impact on health services, as the number of people over the age of 65, who comprise the highest risk group for the development of sporadic GC, has been steadily increasing in these countries. The challenge most countries are facing at the present time is how to improve the healthy life expec‐ tancy with regard to early detection of chronic and degenerative diseases, including cancers.

Research efforts have identified several risk factors, including environmental factors as well as epigenetic and genetic aberrations, which could be implicated in the initiation and progres‐ sion of gastric malignancies. Advances in high‐throughput technologies and bioinformatic systematic analyses have been complementing our knowledge of an intricate network of genetic and epigenetic changes associated with stomach carcinogenesis. Unfortunately, only a few of common mutations could be associated with the development of sporadic gastric adenocarcinomas, which is the most common type of GC in the non‐Asian world regions. In addition, breakthroughs in next‐generation sequencing and SNP profiling microarrays have revealed another dimension, contributing to the heterogeneity of cancers. Genetic back‐ ground, which affects the susceptibility for developing GC, could also be responsible for dif‐ ferences in responses to drugs and outcome measures evaluating survival, efficacy and safety

Discovery‐oriented research performed in different world populations revealed that molecu‐ lar aberrations found in sporadic GCs do not correlate well with macroscopic and microscopic

**2. From basic research to clinical needs**

86 Gastric Cancer

of novel biological therapeutics in distinct populations.

In recent years, molecular classifications, based on the results from high‐throughput tech‐ nologies, revealed the existence of different molecular subtypes regardless of pathohistologi‐ cal subtypes [17, 22–24]. The advantage of these novel classifications is that distinct aberrant molecular changes that characterize different subtypes could be exploited to develop novel treatment approaches. For example, the EBV subtype, recognized in the TCGA study, is defined by frequent amplification of *JAK2*, *CD274* (*PD‐L1*) and *PDCD1LG2* (*PD‐L2*) together with DNA hypermethylation and *PIK3CA* mutations [22]. Thus, patients with aberrations in PD‐1 signaling pathways could benefit from addition of pembrolizumab or other antibodies targeting PD‐1 axis [25]. Frequent occurrence of characteristic CpG island methylator pheno‐ types (CIMP) in GCs, particularly in association with *H. pylori* or Epstein‐Barr virus infection, could lead to introduction of epigenetic modulators into standard treatment regimens used against early and advanced forms of adenocarcinomas [22]. Deciphering molecular heteroge‐ neity of malignant gastric tumors and subsequent translation of this information into precision medicine or eventually into personalized medicine is the subject of several ongoing collabora‐ tive projects, such as The Cancer Genome Atlas (TCGA) based at the National Cancer Institute, the Cancer Genome Project at the Wellcome Trust Sanger Institute, and the International Cancer Genome Consortium, based at Ontario Institute for Cancer Research [22, 26–28].

However, the novelties of molecular classifications brought additional obstacles in transla‐ tional research. It has become evident that there is a gap between real clinical needs and cur‐ rent genetic research. The resources being put into high‐throughput identification of genetic and epigenetic changes accelerated the understanding of the molecular mechanisms underly‐ ing human diseases; however, the progression of this knowledge to patient benefit is lagging behind. In particular, surgical resection of stomach is still the main curative approach in the treatment of gastric cancer [29]. Although different types of nonsurgical treatment modalities, including chemotherapy, radiation therapy, chemoradiation, as well as targeted therapies, have been evaluated in clinical studies and have been subsequently integrated in clinical set‐ ting, these regimens have not been internationally standardized and remain in the form of guidelines and recommendations [30]. In recent years, several roadmaps and initiatives have been established, with the aim to advance the knowledge transfer, promote collaborations between different scientific disciplines and medical environment, and determine the main obstacles, which hinder the progression and implementation of effective health care solu‐ tions [31–33]. The main recognized barriers have been associated with (i) the explosion of molecular research conducted by highly specialized scientists, (ii) the fragmented fields of biomedical research, (iii) the dynamics of basic research with regard to promotion, obtaining funding and grants, which resulted in separation of basic and clinically relevant research, (iv) differences in education and training, (v) lack of communication between clinicians and researchers and (vi) the separation of methodologies and infrastructure available in clinical environment and specialized molecular research laboratories [32, 33]. In addition, complex regulatory issues, associated with research ethical procedures and approvals and clearances of innovative biomedical devices or approaches, have been recognized as limiting factors in translational research [34]. One of the most pressing medical research problems in hetero‐ geneous diseases, such as GC, issuing from the accumulating research data, is the biological elucidation of molecular changes and how they affect processes and metabolic pathways in malignant cells. Although several molecular targets have been identified in complex diseases, only a few targeted therapies and other novel treatment approaches have been found to be effective in the management of malignant diseases. Another concern, which also has roots in underlying molecular changes driving the malignant phenotype, is the development of drug resistance, which results in therapeutic failure. Although multidisciplinary research efforts have identified main pathways as well as some specific genetic determinants implicated in this phenomenon, innate or acquired resistance of cancer cells remains a significant challenge of translational medicine [33, 34].
