|Ahead of print publication
Gastric cancer in Jammu and Kashmir, India: A review of genetic perspectives
Ruchi Shah1, Puja G Khaitan2, Tej K Pandita3, Adnan Rafiq4, Deepak Abrol5, Jyotsna Suri5, Sandeep Kaul6, Rakesh Kumar1, Swarkar Sharma1
1 Department of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
2 Division of Thoracic Surgery, Medstar Washington Hospital Center, Georgetown University School of Medicine, Washington, DC, USA
3 Department of Radiation Oncology, The Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA
4 Department of Medicine, Division of Gastroenterology, Acharya Shri Chander College of Medical Sciences, Jammu, Jammu and Kashmir, India
5 Department of Pathology, Government Medical College and Hospital, Jammu, Jammu and Kashmir, India
6 Department of Surgical Oncology, Shri Mata Vaishno Devi Narayana Superspeciality Hospital, Katra, Jammu and Kashmir, India
|Date of Submission||05-Jan-2019|
|Date of Acceptance||17-Jul-2019|
|Date of Web Publication||27-Jan-2020|
Mata Vaishno Devi University, Katra - 182 320, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Gastric Carcinoma (GC) is one of the most common malignancies, which accounts for 6.8% of total cancer population worldwide. In India, the northeastern region has the highest gastric cancer incidence, and the Kashmir Valley has a very high incidence of gastric cancer as compared to other parts of Northern India. It exceeds 40% of total cancers with an incidence rate of 3–6-fold higher than other metro cities of India. Gastric cancer is a heterogeneous disease where most of the cases are sporadic, and <15% are due to obvious familial clustering. The heterogeneous nature of the disease can be associated with differences in genetic makeup of an individual. A better understanding of genetic predisposition toward GC will be helpful in promoting personalized medicine. The aim of this review is to analyze the development and progression of GC and to explore the genetic perspectives of the disease with special emphasis on Jammu and Kashmir, India.
Keywords: Cancer, candidate genes, dietary habits, gastric carcinoma, Jammu and Kashmir, single-nucleotide polymorphism
|How to cite this URL:|
Shah R, Khaitan PG, Pandita TK, Rafiq A, Abrol D, Suri J, Kaul S, Kumar R, Sharma S. Gastric cancer in Jammu and Kashmir, India: A review of genetic perspectives. J Can Res Ther [Epub ahead of print] [cited 2020 Apr 2]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=276928
| > Introduction|| |
Gastric carcinoma (GC) ranks fourth among the most common malignancies in the world. In Asian countries like China, Japan, and Korea, the incidence rate of GC is very high. In India, the incidence of GC is low as compared to the developed countries, but in the southern and northeastern states of the country, the incidence is comparable to high-incidence areas of the world. While GC ranks fifth among males and seventh among females in India, its incidence is low as compared to developed countries. Gastric cancer is the most commonly encountered cancer (18.8%), followed by colorectal cancer (16.6%), lung cancer (9%), head-and-neck cancer (7.9%), and breast cancer (6.9%) in Kashmir. However, in Kashmir region, gastric cancer is highly prevalent [Figure 1] and along with esophageal cancer accounts for >60% of all cancers. The World Health Organization classifies gastric cancer into four subtypes: tubular, papillary, mucinous, and poorly cohesive or signet-ring type. Both environmental and genetic factors have been associated with the risk of GC.
| > Risk Factors Associated With Gastric Carcinoma in Kashmir Region|| |
There are various factors that contribute to the high incidence of GC [Figure 2] and can be characterized into three main components:
|Figure 2: Potential risk factors associated with gastric cancer in the population from Jammu and Kashmir|
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Helicobacter pylori are a Gram-negative bacterium that colonizes gastric epithelium and leads to chronic inflammation and markedly increases the risk of developing gastric ulcers and GC.
One of the major routes of extraneous factors affecting the gastric tract is through diet. The Kashmir valley is a geographically isolated land covered by the Himalayas on the north-to-eastern border and remains covered with snow for 4–5 months in winter, leading to limited human connectivity. The people, therefore, look for alternative foods which are readily available including salted tea, spicy pickles, sun-dried fish, and dried vegetables and vegetables of Brassica family (Haakh and Brassica oleracea). In addition, N-nitroso compounds are found in most of the dietary supplements of native Kashmiris, which are considered as plausible factors in the pathogenesis of GC. Tobacco consumption in the form of cigarette smoking, hookah, and sniffing by nose or rubbing on gums is also very high in the state.
Potential genetic factors
Acquired genetic factors
Several acquired genetic abnormalities are known to be associated with GC.
Chromosomal instability occurs either in early or late events in the disease progression., These typically occur due to change in DNA content with loss or gain of function of important genes such as oncogenes, tumor suppressor genes, or genes involved in DNA repair or cell cycle checkpoints. Other causes of chromosomal instability are translocation, amplification, deletion, or allelic loss (loss of heterozygosity [LOH]).,
Microsatellite instability (MSI) involves frequent mutations in mismatch repair (MMR) genes and tumor suppressor genes. MSI is found in about 5%–50% of sporadic GC., MSI is an important tool in identifying patients with precancerous lesions and genetic instability because of its presence in both gastric adenoma and intestinal metaplasia.
Epigenetic alterations include DNA CPG island hypomethylation, hypermethylation, histone modification (acetylation, phosphorylation, acetylation, ubiquitination, and sumoylation), and chromatin remodeling or changes in microRNA (miRNA) binding or expression. These epigenetic alterations have been associated with malignancies such as GC and its pathogenesis., Hypermethylation of various genes such as Tp53, CDKN2A, CDH-1 (cadherin 1), and adenomatous polyposis coli has also been associated with GC tumorigenesis via several known/unknown mechanisms.,,,,,, In addition, methylation of tumor suppressor genes such as dickkopf-related protein 1 has been demonstrated to enhance the ability of gastric cells to overcome cell death and aging, thus predisposing an individual to GC. Various hypomethylated genes are associated with tumorigenesis, progression, and metastasis of GC. For example, hypomethylation of the promoter for ASCL2 gene (achaete–scute family bHLH transcription factor 2) is hypomethylated in GC, and overexpression of this hypomethylated gene results in poor survival of GC patients. Modification of histone proteins such as acetylation, methylation, phosphorylation, and ubiquitination can alter expression of genes, thus affecting tumor progression. For example, histone deacetylase sirtuin 1 is associated with tumor suppression in GC by inhibiting NF-kB signaling.
MicroRNA profile affecting gene expression
miRNAs are short, stable, noncoding RNAs that inhibit protein translation by binding to mRNAs. miRNAs that inhibit the expression of tumor suppressor genes are known as “oncomiRs.” In GC, miR-196a and mir-197b are known to play an important role. Because miR-196 is overexpressed consistently in GC, can act as a novel biomarker in diagnosing GC.
Germline genetic factors
These are inherited directly from a parent to children. Variations in both coding and noncoding regions have been associated with GC. Some of the potential genes associated with GC are given below.
Mutations of potential genes involved in GC
RAS family consists of three genes: K-RAS, H-RAS, and N-RAS. These three genes have similar structure. k-ras encodes for P-21 RAS protein. Activated RAS excites mitogen-activated protein kinase (MAPK) pathway by recruiting RAF protein. This MAPK/ERK/RAS/RAF pathway plays a critical role in cell proliferation and is frequently activated in GC cells.
FBXO31 is located on chromosome 16q24.3 and is known to play a significant role in number of biological pathways such as neuronal development, tumorigenesis, and tumor suppression. In GC, FBXO31 is downregulated and is directly correlated with size of tumor and depth of tumor infiltration, but not with age, gender, or local lymph node metastasis. Whereas, FBXW7 regulates cell-cycle exit and reentry via c-Myc degradation. It is a tumor suppressor gene, which is transcriptionally controlled by p53. Deregulation of this gene leads to carcinogenesis.
TP53 gene regulates cell cycle and is a tumor suppressor gene. p53 mutations are linked to 50% of primary human tumors including that of gastrointestinal tract. Genetic mutations are widely distributed from exons 4–11, with variation hotspots at codons 175, 213, 245, 248, 273, and 282. In addition, G:C>A: T transitions at CPG sites are the most common types of disease-causing variations. In about 50% of all cancer cases including GC, it has been observed that missense allele of TP53 is coupled with deletion of the second allele. Overall, p53 LOH has been observed in 26%–83% of GC.
Single-nucleotide polymorphism in other candidate genes
Single-nucleotide polymorphisms (SNPs) are genetic variations that occur naturally within different populations, but with variable frequencies. The functional variations in a gene may result in increased susceptibility to a range of diseases, including cancers. Genome-wide association study (GWAS) or next-generation sequencing (NGS) can identify a large number of variants in different genes associated with disease like cancer. These new technologies have also offered an insight into the pathogenesis of GC. For example, MUC1 is an oncoprotein and has been implicated in a number of cancers. A study carried out in the Japanese and Korean population identified SNP rs2070803 in MUC1 gene in association with diffused gastric cancer (odds ratio = 1.63) in 606 cases and 1465 controls. The MUC1 protein is expressed in gastric epithelial cells, and infection with H. pylori blocks this protein from binding directly to epithelial cells, ultimately interrupting and attenuating the host inflammation response, thus predisposing them to malignancy.
High-throughput techniques (microarray, next-generation sequencing, and genome-wide association study) to analyze gastric carcinoma
Previous studies have investigated only selected genes to give an overall picture of gastric carcinoma in terms of molecular composition. Recent high-throughput techniques such as microarray, next-generation sequencing, whole-exome sequencing, and GWAS have investigated genetic alterations in cancer genome and identified novel genetic changes. Microarray and next-generation sequencing are high-throughput mutation screening techniques. In order to make full use of NGS data, a user-friendly public access, The Cancer Genome Atlas, has also been developed. NGS has helped understand gastric cancer genome alterations from initiation of cancer to its progression. miRNA analysis is also helpful to investigate the role of miRNAs in cancer development and developed progression. So far, five miRNAs (mir548d-3p, mir135b, mir20b, mir93, and mir19a) are found to be associated with gastric cancers and can be used as diagnostic and prognostic markers as well as chemotherapeutic tool. The high-throughput study, including microarray, NGS, and GWAS, has helped in molecular characterization of wide varieties of malignancies including gastric cancer. High-throughput screening techniques have not only helped in better understanding of molecular landscape of gastric cancer but also to classify gastric cancer in terms of molecular composition. Novel molecular classification of GC on the basis of NGS is shown in [Figure 3].
|Figure 3: Novel molecular classification of GC on the basis of next-generation sequencing|
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| > Genetic Components Associated With Gc in Kashmir|| |
Epigenetic changes that have been linked to GC in Kashmir
Hypermethylation-mediated silencing of the human mut-L homolog 1 (hMLH1) MMR gene promoter results in diminished hMLH1 expression that has been associated with GC carcinogenesis. In a study involving 70 GC patients from Kashmir, a high prevalence of hMLH1 promoter hypermethylation compared to general population was reported. A statistically significant association between methylated hMLH1 gene promoter and smoking and consumption of sun-dried vegetables and hot salted tea has also been reported. The human MMR genes repair errors that are caused during replication or due to any physiochemical stress, but abnormality in these genes including hypermethylation has been associated with GC.p16 is a tumor suppressor gene located on chromosome 9p21, which inhibits the function of cyclin D1/CDK4 and CDK6 complex and causes p53-independent G1 arrest through phosphorylation of pRb., In a study, it was observed that hypermethylation of promoter region or improper functioning of p16 can lead to GC development and progression.
E-cadherin is a transmembrane glycoprotein expressed on epithelial cells, helps in cell–cell adhesion, and plays a role in neoplastic transformation and metastasis. Any dysfunction or abnormality of E-cadherin can lead to tumorigenesis. Promoter methylation of this gene in gastric mucosa is associated with H. pylori infection and gastric adenocarcinoma. In an independent study, hypermethylation of the E-cadherin promoter was reported in 51% of primary GCs. In a study involving Kashmiri population, it was found that 65% of primary gastric cases showed hypermethylation. In another study, it was shown that hMLH1 was the most frequently affected gene (80%), followed by E-cadherin (58.4%) and p16 ( 40%). Methylation percentage of these genes in nonneoplastic gastric tissues was lower than that observed in adjacent tumor cells such as hMLH1 ( 68%), E-cadherin (37%), and p16 ( 24%). The methylation of all three genes was significantly associated with GC. These combined data indicated the role of methylation in the development of GC and a potential genetic link to carcinogenesis.
Single-nucleotide polymorphisms reported in gastric cancer in Kashmir
SNPs in various candidate genes have been reported in gastric carcinogenesis in Kashmir. Different studies showed that SNPs at different loci near the genes such as OGG1, XRCC3, IL-1RN, XRCC2, and MMP-7 are associated with high risk of GC. Although these studies indicate the association of SNPs with GC, most of the studies lack reasonable sample size warranting replication to evaluate the association. In addition, keeping in mind this prevalence of disease in the Kashmiri population, it is critical to evaluate other candidate genes too in the population.,,,,
Toll-like receptors (TLRs) play a vital role in controlling infection by H. pylori and clinical outcome of gastric cancer is also explained by it. Asp299Gly and Thr399llc polymorphism has been associated with a number of malignancies, including gastric cancer. However, in Kashmiri population, no significant association between TLR4 and IL-8 polymorphism with gastric cancer was observed.
Carcinogens such as nitrosamines are catalyzed by NQO1 and NQO2 enzymes (NADPH: quinone oxidoreductase 1 and dihydronicotinamide riboside), leading to reductive activation of these carcinogens. The genetic variants in NQO1 (609 C>T) and NQO2 (3423 G>A) showed a significant association with gastric carcinoma risk whereas there was no association between genetic variant of NQO2 and gastric cancer. Genetic variants in Tp53 are found to be associated with a number of malignancies. In a study involving Kashmiri population, it was observed that genetic variant rs17878362 is strongly associated with the risk of esophageal carcinoma and gastric cancer. In a case–control study (108 cases and 195 controls), the association of genetic variants in GSTM1, GSTT1, GSTP1, GSTM3, CYP1A1, and CYP2E1 genes with increased risk of gastric cancer in the Kashmiri population was evaluated. It was observed that only GSTM1 and CYP2E1C genotypes were significantly associated with increased risk of gastric cancer, and GSTM3AB showed reduced risk to gastric cancer. Functional polymorphism of N-acetyltransferase-2 (NAT2) was also explored for the association of genetic variants in NAT2 gene and increased risk of gastric carcinoma. Genetic variants such as rs1799929, rs1799930, and rs1799931 in NAT2 gene were found not to be associated with the risk of gastric cancer or esophageal carcinoma, but haplotypes such as C481, A590, G857 and T481, A590, and G857 were significantly associated with the risk of esophageal carcinoma and gastric cancer.
Caspase 8 gene performs a vital function in regulating programmed cell death and apoptosis. Genetic variant rs3834129 in Caspase 8 was studied, and it was observed that genetic variant modulates gastric cancer risk in the Kashmiri population. Some of the associated variants are tabulated in [Table 1].
Changes in protein expression
MGMT is a DNA repair protein. Mutation in DNA repair protein can halt its function, which can lead to cancer progression at any stage. Molecular dynamics helps understand the effect of a novel mutation on MGMT protein, which effects not only the overall structure of MGMT but also the secondary elements located at different positions of the protein. Mutation in exon 5 of the MGMT gene effects DNA–protein interaction that impairs DNA repair mechanism that can cause genomic instability.
In a study, protein expression of MKK6 (MAPK) was evaluated in the population of the Kashmir valley. It has been observed that there is upregulation of protein expression in various cancers including gastric cancer, colon cancer, and esophageal cancer as compared to healthy controls. Upregulation of protein expression indicates its role in gastric cancer as well as esophageal cancer under study; it can be used as a novel biomarker for diagnosis in all the cancers under study.
Protein expression of α-1-syntrophin protein was investigated in esophageal squamous cell carcinoma (ESCC); esophageal adenocarcinoma (EAC); gastric, colon, lung, rectal, and breast cancers in the Kashmiri population. In ESCC and EAC, there was a significant decrease in the expression level of α-1-syntrophin protein, whereas in gastric, colon, lung, and breast cancers, there was no change in protein expression.
Mutation in coding genes
Two coding genes such as p16 and TP53 have been evaluated so far in the Kashmiri population in terms of genetic mutations. Both p16 and TP53 are tumor suppressor genes. In a case–control study involving 84 gastric cancer cases, it was observed that, in all 84 cases, there was not a single somatic mutation or deletion in all the three exons of p16 gene. Above mentioned study was in affirmation with the study by Igaki et al. Above mentioned study indicates that mutation is not an important mechanism for p16 inactivation in primary gastric cancer tumors, but other factors such as epigenetic alterations or improper protein expression can play a vital role in it. Mutation in TP53 has been observed in a number of malignancies.
mRNA expression was investigated in a study involving 200 gastric cancer cases and 200 controls. The expression profile of ppGalNAc-T6, GlcNAcT-V, ST3Gal I, ST3 Gal IV, and ST6GalNAc-I in cases was compared to healthy controls. It was observed that expression of ppGalNAc-T6 and ST6GalNAc-I was higher in cases as compared to controls, whereas there was no difference in mRNA expression of GlcNAcT-V, ST3Gal I, and ST3 Gal IV in cases and controls.
| > Discussion and Future Perspective|| |
It has been observed that there are about 2–2.5 million cancer cases registered in India, and it has been predicted that about 20 million new cases will be registered in future. The Kashmir valley being geographically isolated, its culture, and dietary habits are also peculiar. A total of 24,768 cancer cases have been reported to RCC (SKIMS) from 2000 to 2012. The average age of gastric cancer is 35–55 years. Cancer is predominant among males than the females (3:2 M/F) in the Kashmir valley due to high tobacco consumption. Dietary habit is one of the chief risk factors associated with gastric carcinoma in the Kashmir valley. In the Kashmir valley, most of the dietary products are rich in nitrosamines which are carcinogenic and they cause inflammation of the epithelium which later leads to carcinogenesis. Kashmir is socially and politically disturbed from the past 30 years and that is the reason there has been very limited research work done on gastric cancer. After literature survey, it was observed that genetic analysis what so ever done is limited to few loci only. Early diagnosis and treatment can increase survival time. Advanced techniques such as microarray, GWAS, and NGS are very powerful tools that facilitate comprehensive research and help in understanding functional genomics and evaluation of molecular basis of gastric cancer. These techniques help analyze candidate gene and also help in identifying potential chemotherapeutic tools. The aim of this review is to propose that the advanced molecular techniques should be used in screening of gastric carcinoma patients from Kashmir to evaluate the risk factors associated with the diseases which include mutation in coding genes, SNPs, miRNAs, and oncogenic pathways. The investigated information can be used to create diagnostic and prognostic markers as well as in the development of personalized medicine. Cancer control programs can be successful across the globe only if the cancer menace is uprooted at the regional level also.
In background of high incidence of GC in the Kashmiri population, various preliminary studies were carried out but an extensive study on the basis of large sample size is critically warranted. Further, the smaller sample size in the previous studies highlights the need of replication in large sample cohorts to clearly elucidate the role of environment and genetic factors in the etiology of GC in the Kashmiri population, a quest undertaken by us. It is anticipated that screening of all the reported variations from literature as well as coupling such findings with the role of epigenetic factors will help better understanding the disease occurrence in the population. At the same time, we are putting efforts to make local population aware of the disease and share opinion from research literature to help them modify their dietary habits, to curb the menace of disease in the population.
RS and SS acknowledge the Women Scientists Scheme-A, Department of Science and Technology (Grant No. SR/WOS-A/LS1067/2015), India, for financial support.
Financial support and sponsorship
The study was financially supported by the Women Scientists Scheme-A, Department of Science and Technology (Grant No. SR/WOS-A/LS1067/2015), India.
Conflicts of interest
There are no conflicts of interest.
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