Published online Dec 28, 2017. doi: 10.3748/wjg.v23.i48.8533
Peer-review started: September 15, 2017
First decision: October 10, 2017
Revised: October 25, 2017
Accepted: November 8, 2017
Article in press: November 8, 2017
Published online: December 28, 2017
Our research group, located in the North region of Brazil, has been working with population genetics for many years. More recently, we have designed a set of 12 markers that are able to be genotyped in a single multiplex PCR and capillary electrophoresis, which is faster than Sanger sequencing and cheaper than real-time PCR. All markers in this set are in genes related to different pathways (e.g. inflammatory and immune response, and cellular and genomic stability). We have previously investigated not only the association of this set with the development of different diseases (i.e. acute lymphoblastic leukemia and leprosy), but also the distribution of these markers in individuals from the five regions of Brazil (North, Northeast, Midwest, Southeast and South) and in individuals representative of the main parental populations of this country (Europeans, Africans and Native Americans). However, we believe it also is important to investigate the association of this set with the development of other types of cancer, such as gastric cancer (GC) and colorectal cancer (CRC).
GC and CRC are two of the most incident and aggressive types of malignant neoplasms in Brazil. A notable aspect of the Brazilian population is that it is highly admixed and, then, it is important not to extrapolate results from one region to another. For instance, these types of cancer are particularly frequent in the North region of Brazil. In general, most cases of GC and CRC are diagnosed in advanced stages and the death rate related to these types of cancer is high. To help early diagnosis, many research groups worldwide have been working to identify biomarkers able to detect increased risk of developing such types of cancer. Considering the high incidence of GC and CRC in the North region, we believe that it is important to study such neoplasms in this region.
In this study, we analyzed the association of 12 polymorphisms in genes involved in inflammatory pathways, immune response or cellular and genomic stability (namely, CASP8, CYP2E1, CYP19A1, IL1A, IL4, MDM2, NFKB1, PAR1, TP53, TYMS, UGT1A1 and XRCC1) regarding GC and CRC development in a population from the North region of Brazil. Understanding the distribution of these markers in the studied population helps to improve the knowledge of the different factors that lead to cancer development.
We collected blood samples from the participants (125 GC patients, 66 CRC patients and 475 cancer-free individuals), from which we extracted the DNA using a phenol-chloroform-based method. The studied 12-polymorphism set can be genotyped through amplification in a single multiplex PCR, followed by capillary electrophoresis. The different statistical analyses were performed in Structure v.2.3.4 and SPSS v.20 programs, and the R language. We analyzed the allelic and genotypic distribution of these markers, as well as the combined effect of the statistically significant alleles. The latter approach is not a common approach for studying GC and CRC. In fact, to the best of our knowledge, this is the first study using this kind of approach for these types of cancer in the Brazilian population. It gave us interesting results.
After performing the statistical analyses with correction of confounding factors, we observed positive associations between the markers rs79071878 (IL4 gene), rs3730485 (MDM2 gene) and rs28362491 (NFKB1 gene) and GC development, as well as between the markers rs28362491 (NFKB1 gene) and rs8175347 (UGT1A1 gene) and CRC development. When we analyzed the combined effect of the alleles of the statistically significant genotypes of each marker (RP1 allele of rs79071878, INS allele of rs3730485, DEL allele of rs28362491 and *36 and *37 alleles in rs8175347), we obtained statistically significant results for both types of cancer. From these results, we highlight that: (1) individuals carrying both RP1 (IL4 marker) and DEL (NFKB1 marker) alleles have more than 10-fold increased chances of developing GC than carriers of the other alleles; and (2) individuals carrying the DEL allele (NFKB1 marker) and at least one of the rare alleles *36 and *37 (UGT1A1 marker) have almost 12-fold increased chances of developing CRC than carriers of other alleles of these markers. Our results reinforce the importance of knowing the role that different markers play in the development of cancer, which may contribute to the early detection of GC and CRC.
In this study, we observed that the individual or joint presence of some alleles of the 12 polymorphisms of the set may affect the development of GC (RP1 allele of rs79071878, INS allele of rs3730485 and DEL allele of rs28362491) and/or CRC (DEL allele of rs28362491 and *36 and *37 alleles in rs8175347) in a population from the North region of Brazil. To the best of our knowledge, this is the first time it has been reported, and it supports the notion that more attention should be given to these polymorphisms in relation to the development of GC and CRC. Considering the results we obtained, we recommend that the individual and the joint presence of these markers should be further investigated in the other regions of Brazil, due to the high levels of admixture in this country, and in other types of cancer.
Although there have been many advances in the complex field of oncogenetics, there is still a lot remaining to be discovered. The present study investigated 12 polymorphisms, some of them not frequently studied, and showed statistically significant association between four of these markers and the development of GC and CRC in a population from the North region of Brazil. It shows the importance of studying different polymorphisms in important genes, some of which may be involved not only in the development of GC and CRC but also of other types of malignant neoplasms. In addition, our study reinforces the notion of investigating different types of cancer in genetically admixed populations, such as the Brazilian population.