transcriptase (TERT) catalytic subunit have recently been described in bladder cancers14,
melanomas,15 gliomas,16 and thyroid cancers,17 but not in breast, colorectal and prostate
cancer. In addition, TERT promoter mutations could not be detected in esophageal SCC.18
In chapter 3 of this thesis, for the first time, the occurrence of TERT promoter mutations in EAC was evaluated with the use of a multiplex SNaPShot assay. Telomerase increases telomere length at chromosome ends. It is active in stem cells to prevent chromosome shortening, replicative senescence and genomic instability. In differentiated cells of somatic tissues, telomerase becomes downregulated, however in cancer cells it can become reactivated.19 However, since TERT promoter mutations were not detected in
EACs, these tumors might have alternative mechanisms to maintain telomere length, and therefore would be less likely to benefit from activating mutations in TERT.
Many studies have focussed on the molecular biology of EACs using the tumor as a start- ing point, by which tumor-specific (somatic) mutations in the genes TP53, P16, SMAD4,
PIK3CA, ARID1A were identified.8-10 However, research into the genetic alterations of BE
developing into EAC is important as well. Assessing an individual’s genetic susceptibil- ity, based on common genetic variants in the population, may identify patients with BE, who have a high risk for malignant progression. Single nucleotide polymorphisms (SNPs) are the most common type of genetic variations and represent differences of single nucleotides at specific positions in the DNA sequence. Each variation is present to some appreciable degree in a population. SNPs within the coding sequences of genes, i.e. ex- ons, can change the amino-acid sequences of a protein and therefore the activity of the protein. SNPs located upstream or downstream from a gene may affect gene expression, when located in the promotor region. SNPs located in the non-coding regions of a gene, i.e. introns, do not affect the amino-acid sequence but, can still be related to variants located in an exon. However, the vast majority of the SNPs are located outside the genes and functional consequences of these genomic variations are mostly unknown (www. nature.com). Genome-wide association studies (GWAS) screen thousands of unrelated cases (diagnosed with the disease of interest) and controls to identify common genetic variants that have an association with a specific disease. The first GWAS on BE and EAC revealed several associated SNPs: rs10419226 (CRTC1), rs11789015 (BARX1), rs2687201 (FOXP1), rs9936833 (FOXF1), rs2178146 (FOXF1) and rs3111601 (FOXF1).20
In chapter 4 of this thesis the association between these six SNPs and the risk of EAC was validated in an independent and large case–control study. The SNPs rs10419226 (CRTC1) and rs11789015 (BARX1), were associated with EAC, based on a significantly increased
Chapter 10
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dose-effect in the genotypic analysis: homozygosity for two minor alleles gave a stronger effect than heterozygous genotypes. Rs10419226 as well as rs11789015 are located in the first intron of the genes CRTC1 and BARX1, respectively. Both variants have no obvious effect on the coding sequence of the gene but could be linked to an associated variant located in an exon. Alternatively, since the SNPs are both located in the first intron of the gene, they might affect the promoter and cause up- or downregulation of the expression of the gene.
A more recent GWAS17 supported the association of rs11789015 (BARX1) and rs2687201
(FOXP1) with the risk BE (not EAC), as previously reported by Levine et al.,20 but not
replicated by our study. In addition, two new SNPs were identified: rs3072 (GDF7) and rs2701108 (TBX5).21 The impact of SNPs on the function of the genes must be interpreted
with caution. Functional studies are required to determine whether the SNPs cause up- or downregulation of gene expression and impact on cell behaviour. In addition, the effect of the SNPs can be cell type specific or stage specific or can be influenced by environmental factors. These results provide evidence that the risks of BE and EAC are influenced by genetic variants that are common in the population, and therefore the susceptibility to BE and EAC is not equally distributed among individuals in the popu- lation. Clearly, some people have a higher susceptibility than others because of their genetic load, which in the context of changing environmental conditions may increase their absolute risk of cancer. Although the individual effect size of any given SNP is small, collectively these SNPs could still account for a substantial proportion of variation in risk. familial clustering of EAc
Chapter 5 of this thesis consist of a review about familial EAC. Since 1978 several families have been described with clustering of BE and EAC.22-27 Families consisting of two or
more first- or second-degree family members diagnosed with BE and/or EAC are termed familial Barrett’s esophagus (FBE). This group comprises approximately seven percent of all patients diagnosed with BE or EAC.28-30 The majority of the patients meeting the
criteria of FBE are diagnosed at a younger age compared to sporadic cases.29-31 In addi-
tion, a segregation analysis of 881 pedigrees of FBE supports an incompletely dominant inheritance model with a polygenic component,32 i.e. a trait influenced by many genes.
Moreover the presence of BE and EAC cases among multiple generations of one family also suggests a phenotypic autosomal dominant pattern of inheritance. 24,33 Orloff et al.
identified germline mutations in the genes MSR1, ASCC1, and CTHRC1 with the use of a linkage analysis on affected siblings diagnosed with BE or EAC.34 However, information
about the presence of identical germline mutations in affected siblings is lacking and the role of these genes in the development of FBE is unknown. The presence of several cases of BE and EAC among one family can be based on a coincidence, can be explained by