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Annals of Surgical Oncology 9:88-93 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

T-Cell Receptor {gamma}: A Microsatellite Marker for Colorectal Cancer

Sonja M. S. Uthoff, MD, Louise E. Hunt, FRCS (Ed), Brooke S. Grant, BS, VyVy Young, BS, M. Robert Eichenberger, BA, Gary A. Cobbs, PhD and Susan Galandiuk, MD

From the Digestive Surgery Research Laboratory (SMSU, LEH, BSG, VY, MRE, SG), Price Institute of Surgical Research, Department of Surgery, and the Department of Biology (GAC), University of Louisville, Louisville, Kentucky.

Correspondence: Address correspondence and reprint requests to: Susan Galandiuk, MD, Department of Surgery, University of Louisville, Louisville, KY 40292; Fax: 502-852-8915; E-mail: s0gala01{at}gwise.louisville.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: T-cell receptor {gamma} (TCR-{gamma}) is involved in maintaining host cell integrity and homeostasis of the human immune system. We hypothesize that polymorphism of the TCR-{gamma} complex may be involved in the pathogenesis of colorectal cancer.

Methods: The microsatellite markers D7S1818 and D7S2206 located within the TCR-{gamma} antigen locus on chromosome 7p were amplified by polymerase chain reaction, and genotypes were determined for 22 patients with early onset of colorectal cancer (<60 years old) and for 38 population-based control subjects.

Results: Genotype BC of D7S1818 (P = .049) and haplotype AC of D7S1818/D7S2206 (P <= .003) were associated with colorectal cancer as compared with the control population (extended Fisher’s exact test).

Conclusions: This study identifies a novel genetic and clinical association between TCR-{gamma} and early-onset colorectal cancer. Many young patients do not fulfill the criteria for hereditary colorectal cancer syndromes and are therefore not identified by established screening programs. Markers such as D7S1818 and D7S2206 may become useful in the identification of patients at risk of developing colorectal cancer and permit earlier therapeutic intervention.

Key Words: T-cell receptor • Subunit gamma • Microsatellite analysis • Host immune response • Hereditary colorectal cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Even though the average age of patients diagnosed with colon and rectal cancer is 64 years, many patients develop colorectal cancer at younger ages. Some of these patients are affected with known hereditary cancer syndromes such as hereditary nonpolyposis colon cancer (HNPCC) or familial adenomatous polyposis. Patients with a positive history of HNPCC or familial adenomatous polyposis participate in targeted surveillance programs. Unfortunately, many patients with HNPCC have no known history of these hereditary syndromes or any known risk factors for developing colorectal cancer at an early age. It is in this population that identification of a predisposition to develop colorectal cancer would permit screening and possibly intervention before development of malignancy.

Changes in cell surface receptor expression in gastrointestinal mucosa may play a role in the pathogenesis of colorectal cancer. Activation of T lymphocytes is initiated by binding of the T-cell antigen receptor (TCR).1–3 TCR is a multimeric protein complex consisting of a disulfide-linked {alpha}/ß heterodimer that is noncovalently associated with the CD3 {gamma}, {delta}, {epsilon}, and {zeta} chains.4–6 Whereas the {alpha} and ß proteins contain all of the information necessary for antigen recognition, the CD3 molecules are responsible for signal transduction.7,8 The immunoglobulin-like {gamma} chain, along with the {delta} chain, is expressed at the surface of a subset of T lymphocytes.

Two different chain combinations of the TCR complex are used for antigen recognition: TCR-{alpha}/-ß and TCR-{gamma}/-{delta}.9 Gamma and {delta} T cells share numerous features with their {alpha} and ß counterparts but have several unique properties.10 Gamma and {delta} T cells are more prominent in the skin and gastrointestinal mucosa than in peripheral blood and conventional lymphoid organs. These T cells play an important role in maintaining host cell integrity. TCR-{gamma} expression in tumor-infiltrating lymphocytes is significantly lower than in normal intestinal tissue, suggesting T-cell localization in colorectal tumors.11,12

Even though tumor cells express antigens that are capable of activating a host immune response,13 colorectal cancers still develop.14 It has been suggested that an inadequate T-cell response may in part be responsible for this phenomenon.15,16 Colorectal cancer cell lines can also produce factors that, in turn, inhibit T-cell function. TCR-{gamma}/-{delta} cells are selectively and consistently localized in colorectal tumor tissue.11,17

We hypothesize that germline DNA mutations in the TCR complex—the {gamma} receptor in particular—may play a role in this failure of host response and, therefore, result in colorectal cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
This study was approved by the University of Louisville institutional review board, and written informed consent was obtained from all subjects. We undertook a case-control study comprising a cohort of 60 individuals, including 22 nonrelated patients with early-onset colorectal cancer and 38 unrelated population-based control subjects, who had also been evaluated for nonmalignant, noninflammatory bowel conditions (e.g., hemorrhoidal bleeding, diverticulosis) by the same surgeon. Individuals with a family history of cancer that could possibly be associated with hereditary colorectal cancer were excluded from the control group. Appropriate matching of the case-control groups and elimination of possible effects due to race or ethnicity were ensured by limiting analysis to white patients.

In an attempt to define a marker distinguishing younger patients at high risk of developing colon cancer, this study was limited to patients younger than 60 years at disease diagnosis. There were no significant differences in age of diagnosis between cancer and control groups. The mean age of disease diagnosis in colorectal cancer patients was 46 years (SD ±12), and for the control group it was 44 years (SD ±12). The sex distribution was similar between the groups, with 70% women and 30% men in the cancer group compared with 78% women and 22% men in the population control.

Genotyping
Genomic DNA was isolated from peripheral blood leukocytes by use of a commercially available kit (PuregeneTM; Gentra Systems Inc., Minneapolis, MN). The microsatellite loci D7S1818 and D7S2206 were identified from Fondation Jean Dausset database panels (Center d’Etude du Polymorphisme Humaine; http://www.cephb.fr/cgi-bin/wdb/ceph/systeme/form). These microsatellite markers are repetitive (GATA)n tetranucleotide sequences in the vicinity of the TCRG gene on chromosome 7p. Previously electronically published oligonucleotide primers (National Center for Biotechnology Information; http://www.ncbi.nlm.nih.gov/genome/sts), forward 5'-CCCTAACTCCCATGTTGATG-3' and reverse 5'-CACCCAGGATTGTGCTAACCT-3' specific for D7S1818 and forward 5'-TTACAAATGTCAGAGCAG-3' and reverse 5'-CAGAACCAAAAAGAAGAG-3' specific for D7S2206, respectively, were custom synthesized (Ransom Hill Bioscience, Ramona, CA). D7S1818 and D7S2206 were amplified by polymerase chain reaction (PCR; Perkin-Elmer thermocycler, Norwalk, CT). The PCR mixture consisted of a 10-µL reaction volume, including 100 ng of genomic DNA, 70 µM of each deoxyribonucleotide triphosphate, 1 µCi of [32P]{alpha}-labeled deoxycytidine triphosphate, 1.0 µM of forward and reverse primer, 50 mM of KCl, 10 mM of Tris-HCl, 1.5 mM of MgCl2, and 1 U of Amplitaq GoldTM DNA polymerase (Perkin Elmer, Applied Biosystems Division). Thermal cycling parameters were applied for amplification of both D7S1818 and D7S2206. They comprised an initial denaturation step at 94°C for 10 minutes, followed by 27 cycles of denaturation at 94°C for 30 seconds, primer annealing at 68°C for 75 seconds, extension at 72°C for 15 seconds, and a final extension at 72°C for 6 minutes. PCR products were subsequently subjected to electrophoresis in 10% nondenaturing Long RangerTM polyacrylamide gels (BioWhittaker Molecular Applications, Rockland, ME) with 5% glycerol in .6x Tris-borate EDTA buffer and electrophoretically resolved at 60 W for 6 to 12 hours at room temperature. Genotypes were determined autoradiographically (Eastman-Kodak, Rochester, NY). Allelic band shifts were called by two independent investigators blinded to disease diagnosis and patient identity.

Statistical Analysis
For nomenclature, alleles are inherited variants of a gene or a marker close to a gene that originate from changes at the level of genomic DNA. Genotypes are composed of observed alleles at a specific genetic locus for an individual. For autosomal loci, a genotype is composed of two alleles on two different chromosomes, one of which is paternally and the other maternally transmitted. Haplotypes are linearly ordered arrangements of alleles on one chromosome. Two marker alleles on one chromosome determine one haplotype, and each individual will thus encounter two haplotypes for two markers on analogous chromosomes.

Haplotype frequencies were estimated by use of the LAPD program (Linkage Analysis Using Pedigree Data), which can be adopted for analysis of unrelated individuals.18 LAPD is based on an expectation-maximization algorithm, which allows estimation of maximum likelihood two-locus haplotype frequencies. Cancer and control groups were compared by use of the generated maximum likelihood ratio expressed as an approximate P value. Row x column contingency comparison was performed by applying the extended Fisher’s exact method with SASTM (STAT Institute Software 1997, release 6.12, Cary, NC), especially allowing inclusion of low-value frequencies. For global comparisons, a corrected P < .005 was considered significant. This corresponds to an overall significance level of P < .05 when applying a Bonferroni correction for tests of multiple comparisons.

The crude measure of association between genotypes or haplotypes and disease was expressed as relative odds. Odds ratios (OR) were estimated from cross-products of contingency tables. The OR of a given genotype is the ratio of the odds of control subjects presenting with the genotype to the odds of patients with the disease presenting with this given genotype. An OR >1.0 indicates a positive association of a genotype or haplotype with the disease, and an OR >3.0 is considered to be clinically important. Confidence limits were derived with the test-based method.

For infrequent diseases, assuming that cases and control subjects are representative of the general population, the estimated OR will approach the estimated relative risk (RR). The risk ratio compares the risk of disease in exposed and unexposed individuals. The RR, therefore, quantifies how many times the disease is more or less likely in exposed compared with unexposed individuals. In genetic studies, exposure is represented by the underlying genotype or haplotype. A null value of 1.0 indicates that the disease is equally likely in exposed and unexposed individuals, and a value >1.0 indicates that the disease is more likely in the exposed individuals, meaning in those who have the given genotype or haplotype.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
D7S1818 is a highly polymorphic microsatellite locus with a heterozygote frequency of .70 (Fig. 1). Seven alleles yielding 13 distinct genotypes were observed for D7S1818, of which 5 occurred only in <=5% of the sample. Genotype BC was the most common genotype, with a frequency of .40 in the overall sample. This genotype was observed in 50% (11 of 22) of colorectal cancer patients compared with only 24% (9 of 38) of the population controls (P = .049; Fig. 2).



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  		FIG. 1. Representative autoradiograph of identified alleles for the microsatellite locus D7S1818. Alleles were labeled consecutively according to molecular weight, with allele Z being the largest and traveling the least distance on polyacrylamide gel and allele E being the smallest and traveling the farthest.

 


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  		FIG. 2. D7S1818 microsatellite polymorphism in each population. There were statistically significant differences in genotype distribution between colorectal cancer and population controls for genotype BC (P = .049). Genotypes with a frequency <=5% have been grouped for clarity (*).

 
Six alleles yielding nine genotypes were observed for D7S2206, which was likewise highly polymorphic, with a heterozygote frequency of .82. The overall contingency comparison was not significantly different for the genotype distribution, yet it approached significance for allele distribution, with a P value of .074.

Haplotypes were subsequently determined by combining both marker alleles on each of the complementary chromosomes. Nine haplotypes were identified in 79% of the sample, and an additional 10 haplotypes were identified in 21% of the overall sample. Cancer and control groups were compared by using the likelihood ratio test, which generated a ratio of 9.0 x 10-5. This corresponds to an approximate P value of .0001, indicating that the haplotype frequency distribution for the cancer subgroup is significantly different from the frequency for the control group. Examination of these estimates revealed that the primary difference is due to the distribution of haplotype AC. This haplotype occurred in 40% (4 of 10) of colorectal cancer patients, compared with only 2% (1 of 46) of the population controls (Fig. 3). Separate analysis with the extended Fisher’s exact test revealed a two-sided probability between the cancer and control groups that is highly significant, with P <= .003. This holds true even after adjustment of critical values by use of a Bonferroni correction with {alpha} <= .005.



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  		FIG. 3. D7S1818/D7S2206 microsatellite polymorphisms in each population. There was a significant difference in haplotype distribution between colorectal cancer and population controls for haplotype AC (P <= .003; extended Fisher’s exact test). Significant 10 x 2 contingency table analysis for haplotype distribution considered all variables (P < .0001). Haplotypes with a frequency <=5% have been grouped for clarity (*).

 
An estimate for the ratio of odds for D7S1818 genotype BC to be associated with colorectal cancer is OR = 3.2 (95% confidence interval, 1.04–9.82). The ratio of odds for haplotype AC is OR = 30 (95% confidence interval, 2.86–314.91), illustrating that D7S1818 and D7S2206 might be used as a marker in clinical screening for susceptibility to colorectal cancer.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Research on the TCR genes has reported an additional immunoglobulin-like gene called gamma, which binds to the TCR complex.19,20 Transcription of this rearranged {gamma} locus results in protein biosynthesis of the {gamma} chain, which is expressed along with the {delta} chain at the surface of T lymphocytes.21,22 The {gamma} chain is part of a {gamma}/{delta} heterodimer associated with CD3, which is situated on the surface of peripheral T lymphocytes and thymocytes.23 Gamma- and {delta}-positive T cells are thought to play a decisive role in the maintenance of host cell integrity and in immune system homeostasis.24 Gamma and {delta} T cells secrete various cytokines and express cytolytic functions.25 In particular, interferon {gamma} has been shown to be produced by stimulated {gamma}/{delta} T cells. Preferential localization of {gamma}/{delta} T cells in epithelial layers suggests their involvement in immune surveillance functions.15

The TCR subunit {gamma} is assigned to human chromosome 7p15–14.26 The TCR-{gamma} locus comprises two gene regions, which are immutable but can undergo rearrangements.27–33 These rearrangements have been observed in all types of T cells investigated, providing evidence that the TCRG gene may be a marker of clonality for various T-cell pathologies.24,34–40 The intergenic joining of segments among different antigen receptor genes and the presence of chimeric TCRG/D gene rearrangements have both been described.41–46 It has thus been proposed that TCR hybrid gene products may possibly lead to, or contribute to, the increased diversity within the antigen receptor repertoire.47–52

Previously performed linkage analysis has been used to investigate genetic disorders involving the TCR-{gamma} locus.52 The linkage of microsatellite markers with this locus was expressed as logarithm of odds (LOD) scores. The LOD score is described by the base-10 logarithm of the likelihood of the OR for linkage. This means that a LOD score >=3.0 provides evidence in favor of linkage, where the marker is 1000 times more likely to be associated with the gene of interest than not to be associated. This is important, because the markers D7S1818 and D7S2206 were shown to be linked to the TCR-{gamma} locus with vast LOD scores >11.0 and 15.0, respectively (Marshfield Clinic database, http://research.marshfieldclinic.org/genetics/). This suggests that D7S1818 and D7S2206 are located close to the TCRG gene locus. The recombination fraction (theta) describes the frequency of crossover between two marker loci or a marker and the gene of interest during meiosis. Theta is inversely related to the distance between the markers. Because D7S1818 and D7S2206 are flanking the TCRG gene upstream and downstream, respectively, theta is very low.10 These microsatellite markers and the TCRG gene, therefore, tend to segregate together. Inherited polymorphisms within these microsatellite markers, therefore, predict polymorphism within the TCRG gene itself. Because we have demonstrated an association of a haplotype of these microsatellite markers with colorectal cancer, we hypothesize that rearranging units of the TCR may be implicated in the failure of host immune response with respect to early onset of colorectal cancer.

The initial intent of our investigation was, however, to determine whether the locus that encodes the immunologically crucial {gamma} chain of the TCR might qualify as a candidate gene for colorectal carcinogenesis. We implemented microsatellite analysis to determine heterogeneity surrounding the joining point of the TCRG gene segments, which in turn would portend heterogeneity of the antigen locus itself. With respect to colorectal carcinogenesis, this would further establish a basis for the individuality of tumor host responses. Microsatellite polymorphism does not parallel functional differences of the receptor itself. Haplotype distributions of those microsatellites chosen for this study do, however, seem to confer either an increased or decreased risk of developing colorectal cancer. They might, therefore, be informative for identification of individuals at risk for developing early-onset colorectal cancer.

Because studies such as this use microsatellite markers in germline DNA, analysis of such microsatellite markers has the advantage of being performed before the development of cancer. These markers, in combination with others, may have potential use in screening and identification of patients without known hereditary cancer syndromes, such as HNPCC and adenomatous polyposis coli-associated colon cancer, but who may be at an increased risk of developing colorectal cancer.

Decision trees will become essential in assessing increased susceptibility to colorectal cancer. Early diagnosis is critical, because it would permit earlier therapeutic intervention in patients with premalignant disease of the colon or colorectal cancer. An assortment of molecular markers identifying individuals with increased susceptibility to disease would be beneficial to both the surgeon and the patient seeking professional advice.

Our results show that polymorphisms in the microsatellite markers D7S1818 and D7S2206 may predict polymorphism in the TCRG gene and seem to be associated with colorectal cancer patients who are younger than 60 years. Individuals carrying D7S1818 genotype BC are two times more likely to develop colorectal cancer than control subjects with any other genotype (RR = 2.0). Individuals carrying D7S1818/D7S2206 haplotype AC are approximately 7 times more likely to develop colorectal cancer than control subjects with any other haplotype (RR = 6.8). The representative ratio of odds to develop colorectal cancer exceed the conventional threshold of clinical significance. In cancer patients, this is true for D7S1818 genotype BC (OR = 3.2) and D7S1818/D7S2206 haplotype AC (OR = 30). Even though the numbers of subjects in both groups seem modest, the statistical power for the AC haplotype and global contingency table analyses are .85 and .86, respectively ({alpha} = .005). We recognize the need to confirm our data in a large patient sample and are currently accruing more patients with colorectal cancer who are younger than 60 years for further analysis and replication. These patients do not fulfill the criteria for hereditary cancer syndromes, and, as such, there is as yet no method of identifying them by use of standard screening parameters. Our data invite confirmation as a potential screening tool to permit earlier detection and treatment in this particular group of patients.

We believe that with increasing knowledge about gene structure and function, diverse genes will be shown to participate in colorectal carcinogenesis. Distinct gene carrier status may enable targeted surveillance for individuals. We therefore wished to identify genetic markers that would be predictive of increased susceptibility, which would also facilitate screening for colorectal cancer, especially in a younger patient population. This population would ordinarily be excluded from the average-risk screening routine.


   Footnotes
 
Presented at the Annual Meeting of the Society of Surgical Oncology, New Orleans, March 16–19, 2000.

Received for publication December 28, 2000. Accepted for publication July 30, 2001.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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