The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4911-4916
Copyright © 2003 by The Endocrine Society
Intronic Single Nucleotide Polymorphisms in the RET Protooncogene Are Associated with a Subset of Apparently Sporadic Pheochromocytoma and May Modulate Age of Onset
Sarah R. McWhinney,
Getachew Boru,
Philip K. Binkley,
Mariola Peczkowska,
Andrzej A. Januszewicz,
Hartmut P. H. Neumann and
Charis Eng
Department of Molecular Genetics (S.R.M., C.E.); Divisions of Human Genetics (P.K.B., C.E.) and Cardiovascular Medicine (P.K.B.), Department of Internal Medicine; Division of Human Cancer Genetics (G.B., C.E.), Department of Molecular Virology, Immunology, and Medical Genetics; Clinical Cancer Genetics Program (C.E.) and Human Cancer Genetics Program (S.R.M., G.B., C.E.), Comprehensive Cancer Center; and Dorothy M. Davis Heart and Lung Research Institute (P.K.B., C.E.), The Ohio State University, Columbus, Ohio 43210; Department of Hypertension (M.P., A.A.J.), Institute of Cardiology, Warsaw, Poland; Department of Internal Medicine IV Nephrology and Hypertension (H.P.H.N.), Albert-Ludwigs-University of Freiburg, D-79106 Freiburg im Bresgau, Germany; and Cancer Research UK Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 2XZ, United Kingdom
Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Human Cancer Genetics Program and Division of Human Genetics, The Ohio State University, 420 West 12th Avenue, Suite 690, Tzagournis Medical Research Facility, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu, or Hartmut P. H. Neumann, M.D., Medizinische Universitätsklinik, Hugstetterstrasse 55, D-79106 Freiburg im Bresgau, Germany.
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Abstract
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Approximately 75% of pheochromocytomas are sporadic. Germline mutations in RET, VHL, SDHB, and SDHD have been shown to cause the 25% that are hereditary. Germline high penetrance gain-of-function RET mutations cause multiple endocrine neoplasia type 2, of which medullary thyroid carcinoma (MTC) and pheochromocytoma are components, whereas loss-of-function mutations cause Hirschprung disease (HSCR). A low-penetrance founder locus, in linkage disequilibrium with a RET ancestral haplotype comprising specific alleles at three intron (IVS) 1 single nucleotide polymorphisms (SNPs) (haplotype 0) and SNP A45A, predisposes to the majority of isolated HSCR. A different low-penetrance locus, in linkage disequilibrium with IVS 1 haplotype 2 and SNP S836S, was associated with a subset of sporadic MTC. We, therefore, sought to determine whether RET might also be a low-penetrance gene for apparently sporadic pheochromocytoma. We analyzed 104 pheochromocytoma cases without germline mutations in RET, VHL, SDHD, and SDHB for their status at A45, S836, three IVS 1 SNPs, and a novel upstream insertion/deletion variant. Pheochromocytoma cases were not associated with either A45A or S836S, but we found that cases were associated with haplotype 0 (P = 0.032). However, unlike HSCR, this pheochromocytoma-associated haplotype 0 was not associated with A45A. Taken together with the strengthening of association with the addition of the 5' insertion/deletion variant data (P = 0.016), our observations suggest the presence of a low-penetrance pheochromocytoma susceptibility locus in a region upstream of the putative loci for HSCR and apparently sporadic MTC.
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Introduction
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PHEOCHROMOCYTOMAS ARE catecholamine-producing chromaffin tumors, 90% of which arise in the adrenal medulla. Extraadrenal pheochromocytomas, which arise in the sympathetic ganglia, are commonly referred to as paragangliomas. Until recently, the assumption was that 10% of all pheochromocytomas are hereditary, whereas the remaining 90% are sporadic. In a population-based study, we found that 25% of apparently sporadic pheochromocytomas are actually hereditary (1). Despite a lack of syndromic features and family history at presentation, they were found to carry germline mutations in one of the four currently known pheochromocytoma-susceptibility genes: RET, the susceptibility gene for multiple endocrine neoplasia type 2; VHL, the gene for von Hippel-Lindau disease; and SDHD or SDHB, susceptibility genes for the pheochromocytoma-paraganglioma syndromes (1). So, 75% of this population-based series of pheochromocytomas do not have mutations in these known genes. Therefore, we postulated that these apparently sporadic pheochromocytoma cases might be accounted for by low-penetrance variants in RET, for the following reasons.
The RET protooncogene, localized to 10q11.2, encodes a receptor tyrosine kinase expressed in neural crest and its derivatives (2, 3). Germline gain-of-function mutations cause multiple endocrine neoplasia type 2, which is an autosomal dominant inherited cancer syndrome that is characterized by the triad of medullary thyroid cancer (MTC), pheochromocytoma, and hyperparathyroidism (4). Loss-of-function mutations in RET are associated with a subset of Hirschsprung disease (HSCR), a common disorder also known as aganglionic megacolon (5, 6). In a population-based HSCR series, only 3% of all isolated (nonfamilial) cases were found to carry germline RET mutations (7). Therefore, working on the hypothesis that common low-penetrance alleles in RET may be responsible for the majority of isolated HSCR, we initially performed association analyses and found that haplotypes associated with a RET exon 2 polymorphic variant [or single nucleotide polymorphism (SNP)] A45A (c.135G>A) was highly associated with the majority of isolated HSCR (8, 9). Furthermore, this variant was found to be in linkage disequilibrium with variants at the 3' end of RET intron (IVS) 1 (Fig. 1
), and also associated with the majority of isolated HSCR (10). Statistical modeling suggests that these associated haplotypes of variants belong to an ancestral haplotype in linkage disequilibrium with a very common but low-penetrance founder mutation that accounts for susceptibility to the majority of isolated HSCR and dates back to the Stone Age (10).
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FIG. 1. Schematic representation of part of the RET protooncogene, illustrating the four IVS 1 polymorphic loci analyzed and the two anchoring SNPs associated with HSCR (A45A) and MTC (S836S) [not to scale].
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Interestingly, we initially found that a different RET polymorphic variant in exon 14, S836S, was associated with a subset of apparently sporadic MTC. This S836S (c.2439C>T) MTC-associated variant was in linkage disequilibrium with a haplotype comprising a different combination of variants at the 3' end of IVS 1 than that for HSCR (10). Statistical modeling suggested that, similar to that for HSCR, the MTC-IVS 1 haplotype was in linkage disequilibrium with a low-penetrance locus within IVS 1 in the vicinity of, but distinct from, that for HSCR (10).
We hypothesized that the RET protooncogene could also act as a low-penetrance susceptibility locus that is strongly associated with apparently sporadic pheochromocytoma. To address our hypothesis, we decided to characterize previously established SNPs in the 3' region of RET IVS 1 and use these data to perform haplotype analysis to test whether haplotypes in this region showed association with pheochromocytoma.
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Patients and Methods
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Patients and controls
Patients with pheochromocytoma have been registered in the population-based registries in Freiburg, Germany, and Warsaw, Poland, and are described in detail previously (1). For this study, we included 104 cases of sporadic pheochromocytoma from this registry because they were identified as not having any germline mutations in RET, VHL, SDHB, or SDHD. A total of 95 race-matched normal control DNA samples were obtained from the same geographical region as the cases.
Analysis of RET sequence variation
Genomic DNA from pheochromocytoma patients and control samples was obtained from blood leukocytes using standard techniques. We analyzed the RET exon 2 codon 45 SNP (c.135G>A), exon 14 codon 836 SNP (c.2439C/T), and the three RET intron 1 SNPs, IVS1-126G/T, IVS1-1370C/T, and IVS1-1463T/C. PCR and genotyping of the A45A and S836S SNPs were performed as previously described (8, 11). For the IVS1 SNPs, PCR was performed using the Qiagen HotStarTaq kit (Qiagen, Valencia, CA) for 38 cycles at 55 C annealing temperature and the appropriate primers (IVS1-126: F primer, 5' GTA TGG TTC AGG TGC CCT TC 3'; R primer, 5' TGA GTG AGG GAT GGT GAG AA 3'; IVS1-1370: F primer, 5' TTT TCC ATT TTC ACC GAC AA 3'; R primer, 5' GTG CCC GGC CTA TCT ATG TA 3'; IVS1-1463: F primer, 5' GAG GTT GCT TCC ACC TTT TG 3'; R primer, 5' CTG TGT GTG GCC AAC ATT TC 3'). An aliquot of the PCR product was purified using ExoI/Shrimp alkaline phosphatase treatment. The purified amplicons were directly sequenced using Big-Dye Terminators v. 20 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA) and analyzed on an ABI Prism 3700 DNA Analyzer (Applied Biosystems).
In a search for SNPs in RET IVS 1, a 16-bp insertion/deletion variation was found in the location IVS1 + 8406 to +8421del16 within the 22 kb spanning this intron, but 13.2 kb upstream of IVS1-1463T/C (Boru, G., and C. Eng, unpublished data). To establish the status at this locus in the pheochromocytoma samples, the 16-bp insertion/deletion polymorphism was detected using fluorescent genotyping. Primers were designed flanking the deletion, and the forward primer was labeled with a fluorescent tag (F primer, 5' HEX CGG CTG AGA GGA GCT TAC AC 3'; R primer, 5' GTT TCT TCA AGC TGA CAA TCC TGA TGC 3'). PCR was performed using the Qiagen HotStarTaq kit (Qiagen) for 38 cycles at 55 C annealing temperature. The PCR products were analyzed on the ABI Prism 3700 DNA Analyzer (Applied Biosystems) using the ROX-400HD size standard to determine the precise size of the two alleles.
Formation of haplotypes and genotypes and statistical analyses
Allele frequencies at the three IVS 1 SNP loci as well as the 16-bp insertion/deletion locus were determined, and subsequently haplotypes consisting of the different combinations of the alleles for just the three SNPs as well as at all four loci were constructed (Table 1). The haplotypes were based on those previously established, designated 0–4, which represent unique combinations of the three RET intronic SNPs: IVS1-126G/T, -1370C/T, and -1463T/C (Ref.10) (Table 1 and Fig. 1
). The extended haplotypes, which include the insertion/deletion locus (0a-4b), were based on the original haplotypes but given the suffix a or b depending on their status at the IVS1 + 8406 to +8421del16 locus (a, deletion absent; b, deletion present). The frequencies of both the haplotypes and the genotypes (the combination of two haplotypes) were resolved and then compared between controls and individuals with pheochromocytomas.
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TABLE 1. Haplotypes based on the combination of allelic variants at four polymorphic loci located within RET intron 1
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Comparisons were performed using a standard 
2 calculation with Yates’ correction, as described previously (8, 9, 10). Nominal statistical significance was considered when P < 0.05. In addition, allele frequencies were compared, and significance was established using the same criteria. Comparison of distributions of haplotypes or genotypes against clinical features was performed using standard 2 analysis with Yates’ correction. The proportion of individuals diagnosed at a certain age per haplotype was compared using odds ratios [±95% confidence intervals (CI)].
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Results
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Association analysis between RET S836S and A45A and individuals with pheochromocytoma compared with controls
Because the S836S (c.2439C>T) SNP was found to be associated with apparently sporadic MTC (11) and in linkage disequilibrium with IVS 1 haplotype 2 (10), our initial hypothesis was that the RET haplotype in linkage disequilibrium with S836S was a general low-penetrance gain-of-function locus that would also predispose to isolated pheochromocytoma. To test this hypothesis, we determined the allele frequencies at this SNP in cases with pheochromocytoma and controls. However, the frequency of the variant c.2439T allele in individuals with pheochromocytoma was no different from that of normal controls (3.8 vs. 3.7%; P > 0.05; data not shown). In addition, it was found that the A45A variant was not associated with sporadic pheochromocytoma (P > 0.05; data not shown).
Association analyses of RET IVS 1 variants in individuals with pheochromocytoma and controls
We have analyzed 104 apparently sporadic pheochromocytoma cases and 100 normal controls at each of four loci in IVS 1 of the RET protooncogene: three SNPs toward the 3' end of the intron and one 16-bp insertion/deletion polymorphism 5' of the SNPs (Fig. 1). Of these four loci, allele frequencies at three showed significant differences between individuals with pheochromocytoma and normal controls (Table 2). Among a total of 208 pheochromocytoma chromosomes, there were 82 (39.4%) with the T variant at the IVS1-1370C/T locus, and 126 (60.6%) with the wild-type C allele. The T variant was statistically significantly underrepresented when compared with normal controls (2 = 4.50; P = 0.034). Similarly, the IVS1-1463 polymorphic C allele was underrepresented in cases compared with controls (2 = 8.28; P = 0.004). Conversely, the IVS1 + 8406 to +8421del16 deletion was overrepresented in individuals with pheochromocytomas compared with the controls (P = 0.022). The allele frequencies at IVS1-126 did not show a significant difference between the two groups (P = 0.70; Table 2).
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TABLE 2. Comparative studies between pheochromocytoma cases and controls of allelic frequencies at four RET intron 1 polymorphic loci using 2 analysis with Yate’s correction
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Analysis of RET IVS 1 haplotypes in cases and controls
Haplotypes were initially constructed that comprised only the three 3' IVS 1 SNPs, and previously designated as haplotypes 0–4 (10). The distribution of pheochromocytoma cases and normal controls across these haplotypes was significantly different (2 = 8.81; P = 0.032; Table 3). Of note, haplotype 0 was overrepresented among cases compared with controls (Table 3).
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TABLE 3. Distribution of haplotypes comprising alleles at three intron 1 SNP loci in pheochromocytoma cases and controls
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Using the information for each locus, we subsequently constructed haplotypes consisting of various combinations and permutations of variants at all four loci, the three 3' IVS1 SNPs and the insertion/deletion polymorphism 5' of these SNPs, adding the designation a or b depending on the absence or presence, respectively, of the polymorphic 16 nucleotides (Table 1 and Fig. 1). The frequencies of each haplotype were compared between individuals with pheochromocytoma and normal controls. The haplotype distribution between the cases with pheochromocytoma and that of the normal control group was found to be statistically significant (2 = 25.27; P = 0.0014; Fig. 2).
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FIG. 2. Frequencies of haplotypes comprising specific alleles at four intron 1 polymorphic loci in pheochromocytoma cases and controls.
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Haplotype 2b was the most common haplotype in the pheochromocytoma samples. This haplotype comprises the IVS1-126, and IVS1-1463 polymorphic alleles in the presence of IVS1 + 8406del16. Haplotype 2b represents 30.5% of all pheochromocytoma haplotypes, and haplotype 1a the second most common (27.6%) (Table 4 and Fig. 2). In the controls, haplotype 1a was the most common (35%) and 2b was the second most common, whereas 3b was the least frequent. Haplotype 0b was overrepresented among cases compared with controls, whereas haplotype 2a was underrepresented in cases vs. controls (Table 4 and Fig. 2).
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TABLE 4. Distribution of four variant haplotypes comprising alleles at four RET IVS 1 loci in pheochromocytoma cases and controls
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Analysis of RET IVS 1 genotypes in individuals with pheochromocytoma and controls
We first analyzed the genotype composition (pair of haplotypes) with the haplotypes established previously, 0-4 (10). The distribution between sporadic pheochromocytoma cases and control was significantly different (P = 0.037; Table 5).
We then analyzed the four-locus genotype composition of each sample and compared the two groups. Genotypes 1b/0a and 1a/2b predominate in individuals with pheochromocytomas (42%), whereas genotypes 1a/1a and 1a/2b were the most common among controls (42%). The overall distribution of the genotypes in the two groups was compared and found to be statistically significant (2 = 23.50; P = 0.0014). Genotypes 0b/0b and 1b/0a were particularly overrepresented in cases compared with controls (Table 6 and Fig. 3).
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FIG. 3. Frequencies of RET genotype in pheochromocytoma cases and controls. Each genotype is comprised of a pair of unique haplotypes.
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Analysis of RET haplotypes and genotypes and clinical features
Clinical data for each of the pheochromocytoma samples with respect to the tumor location, patient gender, and age at diagnosis was compared against RET intron 1 haplotype and genotype. The patients’ ages at diagnoses were divided into three groups: under 40 yr, 40–59 yr, and 60 yr or older (Table 7). The overall distribution of the genotypes for individuals with pheochromocytoma across each of the three age groups was statistically significant (2 = 31.09; P = 0.028; Table 7). In contrast, the overall distribution of haplotypes across each of the age groups was not significantly different. However, there tended to be more individuals carrying the haplotype 0b diagnosed under the age of 40 yr (8 of 21 or 0.38; 95% CI, 0.21, 0.59) compared with those with haplotype 1b under the age of 40 yr (3 of 39 or 0.07; 95% CI, 0.02, 0.21). The location of the pheochromocytomas (adrenal or extraadrenal) and the gender distribution of the patients were not found to be statistically significantly different among haplotypes or genotypes (data not shown).
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Discussion
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In this study, we have found that a haplotype consisting of a unique combination of alleles at four RET IVS 1 polymorphic loci is strongly associated with and overrepresented in individuals with sporadic pheochromocytoma compared with controls. This haplotype, which we denote 0b, comprises the wild-type allele at IVS1-126 and IVS1-1463, with a 16-bp intron 1 deletion 5' of these SNPs. Consistent with this observation, the genotype 0b/0b was found to be overrepresented in individuals with pheochromocytoma compared with race-matched normal controls.
Our observations were initially surprising because we have previously shown that in HSCR, haplotype 0 is also the most common and the most overrepresented haplotype in HSCR compared with controls (10). However, in HSCR, haplotype 0 is in absolute linkage disequilibrium with the presence of the exon 2 A45A polymorphism in contrast to our pheochromocytoma series in which the variant is not overrepresented and not in linkage disequilibrium with haplotype 0. Furthermore, the pheochromocytoma-haplotype 0 association was strengthened when the status at the upstream 16-bp insertion/deletion locus was taken into account. These data suggest that a low-penetrance pheochromocytoma susceptibility locus might be in linkage disequilibrium with haplotype 0b and would likely lie 5' of the 16-bp insertion/deletion locus. Our observation that haplotype 0 is not in linkage disequilibrium with A45A in pheochromocytoma cases additionally suggests that the two putative ancestral haplotype/founder loci, the HSCR-specific haplotype 0-A45A and the pheochromocytoma-related haplotype 0, which is not associated with A45A, diverged during the Stone Age (10).
The association with pheochromocytoma is strengthened when genotypes comprising pairs of haplotypes are examined, e.g. 0b/0b occurs in 12 cases and one control. Thus, we may postulate that this putative low-penetrance locus acts in an additive or autosomal recessive manner. Our observations have an alternative explanation, i.e. that the actual intron variants per se are lending low-penetrance susceptibility to pheochromocytoma. This is a less likely explanation. Although there are several putative transcription factor binding motifs within intron 1, where one may postulate differential binding strengths dependent on the presence or absence of variation, the fact that the identical IVS 1 SNP haplotype, haplotype 0, has been found to be overrepresented in HSCR as well, argues against this alternative. To better define the putative low-penetrance pheochromocytoma locus, the identification and analysis of further IVS 1 and further upstream SNPs should be performed.
Interestingly, we found a significant association between the patients’ age of diagnoses and genotype. This is especially noteworthy because there is not a significant correlation with the individual haplotype. There are two explanations for these seemingly contradictory observations. First, it is possible that sample sizes are relatively small, and so, the effect of individual haplotype was not obvious. Second, this observation supports our above postulate that the additive effect of haplotypes, i.e. the genotype, dictates the outcome, and in this case, age of onset. Analogously, four fifths of German HSCR cases homozygous for the A45A polymorphism had the short-segment phenotype (12), although this particular association was not found among Spanish HSCR cases (8, 9).
In summary, we have genetic evidence that a low-penetrance founder pheochromocytoma susceptibility locus may exist in a region 5' of the insertion/deletion polymorphism within intron 1 of the RET protooncogene, which might account for a subset of apparently sporadic pheochromocytoma. Furthermore, either the combination of intron 1 variants associated with haplotype 0b or the putative founding locus itself can modulate age of onset.
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Acknowledgments
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We are grateful to the members of the Freiburg-Warsaw-Columbus Pheochromocytoma Study Group for access to the sporadic pheochromocytoma DNA samples, and especially to the patients for their continued participation in our studies.
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Footnotes
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This work was partially funded by Grants R01HD39058 (to C.E.) and R01HD39058-02S1 (to G.B.) from the National Institutes of Health, Grant P30CA16058 from the National Cancer Institute (to The Ohio State University Comprehensive Cancer Center), and Grants NE571/5-1 and NE571/4-4 from the Deutsche Forschungsgemeinschaft (to H.P.H.N.).
C.E. is the recipient of a Doris Duke Distinguished Clinical Scientist Award.
Abbreviations: CI, Confidence interval(s); HSCR, Hirschsprung disease; IVS, intron; MTC, medullary thyroid cancer; SNP, single nucleotide polymorphisms.
Received February 13, 2003.
Accepted June 17, 2003.
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Abstract
Introduction
