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Cancer Epidemiology Biomarkers & Prevention Vol. 11, 1449-1453, November 2002
© 2002 American Association for Cancer Research

Multiple Single Nucleotide Polymorphisms on Human Chromosome 19q13.2–3 Associate with Risk of Basal Cell Carcinoma1

Jiaoyang Yin, Eszter Rockenbauer, Mohammad Hedayati, Nicklas Raun Jacobsen, Ulla Vogel, Lawrence Grossman, Lars Bolund and Børn A. Nexø2

Institute of Human Genetics, University of Aarhus, DK-8000 Aarhus C, Denmark [J. Y., E. R., L. B., B. A. N.]; Department of Medical Genetics, Shenyang Medical College, Shenyang 110031, Liaoning, People’s Republic of China [J. Y.]; Department of Biochemistry, Johns Hopkins School of Public Health, Baltimore, Maryland 21205 [M. H., L. G.]; and Institute of Occupational Health, Lersø Parkalle 105, DK-2100 Copenhagen O, Denmark [N. R. J., U. V.]


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In this paper, we present evidence that alleles of several polymorphisms in the chromosomal region 19q13.2–3, encompassing the genes RAI and XPD, are associated with occurrence of basal cell carcinoma in Caucasian Americans. The association of one of these, RAI-intron1, is sufficiently strong to make mass significance unlikely (P = 0.004, {chi}2). We interpret our combined data to indicate that a specific haplotype partly defined by the alleles of three single nucleotide polymorphisms, RAI intron1G, RAI exon6T, and XPD exon 6C, is associated with a protective gene variant in a region spanning from XPD to ERCC1.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SNPs3 are the plankton of genetics. Individually they are tiny, 1-base differences in a 3-gigabase human genome, but by their multitude they constitute a rich source for genetic research. In the wake of the Human Genome Project, myriads of SNPs have surfaced, and it is now estimated that a SNP occurs approximately every 1000 bases. So no matter which part of the genome you are interested in, there are likely to be multiple SNPs located in the vicinity.

SNPs often effectively dichotomize human populations, making them useful for tracking genes of importance to disease in outbred populations by linkage disequilibrium. Specifically, typing of SNPs may facilitate the locating of regions of previously unknown importance for cancer risk. Thus, we have previously reported that polymorphisms in the gene XPD seemed associated with the occurrence of BCC (1) . This finding has later been corroborated by the association of polymorphisms in XPD with BCC in a different population (2) and by the association of markers in the same gene with three other cancers, malignant melanoma (3) , glioma (4) , and lung cancer (5) .

In this paper, we present evidence that alleles of several other polymorphisms in the chromosomal region 19q13.2–3, encompassing the genes RAI and XPD, are associated with occurrence of BCC. We are therefore convinced that a chromosomal variation influencing the risk of getting BCC and possibly other cancers must be located in this region, and we see the present paper as a first step toward identifying this variation.

Of the genes that we have investigated, XPD, ERCC1, and LIG1 relate to DNA repair and are probably directly involved in preventing cancer. FOSB, which is a homologue of an oncogene, and GLTSCR1, which may be a tumor suppressor gene, might well also be involved in carcinogenesis or its prevention. For RAI, which seems to be involved in control of transcription, one might construct a relation to cancer prevention, but no experimental data to that effect are available. The remaining genes are unlikely to play a direct role in cancer. They were chosen simply because they were located in the chromosomal region of interest.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Groups.
The groups of Caucasian Americans with and without BCC have been described previously (2 , 6) . DNAs for the analyses were purified from frozen lymphocytes obtained from blood.

Determination of Polymorphisms by LightCycler.
Genotypes of polymorphisms in CKM exon 8 (position 20076, rs#4884) and RAI intron 1 (position 875, rs#1970764), ERCC1 exon 4 (position 19007; Ref. 7 ), FOSB exon 4 (position 34621, rs#1049698), SLC1A5 exon 8 (position 60620, rs#1060043), LIG1 exon 6 (position 111, rs#20580), and GLTSCR1 exon 1 (position 20775, rs#1035938) were detected using LightCycler (Roche Molecular Biochemicals, Mannheim, Germany; Ref. 8 ). The positions refer to the following accession numbers in GenBank: RAI, L47234; CKM, AC005781; ERCC1, M63796; FOSB, M89651; SLC1A5, AC008622; LIG1, L27710; and GLTSCR1; AC010519. The rs numbers refer to National Center for Biotechnology Information’s database over SNPs, dbSNP. PCR was performed by rapid cycling in a reaction volume of 20 µl with 0.5 µM each primer, 0.045 µM anchor and sensor probe, 3.5 mM MgCl2, 7 ng of genomic DNA, and 2 µl of LightCycler DNA Master Hybridization probe buffer (Roche Molecular Biochemicals, catalogue number 2158 825). This buffer contains Taq DNA polymerase, dNTP mix, and 10 mM MgCl2. Table 1Citation shows the design of primers and fluorogenic probes for LightCycler. Some of the primers were copied from Ref. 8 . Hobolth DNA (Hillerød, Denmark) and TIB-Molbiol (Berlin, Germany) synthesized the primers and probes, respectively. In some cases, the reaction mixture also contained 5% DMSO. The temperature cycling consisted of denaturation at 95°C for 2 s, followed by 46 cycles consisting of 2 s at 95°C, 10 s at 57°C, and 30 s at 72°C. The last annealing period at 72°C was extended to 120 s. The melting profile was determined by a temperature ramp from 50°C to 95°C with a rate of 0.1 degree/s. For RAI intron 1, we ran the melting profile three times and used the last curve.


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  		Table 1 Design of primers and fluorogenic probes for LightCycler

 
Determination of Polymorphisms by Sequenator.
The polymorphisms in XRCC1 exon 7 (position 26651; Ref. 7 ), XRCC1 exon 17 (position 36189; Ref. 7 ), RAI exon 6 (position 8786, rs#6966), and XPD intron 4 (position 19244, rs#1618536) were typed simultaneously on a ABI Prism 310 sequenator (Applied Biosystems, Foster City, CA) using the SNaPshot technique (9) . The position numbers refer to the following accession numbers in GenBank: XRCC1, L34079; RAI, L47234; and XPD, L47234. The relevant primers are listed in Table 2Citation . The PCR reaction consisted of 1 µl of purified genomic DNA, 1 pmol of each primer (DNA Technology, Aarhus, Denmark), 12.5 nmol of each dNTP (Bioline, London, United Kingdom), 100 nmol of MgCl2 (Bioline), and 0.15 µl of BIOTAQ DNA polymerase (Bioline) in a total volume of 20 µl of water. The program consisted of 4 min at 96°C, followed by 25 cycles of 96°C for 30 s, 60°C for 30 s, and 72°C for 60 s. The last cycle was followed by 72°C for 6 min. The primers and dNTPs were removed in reactions containing 2 units of SAP (Roche Molecular Biochemicals), 2 units of exonuclease I (New England Biolabs, Beverly, MA), and 9 µl of PCR reaction in a total volume of 14 µl of water. The reactions were incubated at 37°C for 60 min and 72°C for 15 min. The SNaPshot reactions contained 1 µl of SNaPshot Ready Reaction Mix (Applied Biosystems), 0.5 µl of each of the SNaPshot primers (XRCC-e7-ss1, 4 pmol/µl; XPD-i5-cp1, 0.5 pmol/µl; RAI-e7-cp1, 1 pmol/µl; XRCC-e17-ss1, 2 pmol/µl), 2 µl of the purified PCR product, and 1.5 µl of buffer [200 mM Tris-HCl and 5 mM MgCl2 (pH 9.0)]. The reactions were cycled 25 times: 96°C for 10 s, 50°C for 5 s, 60°C for 30 s. The primers and dNTPs were removed in a reaction containing 1 unit of SAP, 0.8 µl of 10x SAP buffer, and 5 µl of SNaPshot reaction in a total volume of 8 µl of water. Two µl of purified product were added to 10 µl of concentrated deionized formamide (Amresco), incubated for 5 min at 95°C, and analyzed on the sequenator. The two markers in XRCC1, in exon 7 and exon 17, could not be reliably scored, and thus we excluded these.


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  		Table 2 Design of primers and SNaPshot primers for sequenator

 
Determination of Polymorphisms by Real-Time PCR Using Taqman Probes.
The polymorphism in XRCC1 exon 10 (position 28152 - A399G, Ref. 7 ) was analyzed using the ABI Prism 7700 sequence detection system (Applied Biosystems). The position refers to GenBank accession number L34079. PCR primers and Taqman probes (Table 3)Citation were designed using Primer Express v 1.0 (Applied Biosystems). TAG-Copenhagen Aps (Tagc.com, Copenhagen, Denmark) synthesized the primers, and Applied Biosystems synthesized the fluorescent Taqman probes. The reactions were performed in MicroAmp optical tubes sealed with MicroAmp optical caps (Applied Biosystems) containing a 10-µl reaction volume (1x Taqman buffer A; 2.5 mM MgCl2; 200 µM each of dATP, dCTP, and dGTP; 400 µM dUTP; 800 nM each primer; 200 nM each probe; 0.01 unit/µl AmpErase UNG; and 0.025 unit/µl AmpliTaq Gold Polymerase). Thermal cycler conditions were as follows. Tubes were incubated at 50°C for 2 min followed by 10 min at 95°C. The incubation was succeeded by 45 cycles of 95°C for 15 s and 64°C for 1 min. One sample of each genotype from a different cohort (1) previously analyzed for XRCC1 exon 10 (results not published) using restriction enzyme analysis (10) was used as reference sample.


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  		Table 3 Design of primers and probes for Taqman

 
Statistical Methods.
Data recording and tabulations as well as ANOVA analysis were performed with the program SPSS (SPSS, Chicago, IL). Fisher’s exact test was performed online.4 Bonferroni adjustment was performed online.5 A global P was calculated from the individual levels of significance (pi) using the formula:

(1)
where ln is the natural logarithm, n is the number of tests, and 2n is the degrees of freedom for {chi}2. The {chi}2-test was performed using Excel (Microsoft, Redmond, WA). The same program was used to calculate the odds ratios and related parameters. We used the program Arlequin,6 which simulates the genotype data using Markov chains, to calculate the haplotype frequencies and the Ps for linkage disequilibrium. The haplotype frequencies were then converted to Lewontin’s normalized linkage disequilibrium D’ using Excel and the formulas given online.7


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We have investigated the occurrence of the alleles of 10 new SNPs on chromosome 19q13.2–3 among Caucasian Americans with or without BCC. There is no scientific reason why we have used different techniques for typing different polymorphisms. The choices simply reflect which equipment was available to us at the times. Table 4Citation summarizes the results. Most SNPs showed no association with disease, but two markers (namely, RAI intron 1 and RAI exon 6) around the gene RAI, which is immediately 5' to XPD, showed associations with BCC. In particular, the association of the RAI intron 1A allele with cancer was fairly strong (P = 0.004; two-sided).


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  		Table 4 Genotype occurrences of various SNPs among BCC cases and controls

 
When we focused on those persons with early BCC (onset before 50 years of age), the difference in the distribution of the marker RAI intron 1 became even more pronounced (P = 0.0002; two-sided). As this would indicate, the average onset of BCC was later among cases carrying at least one RAI intron 1G allele than among those homozygous for RAI intron 1A [51.9 years (n = 10) versus 45.1 years (n = 43); P = 0.022; two-sided]. The heterozygotes also seemed to have fewer and later cases than expected. A similar analysis indicated that RAI exon 6T also was associated with reduced risk of BCC. Not surprisingly, the two markers were in linkage disequilibrium, and the protective alleles were correlated.

Table 5Citation lists the frequencies of the rare alleles in controls and in all cases as well as in young cases (<50 years at onset). It is quite clear that the RAI intron 1G allele is underrepresented in the cases, and there are suggestions that several of the neighboring SNP variants also differ in frequency between cases and controls.


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  		Table 5 Frequencies of the rare alleles of the SNPs in cases and controls

 
Calculations of odds ratios with confidence intervals and Ps for comparisons of BCC among those with two RAI intron 1A versus those with at least one RAI intron 1G are shown in Table 6Citation for both all BCC cases and early-onset BCC. Clearly, the odds ratios were less than 1, in keeping with the idea that the RAI intron 1G allele was protective. Similar calculations, where the cases and controls were subdivided according to their report of BCC occurring in their family, are shown in Table 7Citation . The association of the SNP with the risk of BCC seemed to be present irrespective of family history.


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  		Table 6 Odds ratios for the SNP RAI intron 1 and total and early BCC

 

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  		Table 7 Odds ratios for the SNP RAI intron 1 and BCC subdivided according to family history for BCC

 
We have made similar calculations for SNP RAI exon 6. Here the T allele was marginally associated with reduced risk of BCC (results not shown).

The previously reported values for DNA repair capacity (6) appeared linearly related to the marker RAI exon 6 in those persons without a family history for BCC [7.5 ± 2.2 (n = 110), 8.4 ± 2.8 (n = 37), and 9.4 ± 1.8 (n = 2) for AA, AT, and TT, respectively; P = 0.035, ANOVA]. Among those persons with a family history, there also was a relation to RAI exon 6, but it was nonlinear [8.1 ± 1.8 (n = 24), 6.4 ± 2.0 (n = 7), and 8.8 ± 0.9 (n = 2) for AA, AT, and TT, respectively; P = 0.043, ANOVA].

Table 8Citation lists the normalized linkage disequilibria between the markers in cases and controls together (this investigation and Ref. 2 ) and also lists the Ps for the linkage disequilibria. Many of the markers were in strong linkage disequilibrium. Presumably, in reality, they are located close together on chromosome 19. We have organized the markers so that strong disequilibria correspond to short distances. The map corresponds to the current National Center for Biotechnology Information map of chromosome 19.


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  		Table 8 Normalized linkage disequilibrium D’ and Ps for linkage disequilibrium among markers on chromosome 19q13.2–3 among 129 to 176 Caucasian Americansa

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present paper, we have searched for an association of BCC with 10 different SNPs on chromosome 19q13.2–3. The alleles of neighboring SNPs correlated moderately, and one or two of the SNPs were individually associated with disease.

Bonferroni adjustment is a formula that specifies how low the lowest of a series of Ps must be to make the tests as a whole significant, i.e., it is a way of correcting for mass significance when multiple tests are made. Bonferroni adjustment allows the different tests to be partly related and includes a way to correct for this by using the mean absolute correlation coefficient of the variables as a parameter. When we performed Bonferroni adjustment for the multiplicity of tests (in total, 10 tests) of variables with a mean absolute correlation coefficient of 0.14, the results indicated that any P < 0.007 would make the whole set significant at the level of 0.05. The P for an association of the marker RAI intron 1 with cancer was lower (P = 0.004), i.e., this association was still significant after correction for the multiplicity. Leaving out the correction for the correlation among the variables did not change this conclusion. We have also calculated the global P from the 10 Ps for associations between all markers and BCC using a formula (Ref. 1 ; see "Materials and Methods") that assumes no correlation between variables. The result was a global P of 0.045. Thus, either way, the result is globally significant. Moreover, using the formula (1) on early skin cancers further reduced this global P considerably (P = 0.004). Consequently, it is unlikely that our results were caused by mass significance; rather they indicate the presence of a genetic variation influencing the risk of BCC.

In a previous paper we suggested that such a causative variation influencing the risk of skin cancer should be found in the 5' end of XPD or 5' to the gene (2) . In the present paper we show that two markers next to or inside the gene RAI, located immediately 5' to XPD, are associated with risk of BCC. Thus, a total of three closely linked markers seem to confer resistance: RAI intron 1G; RAI exon 6T; and XPD exon 6C. As one would expect the three alleles associated with protection tended to occur together. Presumably, the causative gene variation is located nearby. The data suggest fairly strongly that the etiological mutation resides in a block of linkage disequilibrium that encompasses at least XPD and RAI. However, deviations from monotonicity are known to occur in maps of linkage disequilibrium, so the boundaries must be viewed with caution (11) . Neither of the polymorphisms in RAI changes protein coding. Also, we would like to point out that a slight ambiguity exists with respect to the positions of the markers RAI intron 1 and RAI exon 6. Previous maps of the region put the markers at different locations in the gene.

Our results are strong evidence that occurrence of BCC, the most common cancer among Caucasians, is genetically nonrandom. This is not at issue with the fundamental concept that carcinogenesis is a stochastic process, but it does indicate that the parameters governing this process differ between persons. Ultimately, the treatment of the majority of the population as homogeneous vis-à-vis cancer may prove fallible.

The present data, which locate a gene influencing cancer occurrence to a certain region of chromosome 19q13.2–3, only relate to BCC. However, it is likely that whatever gene variation causes the differences also influences other forms of cancer. First, many protective mechanisms against cancer are rather general in nature, e.g., DNA repair. Secondly, a number of studies of other cancer forms have also found associations of markers in this region with disease (3, 4, 5) . In this context, it should be noted that others have described evidence of a glioma tumor suppressor gene in the same general region (12) . We think this is a different gene because the present map of chromosome 19 puts it at a fair distance (13) . Neither XRCC1 nor LIG1 seems to play a role in our study.

These investigations were started with the notion that variations in nucleotide excision repair genes could influence the risk of getting cancer, and it is still quite possible that a difference in the 5' end of XPD (for instance, in a regulatory region) modulates repair. Alternatively, RAI, which is known to play a role in transcription (14) , may be involved in regulation of genes for DNA repair.

We have reported previously that the mRNA levels of XPD and ERCC1 in lymphocytes are closely correlated and also correlate with the DNA repair capacity in such cells (15) . It is intriguing that the region described here as related to occurrence of skin cancer may span regulatory regions for both genes and that a genetic variation in this region is correlated to DNA repair capacity.

Definitive identification of the causative gene will likely require sequencing of the genomic region on disease-associated versus non-disease-associated chromosomes. We have embarked on this project.


   Acknowledgments
 
We thank Thrine Schneidermann for expert technical assistance, Helle Binderup for help with the SNaPshot typing, and Dr. Olfert Landt (TIB-Molbiol) for advice on the design of probes for the LightCycler.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by The Karen Elise Jensen Foundation, the Danish Cancer Society (Grant 9810028), the Danish Medical Research Council (Grant 9600259), the Danish SUE program (Grant 9800647-67), and the Novo Nordisk Foundation. Back

2 To whom requests for reprints should be addressed, at Institute of Human Genetics, Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark. Phone: 45-8942-1686; E-mail: nexo{at}humgen.au.dk Back

3 The abbreviations used are: SNP, single nucleotide polymorphism; BCC, basal cell carcinoma; dNTP, deoxynucleotide triphosphate; SAP, shrimp alkaline phosphatase. Back

4 http://www.stat.ncsu.edu/~berger/tables.html. Back

5 http://home.clara.net/sisa/bonfer.htm. Back

6 http://lgb.unige.ch/arlequin/. Back

7 http://www.fmv.ulg.ac.be/genmol/Guelph/Linkage%20disequilibrium.htm. Back

Received 9/21/01; revised 6/25/02; accepted 7/ 3/02.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Dybdahl M., Vogel U., Frentz G., Wallin H., Nexø B. A. Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. Cancer Epidemiol. Biomark. Prev., 8: 77-81, 1999.[Abstract/Free Full Text]
  2. Vogel U., Hedayati M., Dybdahl M., Grossman L., Nexø B. A. Polymorphisms of the DNA repair gene XPD: correlations with risk of basal cell carcinoma revisited. Carcinogenesis (Lond.), 22: 899-904, 2001.[Abstract/Free Full Text]
  3. Tomescu D., Kavanagh G., Ha T., Campbell H., Melton D. W. Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma. Carcinogenesis (Lond.), 22: 403-408, 2001.[Abstract/Free Full Text]
  4. Caggana M., Kilgallen J., Conroy J. M., Wiencke J. K., Kelsey K. T., Miike R., Chen P., Wrensch M. R. Associations between ERCC2 polymorphisms and glioma. Cancer Epidemiol. Biomark. Prev., 10: 355-360, 2001.[Abstract/Free Full Text]
  5. Butkiewicz D., Rusin M., Enewold L., Shields P. G., Chorazy M., Harris C. C. Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis (Lond.), 22: 593-597, 2001.[Abstract/Free Full Text]
  6. Wei Q., Matanoski G. M., Farmer E. R., Hedayati M. A., Grossman L. DNA repair and aging in basal cell carcinoma: a molecular epidemiology study. Proc. Natl. Acad. Sci USA, 90: 1614-1618, 1994.[Abstract/Free Full Text]
  7. Shen M. R., Jones I. M., Mohrenweiser H. Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res., 58: 604-608, 1998.[Abstract/Free Full Text]
  8. Wittwer C. T., Ririe K. M., Andrew R. V., David D. A., Gundry R. A., Balis U. J. The LightCyclerTM: a microvolume multisample fluorimeter with rapid temperature control. Biotechniques, 22: 176-181, 1997.[Medline]
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  10. Lunn R. M., Langlois R. G., Hsieh L. L., Thompson C. L., Bell D. A. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res., 59: 2557-2561, 1999.[Abstract/Free Full Text]
  11. Taillon-Miller P., Bauer-Sardiña I., Saccone N. L., Putzel J., Laitinen T., Cao A., Kere J., Pilia G., Rice J. P., Kwok P-Y. Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nat. Genet., 25: 324-328, 2000.[Medline]
  12. Rosenberg J. E., Lisle D. K., Burwick J. A., Ueki K., von Deimling A., Mohrenweiser H. W., Louis D. N. Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval. Oncogene, 13: 2483-2485, 1996.[Medline]
  13. Smith J. S., Tachibana I., Pohl U., Lee H. K., Thanarajasingam U., Portier B. P., Ueki K., Ramaswarmy S., Billings S. J., Mohrenweiser H. W., Louis D. N., Jenkins R. B. A transcript map of chromosome 19q-arm glioma tumor suppressor region. Genomics, 64: 44-50, 2000.[Medline]
  14. Yang J. P., Hori M., Sanda T., Ohamoto T. Identification of a novel inhibitor of nuclear factor-{kappa}B, RelA-associated inhibitor. J. Biol. Chem, 274: 15662-15670, 1999.[Abstract/Free Full Text]
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