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Effects of Cyclin D1 Polymorphism on Age of Onset of Hereditary Nonpolyposis Colorectal Cancer¹

Departments of Epidemiology [S. K., C. I. A., M. L. F], Pathology [R. L.], and Gastrointestinal Medical Oncology and Digestive Diseases [P. M. L., B. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

	ABSTRACT

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A common polymorphism in the cyclin D1 gene enhances the gene’s alternate splicing. The alternatively spliced product encodes an altered protein that does not contain sequences involved in the turnover of the protein. We found that hereditary nonpolyposis colorectal carcinoma patients who were homozygous or heterozygous for the mutant allele developed colorectal cancer an average of 11 years earlier than patients who were homozygous for the normal alleles. This is the first report indicating that the cyclin D1 polymorphism influences age of onset of cancer. Because cyclin D1 plays an important role in the G₁ to S phase transition of the cell cycle, our findings suggest that cells with the mutant allele accumulate mutations as a result of defective mismatch repair and may also bypass the G₁-S checkpoint of the cell cycle more easily than in cells not carrying the polymorphism. The polymorphism has a dominant phenotype.

	Introduction

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HNPCC³ is caused by germ line mutations in the DNA MMR genes hMSH2, hMLH1, hPMS1, hPMS2, and hMSH6 (1, 2, 3, 4, 5, 6) . The cells of HNPCC carriers are thought to be MMR-proficient, having one mutant allele and one normal allele. During tumor development, the normal allele is lost or mutated (7) , causing the cells to become MMR deficient. As a result, mutations begin to accumulate in the cells, some of which contribute to tumorigenesis.

There is a significant variation in the age of onset of cancer in HNPCC (8 , 9) . The cause of this variation in not known, but it may be due to a combination of genetic and environmental factors. One possible modifier of HNPCC age of onset is cyclin D1, which is involved in both normal regulation of the cell cycle and neoplasia (10) . Cyclin D1 reaches maximal activity during the G₁ phase, in which it plays an important role in the transition from the G₁ phase to the S phase of the cell cycle. Amplification or overexpression of the cyclin D1 gene is common in a variety of different cancers and induces proliferation. The cyclin D1 gene has a G to A polymorphism at codon 242 in exon 4 that increases alternate splicing (11) . However, both the G and the A alleles can produce the alternate transcript arising from the altered splicing. Both the normal and the altered transcripts encode a protein that contains the amino acids (55–161) thought to be responsible for the cyclin D1 function (12) , but the protein encoded by the alternate transcript may have a longer half-life (11) . The A allele is associated with poorly differentiated histology in patients with squamous cell carcinoma of the head and neck (13) . It also has been shown to lead to poorer clinical outcome in patients with squamous cell carcinoma and non-small cell lung cancer (11 , 13) .

The purpose of this study was to determine the association between age of onset in HNPCC subjects and the cyclin D1 genotype. To our knowledge, this is the first study showing that this polymorphism influences age of onset of any cancer.

	Materials and Methods

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Subjects.
We studied a series of 86 mutation carriers from families with HNPCC. Forty-nine of these were colorectal cancer cases and 37 were unaffected carriers. Fifty-seven had hMSH2 gene mutations, 28 had hMLH1 gene mutations, and 1 had a PMS1 mutation. There were 46 truncating mutations and 40 missense mutations. Informed consent was obtained from all of the patients. Age of onset of cancer was defined as the patient’s age at diagnosis. The patients’ demographic data are listed in Table 1 .

PCR and SSCP Analysis.
PCR and SSCP analyses were used to genotype the A/G CCND1 polymorphism in exon 4. PCR fragments were generated from 50 ng of genomic DNA in a 20-µl reaction mixture containing 50 mM KCl; 10 mM Tris-HCl (pH 8.5); 1.5 mM MgCl₂; 0.2 mM dATP, dGTP, and dTTP; 0.1 mM dCTP; 20 pM each primer; 1 µCi of [³²P]dCTP (3000 Ci/mmol); and 1.0 unit of Taq polymerase (Perkin-Elmer Cetus, Norwalk, CN). The PCR was performed for 10 min at 94°C followed by 28 cycles at 94°C for 30 s, 65°C for 30 s, and 72°C for 1 min, and a final extension step at 72°C for 10 min. The PCR primer sequences used were 5'-TACTACCGCCTCACACGCTTCC-3' (primer 1) and 5'-TTGGCACCAGCCT CGGCATTTC-3' (primer 2).

For SSCP analysis, 4 µl of PCR products were mixed with an equal volume of loading buffer containing 95% formamide, 20 mM EDTA, 0.05% xylene cyanol, and 0.05% bromphenol blue; heated at 95°C for 5 min; and quickly chilled on ice for at least 5 min. Four µl were separated on mutation detection enhancement gels, prepared according the manufacturer’s instructions (FMC BioProducts, Rockland, ME), except that the gel solution was diluted 1:4 and adjusted to 1x TBE. The running buffer was also 1x TBE. The gels were vacuum-dried and then subjected to autoradiography.

DNA Sequencing Analysis.
DNA sequencing analysis was used to determine the cyclin D1 genotypes of the three different patterns seen by SSCP analysis. The PCR fragments were amplified in a 30-µl reaction mixture with primer 3 (5'-GTGAAGTTCATTTCCAA TCC-3') and primer 2. The PCR products were mixed with 20 units of exonuclease 1 and 4 units of shrimp alkaline phosphatase and incubated at 37°C for 15 min and then at 85°C for 15 min to remove the large amount of unused primers and residual dNTPs. The products were subjected to electrophoresis in 1.5% agarose gels in 1x TBE. Ethidium bromide was used to visualize the PCR products and to determine the fragment length and concentration. The DNA sequences of PCR products were determined by using primer 3 with an Applied Biosystems model 377 sequencer.

Statistical Analysis.
To analyze the data, we defined age of onset for colorectal cancer as the outcome, and the cyclin D1 genotypes, sex, ethnic group, and MMR gene mutation type as independent variables. We used descriptive methods such as histogram comparisons and evaluation of means and medians to determine whether there were any associations between cyclin D1 genotypes, MMR gene mutations, and age-associated risk. We tested the association between age of onset and cyclin D1 genotype by comparing the Kaplan-Meier survival curves by genotype (Life test, SAS, 1992). The log-rank test and Wilcoxon’s test were used to evaluate the homogeneity of the survival curves by genotype. We also used Cox’s proportional hazard regression analysis to estimate the association between colorectal cancer risk and cyclin D1 genotypes, adjusting for potential confounding factors from demographic factors. Hazard ratios and 95% confidence intervals were calculated from the Cox regression analysis to determine the direction and strength of the association.

	Results

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Subjects’ Characteristics.
Of the 86 study subjects, 42 were male and 44 were female. The sex distribution was almost equal in both colorectal cancer cases (25 males and 24 females) and unaffected carriers (17 males and 20 females). The mean age of onset was 43.3 years and the median age of onset was 40.0 years (Table 1) .

Survival and Type of MMR Gene Mutation.
Because all but one of our cases had mutations in either the hMSH2 or hMLH1 gene, we performed survival analysis comparison by genetic cause that was restricted to exclude the family with the PMS1 germ line mutation. There was no significant difference between age at onset of the subjects with hMLH1 mutations and subjects having hMSH2 mutations as assessed by the log-rank test (P, 0.94). Similarly, we did not observe differences in age-associated risk between missense mutations and truncating or deletion mutations when the data were analyzed by the same survival-analysis procedures (P, 0.70; data not shown).

Cyclin D1 Genotyping.
A 138-bp PCR fragment was generated, and three different genotypes were distinguished by PCR-SSCP analysis. The cyclin D1 genotyping was confirmed by DNA sequencing analysis. Our samples displayed the patterns shown in Fig. 1 . The allele frequencies in all of the study subjects (A, 0.45; G, 0.55), the colorectal cancer cases (A, 0.46; G, 0.54), and the MMR carriers (A, 0.44; G, 0.56) were similar to those observed by Betticher et al. (11) in 22 Europeans (A, 0.42; G, 0.58) and to a series of 45 blood bank donors of unknown ethnicity (A, 0.55; G, 0.45) that we studied. Of all of the study subjects, 22.1% were GG, 66.3% were AG, and 11.6% were AA. The percentages in cases and carriers were somewhat different: 18.4% GG, 73.4% AG, and 8.2% AA in cases, and 27.0% GG, 56.8% AG, and 16.2% AA in the carriers. The affected individuals showed fewer AA genotypes than expected, and the population was not in Hardy-Weinberg equilibrium (₁², 11.61; P, 0007), but the carriers were in Hardy-Weinberg equilibrium (₁², 0.83; P, 0.3608).

View larger version (40K): [in this window] [in a new window]   Fig. 1. Representative screening for the cyclin D1 genotypes. A, patterns detected for each of the three genotypes AG, AA, and GG, when screened by SSCP analysis. B, results of nucleotide sequence analysis that allowed us to determine the genotype for each of the patterns. Arrows, the location of the nucleotide at which the polymorphism occurs.

View larger version (17K): [in this window] [in a new window]   Fig. 2. Kaplan-Meier survival analysis. A, plot of age-of-onset of colorectal cancer for each of the three genotypes of the cyclin D1 polymorphism; B, plot of time to onset of colorectal cancer for the GG genotype relative to the AA and AG genotypes combined.

	Discussion

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We found that a cyclin D1 polymorphism that increased altered splicing of the cyclin D1 RNA seemed to have a major influence on the age of onset of HNPCC. There is no difference between age of onset for hMLH1 mutation carriers and hMSH2 mutation carriers (P, 0.94), any difference in age of onset between mutations carriers with truncating mutations and missense mutation (P, 0.70). The median age of onset of colorectal cancer in our series of patients was 40, similar to the median age of 42 for cancer onset described by Kinzler and Vogelstein (15) .

Our findings demonstrated that the cyclin D1 AG and AA genotypes predispose MMR gene mutation carriers to develop cancer approximately 10 years earlier than patients with the GG genotype. The effect of the cyclin D1 A allele was dominant because the increased age-associated risk was seen in patients with both the AA and the AG genotypes. By using the Cox model, we showed that patients with the AA or AG genotype were 2.46 times more likely to develop colorectal cancer at any age than were patients with the GG genotype.

The mechanism by which the cyclin D1 A allele enhances carcinogenesis in cells with a defective MMR pathway is not known. Alternate splicing of the cyclin D1 RNA is enhanced for transcription products of the A allele. This results in an altered protein that lacks the PEST-rich region (16) ; if that increases the half-life of the protein, it could increase the steady-state levels of the protein in patients with the AA and AG genotypes, which may allow cells that are damaged as a result of defective MMR to pass through the G₁-S phase checkpoint more easily. This would allow them to proliferate rather than to undergo apoptosis.

It is also possible that other as-yet-unidentified mechanisms may be responsible for the observation that the cyclin D1 allele decreases the age of onset of colorectal cancer in HNPCC. For example, there could be a direct or indirect interaction between cyclin D1 and the MMR pathway.

The cyclin D1 polymorphism is an important predictor of age-associated risk for development of colorectal cancer in HNPCC patients. Our findings, combined with the identification of additional risk factors—both environmental and genetic—will be important in identifying families that are more susceptible to developing colorectal carcinoma at an earlier age and may provide important information for preventative strategies. The cyclin D1 gene itself may be an important target for chemopreventive strategies.

	Acknowledgments

 
We thank Frederick O’Donnell and Maureen Goode for their editorial comments.

	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 Grant CA70759 from the National Cancer Institute and by NIH Cancer Center Support Grant CA16672.

² To whom requests for reprints should be addressed, at Box 189, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-6169; Fax: (713) 745-1163.

³ The abbreviations used are: HNPCC, hereditary nonpolyposis colorectal cancer; MMR, mismatch repair; SSCP, single-stranded conformation polymorphism,. TBE, Tris-borate-EDTA [2 mM EDTA, 100 mM boric acid, and 100 mM Tris (pH 8.3)].

Received 10/ 7/99. Accepted 12/ 1/99.

	REFERENCES

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