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Carcinogenesis, Vol. 21, No. 7, 1297-1301, July 2000
© 2000 Oxford University Press

Cancer Biology

Allelotype analysis of chemically induced squamous cell carcinomas in F1 hybrids of two inbred mouse strains with different susceptibility to tumor progression

Mariana C.Stern1, Fernando Benavides, Eric A.Klingelberger and Claudio J.Conti2

The University of Texas, M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA
1 Present address: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
Email: sa83125{at}odin.mdacc.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Loss of heterozygosity (LOH) at specific chromosomal loci is generally considered indirect evidence for the presence of putative suppressor genes. Allelotyping of tumors using polymorphic markers distributed throughout the entire genome allows the analysis of specific allelic losses. In the field of chemical carcinogenesis, the outbred SENCAR mouse has been commonly used to analyze the multistage nature of skin tumor development. In the study reported here we generated F1 hybrids between two inbred strains (SENCARB/Pt and SSIN/Sprd) derived from the SENCAR stock that differ in their susceptibility to tumor progression. We typed 24 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate-induced squamous cell carcinomas for LOH using 56 microsatellite markers distributed among all autosomal chromosomes. The highest percentage of LOH, 78%, was found on chromosome 7, but there was no preferential loss of one particular allele, indicating that the putative suppressor genes found in this area are not involved in genetic susceptibility. High levels of LOH were also found on chromosomes 16 (39%), 6 (29%), 4 (25%), 9 (25%), 14 (22%), 10 (20%) and 19 (20%), but with no preferential loss of the alleles of one strain. The chromosomal regions with LOH on mouse chromosomes 4, 6, 7, 9, 10, 14, 16 and 19 correspond to regions in the human genome where LOH has been reported and have been suggested to harbor tumor suppressor genes.

Abbreviations: DMBA, 7,12-dimethylbenz[a]anthracene; LOH, loss of heterozygosity; SCC, squamous cell carcinoma; TPA, 12-O-tetradecanoylphorbol-13-acetate.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Loss of heterozygosity (LOH) or allelic imbalances at specific chromosomal loci is generally considered indirect evidence for the presence of putative tumor suppressor genes (1). Animal models specifically designed to study the development of a particular tumor type are an ideal tool for LOH studies. The use of F1 hybrids for LOH studies has the advantages that a large number of tumors can be obtained under standard conditions and that crosses can be arranged to maximize the number of polymorphic markers (2). In the field of chemical carcinogenesis the outbred SENCAR mouse has been commonly used to analyze the multistage nature of skin tumors. Previous studies from our laboratory showed that in this model during skin tumor progression there is a sequential trisomization of chromosomes 6 and 7 (3) with a high frequency of LOH at loci distal to the Ha-ras-1 gene on mouse chromosome 7 (4,5). Unfortunately, the lack of a large number of polymorphic markers at that time and the fact that not all squamous cell carcinomas (SCCs) are informative at the loci of interest precluded the extension of these findings. Later studies by Kemp and et al. (6) using (SENCARxBALB/c)F1, [129P2xN:NIH (S)]F1, [N:NIH (S)xMus spretus]F1 and (CBAxMus spretus)F1 mice showed that most of the SCCs analyzed had allelic imbalances throughout chromosomes 6, 7 and 11. Allelic losses on chromosome 6 were also described by our laboratory using (C57BL/6xDBA/2)F1 hybrids (7).

Our laboratory has been characterizing various inbred lines derived from the outbred SENCAR stock and analyzing their differences in susceptibility to tumor progression (8–11). Using the SSIN/Sprd and SENCARB/Pt mice, both inbred strains derived from the outbred SENCAR stock that dramatically differ in their susceptibility to skin tumor progression (10,12,13), we determined that tumor progression is under genetic control and we have been working on the description of a genetic model and mapping of putative susceptibility genes (M.C.Stern, F.Benavides, M.LaCava and C.J.Conti, in preparation). We screened the SSIN/Sprd (resistant for tumor progression) and SENCARB/Pt (susceptible for tumor progression) mice with 453 microsatellite markers and found that 132 were polymorphic, with an average of 30% polymorphic loci (F.Benavides, M.C.Stern, E.Glasscock, L.G.Coghlan and C.J.Conti, in press). The goal of the present study was two-fold: to determine the relevant genetic alterations in mouse skin carcinogenesis with the SENCAR background and to determine whether there was a consistent loss of alleles from either strain, which could suggest the presence of putative susceptibility genes.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
SENCARB/Pt and SSIN/Sprd mice were obtained from the University of Texas M.D.Anderson Cancer Center, Science Park-Veterinary Division (Bastrop, TX). Six-week-old F1 hybrid mice (both reciprocal crosses) were shaved 1–2 days before initiation with 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA) and promoted 2 weeks after with twice weekly applications of 0.5 µg of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. A final incidence of 60% SCC was observed among F1 hybrid mice. Tumors were fixed in formalin and confirmed histologically with hematoxylin and eosin staining. All SCC were histopathologically staged following the classification described by Aldaz et al. (14). Briefly, SCCs were defined as (I) well-differentiated, (II) differentiated, (III) poorly differentiated or (IV) spindle cell carcinomas. A total of 24 stage I or II SCCs were selected and used for LOH analysis. Tumor DNA was extracted from four to six 6 µm thick consecutive sections of SCC samples cut from paraffin-embbeded tissue and microdissected to remove non-neoplastic tissue. Slide sections were deparaffinized with xylene followed by 100% ethanol rinses. Dried samples were resuspended in 200–300 µl aqueous 5% CHELEX solution (Bio-Rad Laboratories, Richmond, CA) and incubated at room temperature for 15 min. Proteinase K (Sigma Chemical Co., St Louis, MO) was added to 0.2 µg/µl, with 1 h incubation at 55°C. Proteinase K was inactivated by boiling samples for 10 min. All tumors were typed by PCR using a panel of microsatellite repeats as described in Table IGo. Primers were obtained from Research Genetics (Huntsville, AL). PCR was performed with 200 ng of DNA in a final volume of 25 µl containing 1x Taq polymerase reaction buffer, 200 µM each dNTP, 180 µM each primer and 0.6 U AmpliTaq polymerase (Perkin Elmer, Foster City, CA). A touchdown PCR protocol from 65 to 55°C for a maximum of 35 cycles was used. The number of cycles used was in the linear part of the amplification process, which allowed us to assume equal amounts of PCR products for each allele if no LOH had occurred. PCR products were resolved in 3.5–5% MetaPhor gels (FMC, Rockland, ME) or non-denaturing 8–10% polyacrylamide gels and stained with ethidium bromide. LOH was scored by comparing the results of each SCC sample with standards that contained either 100% SSIN, 100% SENCARB/Pt or 50% SSIN–50% SENCARB/Pt. LOH was assigned whenever there was 50–100% loss of any one of the two alleles. For several critical markers PCR was repeated and analyzed by a different person to validate our results. For some samples, sensitivity was improved using Vistra Green staining (Amersham International, Little Chalfont, UK) with a FluorImager apparatus (Molecular Dynamics, Sunnyvale, CA) and the intensity of the bands analyzed with IQ Mac 1.2 software (Bio Image, Ann Arbor, MI). Human homology and mapping information were retrieved from the Mouse Genome Database (October 1999; The Jackson Laboratory, Bar Harbor, MA).


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  		Table I. Percentage LOH for each microsatellite marker used
 

   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Table IGo shows the percentage of LOH found for the 56 microsatellite markers analyzed in all 24 DMBA-induced SCCs. Eleven of the SCCs were histopathologically classified as well-differentiated lesions and 12 as differentiated lesions. There were no statistically significant differences in the average total percentage of LOH per sample between these two groups (P = 0.852, Student's t-test). The quality of tumor DNA precluded genotyping of some of the markers; the number of SCCs that were analyzed for each marker is included in Table IGo. All samples analyzed had LOH in at least one chromosome with at least 6% LOH at one of the 19 autosomal chromosomes, an average percentage LOH of 18% and a maximum of 30%. The maximum number of chromosomes affected per SCC was five, with 8% of the samples having only one affected chromosome, 17% having two, 63% having three, 4% having four and 8% having five. We observed that in 33% of the SCCs chromosomes 6 and 7 were affected in the same sample, while 42% of the SCCs had LOH on chromosome 7 together with chromosomes other than 6. The highest percentages of LOH were found at D7Mit223 (52%) and D7Mit37 (42%). Chromosome 16 also had one marker with a high incidence of LOH, D16Mit71 (41%). When we analyzed the percentage of SCCs with any allelic loss in each chromosome, we found that the chromosomes most commonly affected were chromosome 7 (78% of LOH) followed by chromosomes 16, 6, 4 and 9 (39, 29, 25 and 25% of tumors, respectively, with LOH) (Figure 1Go). Chromosomes 14, 10 and 19 had 22, 20 and 20% of tumors, respectively, with LOH. Chromosomes 8, 12 and 15 were not affected in any of the samples.



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  		Fig. 1. Percentage of SCCs with LOH at each chromosome.

 
We did not find consistent losses of allelles of one particular strain for any of the chromosomes studied, suggesting that these loci do not play a role in skin tumor progression susceptibility in these strains. In total, there were 106 allele losses, 53 being SENCARB/Pt and 53 SSIN/Sprd alleles. Furthermore, there were no consistent losses of one particular allele for chromosome 7, the chromosome with the highest percentages of LOH (Figure 2Go). Of the 144 PCRs performed with the six microsatellite markers that map to chromosome 7 and the 24 SCC samples, 7% did not amplify, 59% revealed heterozygosity, 15% revealed loss of the SENCARB/Pt allele and 19% revealed loss of the SSIN allele. In only two samples, SCC 5 and SCC 14, was there a consistent loss of one allele, in both cases the SSIN/Sprd allele, suggesting loss of one entire chromosome by non-disjunction, given the distribution of the markers. In the rest of the samples the most likely mechanism of LOH was somatic recombination or deletion.



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  		Fig. 2. Schematic representation of mouse chromosome 7 showing percentage LOH found at each locus studied and homologies with the human genome. Solid black bars indicate total percentage of LOH found at each locus analyzed. Solid white bars and striped bars indicate the percentages of SSIN and SENCAR B/Pt alleles, respectively, lost for each microsatellite marker analyzed.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
This is the first study done on SENCAR-derived strains that describes the possible involvement of other chromosomes besides 6 and 7 in the development of SCC and the analysis of allelic imbalances in two inbred SENCAR-derived strains. These strains have become promising tools in future studies in mouse skin carcinogenesis given their inbred condition and their different and well-characterized susceptibility to tumor progression (10). In most cases we found that those regions with LOH corresponded to syntenic regions in the human genome where LOH has been reported in a variety of tumors (Table IIGo). In particular, both areas of mouse chromosome 7 with high LOH are syntenic to human chromosome 11, where at least one tumor suppressor gene has been suggested (15–19). It was shown that in head and neck SCC not only is 11q13 the most frequent breakpoint but also that this aberration is a crucial determinant of tumor aggressiveness (20). The previous data reported by our laboratory (5) and our present findings strongly suggest that there are at least two tumor suppressor genes involved in mouse skin tumor development on the distal part of mouse chromosome 7. However, given that the H-ras gene maps at 72.2 cM, close to D7Mit223 (72.4 cM) where we found 52% LOH, it cannot be discarded that losses at this site could reflect a selection for cells that lost the wild-type H-ras allele, rather than loss of a tumor suppressor gene. Analysis of LOH on mouse chromosome 6 on (C57BL/6xDBA/2)F1 hybrids treated with a two-stage DMBA–TPA protocol (7) showed that LOH occurred most frequently at two sites: D6Mit50 (3 cM), syntenic to human chromosome 7; D6Mit29 (36.5 cM), syntenic to human chromosome 2. In the study reported here we also found two regions with LOH: D6Mit138, syntenic to human 7q21.3–q22; D6Mit39, syntenic to human 3p26–p24, a common region of deletions and allelic losses in human tumors (Table IIGo). Chromosome 9 has been implicated in mouse islet cell tumors, where a putative suppressor gene, Loh1, has been mapped relatively close (53 cM) to D9Mit20 (61 cM), where we found 16% LOH. This LOH1 marker shows a low rate of LOH in early stages of tumor formation but higher in the angiogenic islets (the end tumors), suggesting a role in tumor progression (21). Interestingly, this region of human chromosome 9 is the only one that showed frequent LOH in both our study and an analysis of its syntenic region in human cutaneous SCC (22). The area of chromosome 16 where we found quite a high percentage of LOH has not been reported in other mouse studies. However, losses and translocations in the human syntenic region, 21q22, have been reported in several other tumors (Table IIGo). Other studies have found evidence of involvement of chromosome 4 in other mouse tumor models. Chemically induced mouse mammary tumors with acquired autonomous growth showed a high frequency of LOH in chromosome 4 (23). Two studies in mouse lung tumors found frequent allelic losses in this chromosome, including the region syntenic to human 1p (24,25). Interestingly, LOH on chromosomes 10 and 19 have never been reported before in mouse skin carcinogenesis. However, LOH at the corresponding human syntenic regions has been reported for different tumor types (Table IIGo).


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  		Table II. Summary of markers found with LOH and their respective syntenic regions in the human genome where LOH has been reported in different cancer types
 
The results of this genome-wide scan for LOH in mice with a common SENCAR origin will help analyze the role of critical chromosomes involved in the development of SCC, such as 4, 6, 7, 9, 10, 14, 16 and 19. This information will increase our knowledge of the genetics of skin carcinogenesis in such useful animal models as the outbred SENCAR mouse and its derivative inbred lines.


   Notes
 
2 To whom correspondence should be addressed


   Acknowledgments
 
We would like to thank the Histology Service of Science Park-Research Division for processing the samples, Ms Melissa Bracher for secretarial assistance and Dr Maureen Goode from the Department of Scientific Publications for editing this manuscript. We are also very grateful to Dale Weiss, Pam Kille, Donna Schutz, Jimi Lynn Rosborough and April Ott for their assistance with animal handling and care. This work was funded by NIH grants CA 57596, CA 69146 and CA16672 and NIEHS grant ES007784.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received November 2, 1999; revised March 6, 2000; accepted March 15, 2000.


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