(CANCER RESEARCH 52, 1494-1498, March 15, 1992]

Loss of Heterozygosity at Chromosome Iq22 in Basal Cell Carcinomas andExclusion of the Basal Cell Nevus Syndrome Gene from This Site1

John W. Bare, Roger V. Lebo, and Ervin H. Epstein, Jr.2

Department of Dermatology, San Francisco General Hospital [J. W. B., E. H. E., Jr.], and Departments of Obstetrics and Gynecology, and Pediatrics, University ofCalifornia [R. K L.], San Francisco, California 94143

ABSTRACT

Basal cell carcinomas, the most common human tumors, generallyappear sporadically and in small numbers. Rarely, they may appear ingreat numbers and at an earlier age as a manifestation of the basal cellnevus syndrome, an autosomal dominant inherited disorder. Drawing onthe retinoblastoma paradigm, we have begun a search for tumor suppressor genes important in the development of basal cell carcinomas bycomparing DNA of tumors and normal cells. Loss of heterozygosity, afrequent marker of the site of tumor suppressor genes, was found atchromosome Iq in one-third of the tumors studied. However, comparison

of the inheritance of DNA markers versus the inheritance of the basalcell nevus syndrome in one large kindred excluded this area of chromosome Iq as the site of the gene whose abnormality causes this hereditarydisease. These data suggest that large deletions may accompany thedevelopment of cutaneous, low grade tumors just as they accompany thedevelopment of visceral, high grade cancers.

INTRODUCTION

During the past 15 years, it has become clear that geneticchanges underlie the conversion of cells from the normal to themalignant state. The best-studied such alterations have beenmutations causing activation or amplification of dominantlyacting oncogenes—genes whose products drive the cell to excessproliferation, invasion, etc. More recently, the existence of asecond class of genes important in carcinogenesis has becomeobvious. These are the tumor suppressor genes, whose normalproducts slow cellular proliferation and/or enhance cellulardifferentiation. Unlike the first type of oncogene, it is the lossof function of both alíelesof these genes, not the alteredfunction of one alíele,that causes the cell to become malignant(1).

The prototype of such a tumor suppressor gene is the retinoblastoma gene (2). Loss of functional retinoblastoma geneproduct is a crucial step in the development of this childhoodocular cancer and indeed may be the necessary and sufficientrequirement. Mutation of both copies of the gene may occursomatically, or one defective alíelemay be inherited, in whichinstance only a single mutation need occur somatically (3).Disease in the hereditary form is inherited as an autosomaldominant trait and is characterized clinically by earlier age ofonset and by the frequent occurrence of multiple independenttumors.

One common mechanism for loss of a tumor suppressor geneis the physical deletion of a large part of a chromosome onwhich such a gene resides (4). Such large scale deletion providesa large "target" for molecular biological analysis, e.g., by corn-

Received8/19/91;accepted12/27/91.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 inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1This investigation was supported in part by NIH Grants AR39953 (to E. H.

E., Jr.) and NS25541 (to R. V. L.) and a grant from the University of CaliforniaCancer Coordinating Committee (to E. H. E., Jr.). This work was published inpan in abstract form (Clin. Res., 38: 221A, 1990).

2To whom requests for reprints should be addressed, at: Room 269, Building

100, San Francisco General Hospital, 1001 Potrero Street, San Francisco, CA94110.

parison of restriction fragment length polymorphisms in DNAfrom the patient's normal and tumor cells. If the normal DNA

is heterozygous for such a marker, deletion of one alíeleconverts the pattern of heterozygosity to one of hemizygosity (or,if there is duplication of the retained segment, to homo/.ygos-ity). Such loss of heterozygosity in tumor cells suggests that atumor suppressor gene lies in the deleted segment, and suchloss of heterozygosity has pointed the way to cloning of tumorsuppressor genes on chromosomes 1Ip (5, 6), 17p (7), and 18q(8), as well to cloning of the retinoblastoma gene (9-11).

BCCs3 are by far the most common human cancer, occurring

in some populations as commonly as all other cancers combined. Like patients with sporadic retinoblastomas, patientswith sporadic BCCs generally develop only one (or a few) BCCsand do so at a relatively advanced age. As with retinoblastomas,there also are kindreds in which patients develop multiple BCCsat an early age, and this trait is inherited as an autosomaldominant disease—the BCNS (McKusick no. 10940). In addition to developing multiple, early onset BCCs, patients withBCNS also have palmar and plantar pits, keratocysts of thejaw, skeletal abnormalities, and various extracutaneous tumors(12).

Drawing on the retinoblastoma model, we have begun aneffort to find the gene whose abnormality leads to the BCNSby searching for loss of heterozygosity in BCCs in the hopethat regions involved in loss of heterozygosity would identifycandidate regions for linkage analysis and would indicate regions in which a tumor suppressor gene important in BCCdevelopment might be found. To start, we have examined BCCDNA for loss of heterozygosity in regions in which such losshas been reported in other tumors and have performed linkageanalysis in a large kindred with BCNS in regions of loci thatmight be considered candidate genes for this disease. Specifically, weak linkage has been reported with chromosome Iqmarkers (13), and one family has been reported in which thereis apparent co-segregation of BCNS and Charcot-Marie-Toothdisease (14), autosomal forms of which have been linked tochromosomes Iq (15), 17p (16-18), and 19q (19). Hence, wehave performed linkage analysis in these 3 regions.

MATERIALS AND METHODS

Patient Samples. Cutaneous lesions with the clinical appearance ofBCCs were removed by curettage rather than by sharp dissection so asto minimize the admixture of normal cells. Sclerotic BCCs were notused. If not previously confirmed histologie ally, a portion of the tumorwas taken for histopathological examination, and the remainder wasfrozen. Blood samples were anticoagulated with EDTA and storedfrozen in plastic tubes. DNA was extracted from blood by standardtechniques and from tumors as follows: frozen tumors were minced onice; incubated at 4'C for 20 min in 320 mM sucrose, 5 mM MgCl2, 1%

(v/v) Triton X-100, 10 mM Tris, pH 7.5; and then centrifuged at 2500x g for 10 min. The pellet was suspended in 4.25 ml 75 mM NaCl, 25mM EDTA, pH 8.0, containing 0.5% sodium dodecyl sulfate and

3The abbreviations used are: BCC, basal cell carcinoma; BCNS, basal cell

nevus syndrome.

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BASAL CELL CARCINOMA: LOSS OF HETEROZYGOS1TY

Table 1 Loss of heterozygosity in basal cell carcinomas

Chromosome location

Loss of heterozygosityNo. lost/no, heterozygous 4/21% lost 19

Iq22 Iq32 llplS 17pl3.3

7/2133

2/1613

1/128

2/1118

"Loci assessed were lp-DlS57andNGFB, lq22-MUCl, lq32-DlS65, llplS-HRAS,andl7pl3.3-D17S5.

proteinase K, 200 ^g/ml, and incubated with gentle shaking for 18 h at55'C. If solubilization was visibly incomplete, more sodium dodecyl

sulfate:NaCl:EDTA solution was added, and the incubation was continued for another 2-6 h. The solution was extracted with an equal volumeof phenol, of phenol:chloroform:isoamyl alcohol (25:24:1), and ofchloroform:isoamyl alcohol (24:1). The aqueous phase was transferredto a fresh tube, and 0.1 volume of 3 M sodium acetate, pH 7.0, and 2volumes of ethanol were added. After inversion to mix, DNA wasremoved with a sterile needle. Higher yields of DNA were obtained ifthe aqueous phase was centrifuged after incubation for 18 h at -20*C,

but the DNA was of lower molecular weight and was considerablycontaminated with RNA. Hence, it was used only with tumors of 2-4-mm diameter, from which only 50 fig of DNA could be recovered.Larger tumors, however, often yielded more than 1 mg of DNA. Yieldsof DNA were not enhanced by pretreatment of minced tumors withcollagenase and/or trypsin-EDTA.

This study was approved by the University of California San Francisco Committee on Human Research, and informed consent wasobtained from all subjects prior to their participation.

DNA Analysis. DNA was digested with restriction endonucleasesaccording to the manufacturers' instructions, separated by electropho-

resis in agarose, and transferred to sheets of Hybond-N (AmershamCorp.) or Immobilon-N (Millipore Corp.). Loci studied (probe/restriction enzyme used) were as follows: D1S57 (pYNZ2/A/spI), NGFB(N8C6/ßg/II),D1S90 (RL-3/A/spI), MUC1 (pMUClO/Hinfl), SPTA1(3021El/MspI), FCG2(FCGII cDNA/T^I), D1S61 (pMLAJl/tf/n/I),D1S66 (pHBI40/MjpI), AT3 (pAT3c/ft/I), D1S65 (pEKH7.4/7a9l),HRAS (pUC EJ 6.6/flamHI), D17S5 (pYNZ22.1/Mj/?I), D17S71(pAlO-41/MspI), D19S8 (pll.\/Mspl), and APOC2 (pCII-71 \/Taq\).Probes were generous gifts of B. Forget (3021 El), S. Gendler(pMUCIO), K. Moore (FCGII cDNA), Y. Nakamura (pYNZ2,pHBI40, and pEKH7.4), and R. White (pMLAJl) or were obtainedfrom The American Type Culture Collection, Rockville, MD. In eachinstance, the band patterns corresponded to those described in theliterature (20, 21). Linkage analysis was performed with LIPED.

deletions using multiple probes from this area indicated theshortest overlapping region of deletion between the genes forpeanut urinary mucin (MUC1) and for FCG2 (Fig. 2), a distance estimated at approximately 20 centimorgans (22). Usingprobes identifying the 5 polymorphic sites, we detected loss ofheterozygosity only at chromosome Ip in each of 2 tumorsfrom BCNS patients and at no site in the tumor from the thirdBCNS patient. We observed no preferential loss of larger orsmaller bands.

Linkage Analysis in BCNS. Blood samples were obtainedfrom 53 members of a large kindred (Mi) with BCNS (Fig. 3).A portion of this kindred, which is unusual in that both BCNSand inflammatory bowel disease are present (inherited apparently independently), has been the subject of a previous clinicalreport (23). All members diagnosed as affected with BCNS hadat least 2 of the following: («)atleast one BCC prior to the ageof 20 or multiple BCCs thereafter; (h) multiple palmar and/orplantar pits; and/or (c) documented jaw cysts. No affectedmember failed to develop one of these signs by age 18 (usually

32 3

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223»22

13 3

131

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OE

I] NGFB

RESULTS

Loss of Heterozygosity in Sporadic Basal Cell Carcinomas.Despite numerous attempts, we found that we could not extractenough DNA from the more commonly seen smaller (e.g., 3-4mm) BCCs to allow multiple analyses of a single tumor. Incontrast, extraction of larger (e.g., 8-10 mm) BCCs producedDNA ample for multiple analyses. Since the patients withBCNS visited their dermatologists frequently for removal ofnew lesions, larger BCCs were available from BCNS patientsonly rarely and more commonly were available from patientswith sporadic, comparatively neglected tumors. All of thesetumors were from sun-exposed areas of Caucasian individuals,and the ages of the patients at the time of removal were 38-81years.

We analyzed 22 BCCs (sporadic, 19 tumors from 18 patients;BCNS, 3 tumors from 3 patients) for loss of heterozygosityeither at chromosome Iq or at several other regions in whichloss of heterozygosity has been reported frequently for extra-cutaneous cancers (Table 1; Fig. 1). Of the regions surveyed,chromosome Iq22 had the highest frequency of loss of heterozygosity at 33%. Analysis of tumors with chromosome Iq

21 121 3

Hi

MUC1

AT3

ÃœD1S65

Fig. 1. Southern analysis of DNA from leukocytes and from basal cell carcinoma 903 with probes identifying polymorphisms on chromosome 1.

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BASAL CELL CARCINOMA: LOSS OF HETEROZYGOSITY

936 903 912 911 404 935 942

NGFB :D1S90 ;,MUC1 M-SPTA1 LJ

FCG2D1S66AT3

D1S65

Ù

80

100

120

140

160

160

200

Fig. 2. Loss of heterozygosity of chromosome Iq markers in 7 (numbered)basal cell carcinomas. Numbers at left, genetic map distance (in centimorgans)from chromosome Ip telomeric-most probe (22, 24, 40). •¿�.Retention of heterozygosity at indicated locus; D, loss of constitutional heterozygosity in tumor atindicated locus; , areas of retained heterozygosity; , maximum extent ofdeleted regions (i.e., of loss of heterozygosity) in tumors.

earlier), and no person without these signs was scored as unaffected unless that person was more than 24 years old. Inaddition to the probes listed in Table 2, 19 other probes wereused, and in no instance was there evidence for nonpaternity.

Two point linkage analysis (LIPED) excluded linkage (logarithm of the odds < -2.0) of BCNS from the region of shortestoverlap on chromosome Iq—MUC1 to FCG2 (Table 2)—usinga genetic map distance of 24 centimorgans between MUC1 andD1S61 (24), a locus that maps distal to FCG2 (22). This regionalso is that to which Charcot-Marie-Tooth disease, type Ib, hasbeen linked. Also excluded was linkage to a chromosome 17pericentromeric marker (D 17S71 ), and chromosome 19q markers (APOC2 and the nearby D19S8) to which Charcot-Marie-Tooth disease, type la, has been linked (Table 2).

DISCUSSION

Loss of Heterozygosity. Loss of heterozygosity has been foundfor many tumors. Initially, such loss appeared to be at sitesspecific for each tumor, e.g., chromosome 13q in retinoblas-toma or chromosome 1Iq in Wilms tumor. With further survey,it has become clear that such unitary loss, while perhaps common in childhood neoplasms, is not the case for the morecommon adult cancers, in which tumorigenesis is accompanied

by multiple genetic steps. Thus, in colon cancers, perhaps thetumor best studied for sequential mutations, loss of heterozygosity occurs at all chromosome arms, albeit at varying frequencies, with an average of 4 to S deletions per tumor (25).Approximately 25% of colon tumors have loss of heterozygosityof chromosome Iq, a frequency intermediate among chromosome arms in colon cancers (25). Fearon and Vogelstein (26)have suggested 2 explanations for their finding of loss ofheterozygosity at many sites: (a) each of these sites indeedharbors a tumor suppressor gene; or (/>) much of the loss isneutral with regard to tumor growth but occurs during disorderly mitoses in which regions containing true tumor suppressor genes are lost. We interpret our finding of a relatively highincidence of chromosome Iq loss of heterozygosity with confinement to a relatively short region of overlapping deletion,coupled with a low incidence of loss of heterozygosity at severalother sites, as more consistent with the first explanation—mitoses causing loss of heterozygosity at multiple sites seem,at least in this relatively low-grade cancer, to be relativelyinfrequent.

Chromosome Iq alíelesalso have been reported to be lost intumors of another epidermal-derived tissue, the breast, andthere is some concordance between the chromosome Iq regionlost in BCCs and that lost in breast cancer (27, 28). Recently,chromosome Iq also has been identified as the site of a pro-senescence gene, and it is attractive to postulate that such agene might function to promote differentiation and act therebyto suppress tumor cell growth (29).

The BCCs studied were, by their size, an unusual group, andit is possible that the genetic changes found are not characteristic of the more common, smaller BCCs. Even such largerBCCs metastasize only very rarely, and as a first approximationthis correlates with the lack of BCC loss of heterozygosity inthe regions of p53 and DCC, genes whose loss occurs later indevelopment of cancers such as those of the colon (26). However, such correlation requires more study, for we have noevidence as to whether there is normal functioning of transcriptsfrom these genes in BCCs.

Others have reported loss of heterozygosity of distal chromosome lip in BCCs at the c-Ha-ros oncogene—4 of 16tumors (30)—an incidence a bit greater than we found in thisarea—1 of 12 tumors. Together, 5 of 27 tumors, this frequencyof loss of heterozygosity (19%) still is lower than that which wefound at chromosome Iq (33%). This site has been of specialinterest since the first report of its frequent activating mutationsand loss of heterozygosity in experimentally derived skin tumors (31), but ras gene mutations appear to occur infrequentlyin human BCCs (32, 33). We do not know whether the fewBCCs with chromosome lip loss of heterozygosity have activating point mutations in the remaining alíeles.

0-

To Ù 0 6 ó è-r-O *-r-0é-r-00 I è I O

« l r t t M 11 11 1» 14 I 11 W I « W

GTÕ> i * o 1 o ó^él*"*"!r l t w 11 u o i«i«u i? u

Fig. 3. Pedigree of BCNS-Mi family. Persons too young to be judged unaffected are not shown. Shaded areas, affected with BCNS.

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BASAL CELL CARCINOMA: LOSS OF HETEROZYGOSITY

Table 2 Two-point linkage analysis of BCNS-Mi family*

LocusLogarithm of the odds score at 6 of:

MUCID1S61D17S71D19S8APOC20.001-30.81-24.67-15.37-30.05-2.810.01-17.29-14.02-9.43-17.57-1.800.05-7.98-6.72-5.15-8.81-1.030.10-4.31-3.85-3.14-5.53-0.660.20-1.25-1.42-1.21-2.29-0.300.30-0.09-0.40-0.35-0.90-0.110.400.21-0.03-0.01-0.23-0.02

" Paternal and maternal segregation combined.

Linkage Analysis of BCNS. Weak linkage of BCNS to theDuffy blood group on chromosome Iq (13), and one familywith co-segregation of BCNS and Charcot-Marie-Tooth disease, one type of which is produced by an abnormality of a geneclose to that for FcgRII, has been reported (14). Hence, wewere most encouraged to find a relatively high incidence of lossof heterozygosity at that region and then disappointed to findthat linkage analyses in our family as well as that published byothers in abstract form exclude this area as the site of the BCNSgene (34). This is analogous to the findings in several otherinherited tumors, in which sites of linkage of inherited formsof cancer differ from sites of high incidence of loss of heterozygosity, e.g., linkage of MEN2 to chromosome lOq (35, 36)but high loss of heterozygosity of chromosome Ip in pheo-chromocytomas (37) and linkage of familial adenomatous po-lyposis to chromosome 5q (38, 39) but high loss of heterozygosity at chromosomes 17p and 18q in colon cancers (25).

We also searched for linkage to chromosomes 17p and 19qregions to which other forms of Charcot-Marie-Tooth diseasehave been linked. Linkage was excluded to each of these regions.

In conclusion, this study gives evidence that the mutationsunderlying the conversion of keratinocytes to the common,locally invasive but non-metastasizing basal cell carcinomasresemble one type of those underlying extracutaneous carcino-genesis in that both frequently have deletions of large chromosomal regions. Careful comparison of the mutations in these 2classes of tumors may provide clues to help explain clinicallycrucial differences in their biological behavior.

ACKNOWLEDGMENTS

We are grateful to the members of the Mi family for donations ofblood samples; to the patients who donated samples of blood andtumors; to R. Grekin, M. McKinna, and other physicians who helpedus gather patient specimens; to B. Forget, S. J. Gendler, K. Moore, Y.Nakamura, and R. L. White for generously sharing their probes; to M.Lee for assisting in the LIPED analysis; to E. Lynch for technicalassistance; and to M. C. King for encouraging us in this work.

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1992;52:1494-1498. Cancer Res   John W. Bare, Roger V. Lebo and Ervin H. Epstein, Jr.  Gene from This SiteCarcinomas and Exclusion of the Basal Cell Nevus Syndrome Loss of Heterozygosity at Chromosome 1q22 in Basal Cell

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