Basal cell carcinomas and squamous cell carcinomas of human skin show distinct patterns of chromosome loss (original) (raw)
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Journal of Investigative Dermatology, 2000
Basal cell carcinoma of the skin is the most common neoplasia in humans. Previous studies have shown the existence of allelic imbalance (loss of heterozygosity and microsatellite instability) in BCC on several human chromosomes. Chromosome region 9p21± p22 harbors the CDKN2a/p16 INK4a , p19 ARF , and p15 INK4b tumor suppressor genes. To determine the contribution of these genes to the development of basal cell carcinomas we looked for evidence of allelic imbalance in 67 sporadic basal cell carcinoma specimens from Greek patients and screened 28 of them presenting loss of heterozygosity at 9p21±p22 for germline mutations in p16 INK4a and p19 ARF genes. Chromosome regions 17q21 and 17p13 were also screened for allelic imbalance in all the 67 basal cell carcinoma specimens. Overall, 69% (46 of 67) of the specimens displayed loss of heterozygosity in at least one microsatellite marker, whereas only six of the 67 (9%) exhibited microsatellite instability. For the 9p21±p22 locus the overall frequency of loss of het-erozygosity reached 55% (37 of 67) and is the highest reported. The overall frequency of loss of heterozygosity for the 17q21 locus is 34% (22 of 64) and for the 17p13 locus is 11% (seven of 65). Two of the 28 loss of heterozygosity positive cases were heterozygous for a previously described polymorphism, Ala148Thr, in exon 2 of the CDKN2a gene. This is the ®rst demonstration of polymorphism in the CDKN2a gene in human basal cell carcinomas. No sequence variation in exon 1b of the p19 ARF gene was found. Our results provide evidence of a signi®cantly high occurrence of loss of heterozygosity for the 9p21±p22 locus; however, lack of p16 INK4a /p19 ARF mutation suggests that these genes seem not to be implicated by mutational inactivation in the development of basal cell carcinoma. Other(s), yet unidenti-®ed, tumor suppressor gene(s) located in this locus may be related to this speci®c type of skin cancer.
Chromosome 9 Allele Loss Occurs in both Basal and Squamous Cell Carcinomas of the Skin
Journal of Investigative Dermatology, 1994
Linkage studies of kindreds with the nevoid basal cell carcinoma syndrome and the high frequency of chromosome 9 allele loss in sporadic basal cell carcinomas indicate that chromosome 9 may contain tumor suppressor genes important in the development of sporadic and familial basal cell carcinomas. The recent mapping of the Ferguson-Smith syndrome, which predisposes affected individuals to the development of multiple lesions histologically indistinguishable from squamous cell carcinomas, suggests that tumor suppressor genes on 9q may also be important in the development of squamous cell neoplasms of the skin. Fifty-four non-melanoma skin cancers (24 basal cell carcinomas, 14 squamous cell carcinomas, and 16 cases of Bowen's disease) were examined for loss of heterozygosity on chromosome 9. Allelic loss at one or more loci on chromosome 9 was observed in 14 of 24 basal cell carcinomas, four of 14 squamous cell carcinomas, and
Cytogenetic analysis of 33 basal cell carcinomas
Cancer research, 1991
Cytogenetic analysis of short-term cultures from 33 basal cell carcinomas (BCC), a type of neoplasm for which no previous karyological data exist, revealed clonal chromosome aberrations, all of them different, in 8 tumors. In 2 cases, 2 cytogenetically unrelated clones were detected, suggesting a multicellular origin in at least a subset of BCC. A remarkably high level of nonclonal structural rearrangements, mostly in the form of seemingly balanced translocations, was found in 23 tumors; namely, in 6 of 8 BCC with clonal karyotypic abnormalities and in 17 of 25 without. It is possible that some of these aberrations represent additional neoplastic clones, thus indicating an even higher level of cytogenetic heterogeneity in BCC. We think that the most likely interpretation of the results is that BCC may have a multicellular origin, reflecting field cancerization of the skin. During subsequent tumor development, the selection pressure narrows down the number of clones that infiltrate t...
Human Pathology, 2004
A high incidence of skin cancers has been noted around the Semipalatinsk Nuclear Testing Site (SNTS) in Kazakhstan. Recently, basal cell carcinoma (BCC) susceptibility genes, human homolog of the Drosophila pathed gene (PTCH), and the xeroderma pigmentosa group A-complementing gene (XPA), have been cloned and localized on chromosome 9q22.3. To clarify the effect of low-dose irradiation on the occurrence of BCC, we used microdissection and polymerase chain reaction to identify loss of heterozygosity (LOH) at 9q22.3 using BCC samples obtained from this region. Ten Japanese samples were analyzed as controls. LOH with at least 1 marker was identified in 5 of 14 cases from around SNTS, whereas only 1 case with 1 marker was identified among the 10 Nagasaki cases. The total num-ber of LOH alleles from SNTS (8 of 45) was significantly higher than the number from Nagasaki (1 of 26) (P ؍ 0.03). The higher incidence of LOH on 9q22.3 in BCC from around SNTS suggests involvement of chronic low-dose irradiation by fallout from the test site as a factor in the cancers. HUM PATHOL 35:460-464.
Journal of Cutaneous Pathology, 2004
Background: Studies on basal cell carcinoma (BCC) have demonstrated that patched gene and p53 gene located at 9q22.3 and 17p13 are the main genes responsible for the onset of this tumor. In order to identify a possible involvement of other tumor suppressor genes, we screened 19 cases of BCCs for loss of heterozygosity (LOH). Methods: The analysis was performed on tumoral tissue and on corresponding normal tissue by using a panel of 37 polymorphic markers spanning 26 chromosomal regions. Results: We observed that only four chromosomal regions, 4q32 (30.00%), 4q35 (27.27%), 9q21-22 (28.57%), and 9q22-qter (35.71%), demonstrated a significative LOH (>20%), even if others show a borderline percentage (15-20%) of imbalance (1q32, 3p24, 10p22.1, and 17q21.3). Conclusions: Our findings suggest that a new chromosomal region mapping in the long arm of chromosome 4 could be involved in sporadic BCC carcinogenesis. Further analyses indicate that the minimal deleted region in 4q32-35 includes p33ING2/ING1L and SAP30, whose deletion could impair the G1-phase checkpoint control and favor gene silencing, respectively.
Diverse chromosome abnormalities in squamous cell carcinomas of the skin
Cancer Genetics and Cytogenetics, 1989
Short-term (:ultures from three invasive squamous cell car(:inomas of the skin were cyta~4enetically analyzed. Clanal chromosome aberr(zti(ms were .found in all tumors. In the first case. two of three abnormal clones were related, and in the second case. two of five clones demonstrated cytogenetic similarities. Both clones detected in case 3 had a structural re.arrangement in (:()nltlton. Several non(:h)nal changes were seen in all three cases in addition to the oh)hal aberrations. NOlle of the rearrangements de.te.cted. (:l(mal ar non(:l(mal, rarresponds ta any of the consistently can(:er-associated aberratitms known from other neoplasms. The remarkably diverse karyotypic picture (ff the three square(ms cell (:arcinamas. in l)arti(:ular the finding of unrelated clones in two t).f them, hints that these neoplasms may b(: polyrather than manor:lanai. The lack o.f a common (:ytogenetic denominator argues that if chrt)mt~samul chm}ges are of patho,,4,eneth: impartat~¢e in this tumor type. a wide v.riet.v oJ apparently dissimilar (:hanges exist that are roughly equal ill their (:ap(J(:ity to malign(3ntly transform skin epithelium.
Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin
In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P ¼ 0.0007, multiple testing corrected P ¼ 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in noncarriers (P ¼ 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and genderspecific effect by E185Q polymorphism in NBS1.
Multiple cytogenetic clones in a basal cell carcinoma
Cancer Genetics and Cytogenetics, 1991
Chromosome analysis of short-term culture of a basal cell carcinoma showed five clonal chromosome abnormalities, t(9;14)(q12 or q13;p11), del(1)(q23 or q25), trisomy 5, trisomy 7, and monosomy X. In addition, several nonclonal structural and numerical changes were seen in the tumor cells.
Carcinogenesis, 2002
We have previously used single nucleotide polymorphisms to detect an association of basal cell carcinoma (BCC) in Caucasian Americans and Danes with the genome region 19q13.2-3, which contains several genes involved in the nucleotide excision repair of DNA. In this exploratory paper we have extended the data and used them in a chromosomal scan. The results indicate the presence of a gene variation modulating the risk of developing BSS in a submegabase region including and surrounding the gene RAI. Specifically, persons that are homozygous for the haplotype RAI intron 1 A RAI exon 6 A appear at increased risk for BCC. In addition, we have looked for possible synergisms between all pairs of markers. We find that a marker in GLTSCR1, presumably separated from RAI by several million bases, supplements the most significant marker in RAI in separating cases from controls, which may suggest the presence of an independent, risk-modulating variation in this second gene region.