银屑病角质形成细胞p16基因微卫星杂合性缺失研究

目的探讨银屑病皮损区角质形成细胞p16基因D9S171,D9S1604微卫星位点杂合性缺失(lossofheterozygosity,LOH)与银屑病发病的关系。方法采用聚合酶链反应-变性聚丙烯酰胺凝胶电泳-银染技术对体外原代培养的银屑病皮损区和非皮损区角质形成细胞LOH进行分析。结果23例银屑病患者皮损区体外培养的角质形成细胞在D9S171和D9S1604两个微卫星位点,LOH分别为5例和10例。在非皮损区的相应位点LOH分别为2例和3例。D9S1604LOH频率明显高于非皮损区角质形成细胞(P<0.05);寻常性银屑病患者皮损区角质形成细胞中两位点LOH发生频率分别为23.5%(4/17)和47.1%(8/17),非寻常性银屑病分别为16.7%(1/6)和33.3%(2/6),两型银屑病两位点LOH发生频率相比差异均无显著性(P>0.05)。结论D9S1604微卫星位点LOH与银屑病的发生发展相关,而与临床类型相关无显著性。     

Allelic deletion at 9p21-22 in primary cutaneous CD30(+) large cell lymphoma

The genetic alterations responsible for the development of cutaneous lymphoma are largely unknown. Chromosome region 9p21 contains a gene locus encoding an inhibitor of cyclin-dependent kinase 4, and heterozygous deletions of this tumor suppressor gene (p16) have been shown in a variety of malignant tumors. We studied 11 randomly selected cutaneous CD30-positive large cell lymphomas. Several areas containing 20-50 CD30-positive lymphocytes were microdissected in each case and subjected to single-step DNA extraction. Loss of heterozygosity analysis was performed using polymorphic markers at 9p21 (IFNA, D9S171, D9S169) and 17p13 (TP53). Samples from normal cells apart from CD30-positive lymphocytes, e.g., CD30-negative lymphohistiocytic infiltrates and normal epidermal layer, were also obtained in all cases from the same slide for comparison with the tumor samples. Expression of CD30 and T-lineage antigens (CD3, CD45Ro) was confirmed in all cases. Immunohistochemical staining for p16 and p53 was performed using the monoclonal antibodies sc-1661 and DO-7, respectively. Of the 11 informative cases, seven (64%) exhibited loss of heterozygosity at least for one marker at 9p21 (p16), whereas no allelic deletions were found for the polymorphic marker at 17p13 (p53). On immunohistochemistry loss of the p16 protein was detected in two of 11 cases. Nuclear staining for p53 protein was found in four of 11 cases. Here, we provide the first evidence of the involvement of the tumor suppressor gene p16 in primary cutaneous large cell lymphoma. Whether p16 deletion in these lymphomas is associated with disease progression and whether this method could serve as an early marker to detect lymphomas at an early stage needs to be addressed in future studies. J Invest Dermatol 115:1104-1107 2000     

Syringocystadenoma papilliferum: a study of potential tumor suppressor genes

Syringocystadenoma papilliferum (SP) is a benign tumor most commonly located on the scalp or face, which frequently arises from a nevus sebaceus (NS). Transition of SP to basal cell carcinoma (BCC) and, albeit rarely, to metastatic adenocarcinoma may occur. Allelic deletions of the human homologue of the drosophila patched gene (PTCH) occur in both NS and BCC. To search for genetic changes in SP, a microdissection-based genetic analysis using polymorphic markers at 9q22 (PTCH; D9S15, D9S303, D9S287, D9S252) as well as markers at 9p21 flanking the tumor suppressor gene p16 (IFNA, D9S171) was performed. Glandular epithelium consisting of two rows of cells as well as adjacent normal tissue or inflammatory infiltrates in the stroma, when present, was dissected and subjected to single-step DNA extraction and loss of heterozygosity (LOH) analysis. Two of 10 informative SP cases showed LOH at 9q22 (PTCH). Three of 7 informative SP cases showed allelic deletions at 9p21 (p16). Allelic loss at 9q22 is consistent with the clinical observation of transition of SP to BCC. The finding of frequent allelic loss at 9p21 is unlikely to be related to the rare transition of SP to metastatic adenocarcinoma. Our study supports the hypothesis of a gatekeeper role of the tumor suppressor gene p16 in a variety of benign and malignant tumors, including SP.     

High frequency of loss of heterozygosity on chromosome region 9p21-p22 but lack of p16INK4a/p19ARF mutations in greek patients with basal cell carcinoma of the skin

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/p16INK4a, p19ARF, and p15INK4b 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 p16INK4a and p19ARF 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 heterozygosity 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 first demonstration of polymorphism in the CDKN2a gene in human basal cell carcinomas. No sequence variation in exon 1beta of the p19ARF gene was found. Our results provide evidence of a significantly high occurrence of loss of heterozygosity for the 9p21-p22 locus; however, lack of p16INK4a/p19ARF mutation suggests that these genes seem not to be implicated by mutational inactivation in the development of basal cell carcinoma. Other(s), yet unidentified, tumor suppressor gene(s) located in this locus may be related to this specific type of skin cancer.     

Spitz nevi display allelic deletions.

BACKGROUND: Spitz nevi are acquired benign melanocytic lesions that occur in childhood and adolescence. Histologically, they resemble malignant melanoma and were first termed benign juvenile melanoma. Several studies have attempted the difficult task of establishing diagnostic criteria to differentiate between Spitz nevi and malignant melanoma. OBJECTIVE: To elucidate sets of diagnostic criteria for differentiation between the 2 lesions. DESIGN: We aimed to search for allelic deletions in Spitz nevi and to evaluate whether loss of heterozygosity (LOH) or microsatellite instability (MSI) would be a valuable diagnostic tool to differentiate between Spitz nevi and malignant melanoma. SETTING: Two areas within each of 5 lesions were microdissected, and LOH and MSI were evaluated at chromosomes 6q (using polymorphic DNA marker D6S305), 9p21 (D9S171, IFNA, D9S265, and D9S270), 10q (D10S185), and 14q (D14S53). PATIENTS: Five Swiss patients with Spitz nevi. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Allelic deletions may serve as a diagnostic tool to distinguish Spitz nevi from melanoma. RESULTS: All lesions were informative, displaying LOH or MSI with at least one marker. No LOHs were found at 14q. At 6q, MSI was found in 2 dissected areas from the same lesion; the remaining lesions were noninformative. Loss of heterozygosity was found in 2 of 6 areas at D9S171, 2 of 6 at IFNA, 3 of 6 at D9S270, 3 of 4 at D9S265, and 1 of 4 at D10S185. Microsatellite instability was found in 1 of 4 areas at D9S265. CONCLUSIONS: With the markers used in our study, Spitz nevi display LOH and MSI similar to those in melanoma. Analysis of LOH or MSI is therefore not a suitable diagnostic tool in distinguishing Spitz nevi from melanoma.     

Assessment of microsatellite instability and loss of heterozygosity in sporadic keratoacanthomas

Abstract Variations in the length of simple repetitive tandem repeats (microsatellite instability, MIN) between constitutive and tumour DNA, which is characteristic of tumours in patients affected with hereditary nonpolyposis colon cancer (HNPCC), have been found to be very important in the carcinogenesis of a variety of human neoplasms. Recently, MIN has been found in sebaceous and colorectal tumours as well as in keratoacanthomas of Muir-Torre syndrome. In order to elucidate the significance of both MIN and loss of heterozygosity (LOH) in the pathogenesis of sporadic keratoacanthomas, the presence of MIN and LOH at five loci [chromosome 5q21 (D5S346, APC), 9p21 (D9S171, p16), 10pter (D10S89, Mfd28), 11p (D11S904) and 17p12 (D17S520, p53)] was evaluated. MIN was found at only one locus (p53) in 1 of 12 keratoacanthomas and no evidence for the presence of LOH could be detected. Our results suggest that, in contrast to keratoacanthomas associated with Muir-Torre syndrome, neither MIN nor LOH appear to be significant in the induction of sporadic keratoacanthomas. Received: 28 April 1997 / Received in revised form: 4 September 1998 / Accepted: 17 September 1998     

Repetitive DNA alterations in human skin cancers

Repetitive sequences constitute landmarks for genome regulation, evolution, and chromatin architecture. Patterns of specific and non-specific repetitive sequences change in many types and stages of tumor cells, characterized by band loss, gain, and (de) increased staining of pre-existing bands. In this work, repetitive DNA was studied in search of genome instability of skin cancers: basal and squamous cell carcinomas (BCC and SCC), malignant melanoma (MM), melanocytic nevus (MN), and actinic keratosis (AK) lesions. DNAs were extracted from blood and tumor samples from 21 BCC, 7 SCC, 11 MM and 7 lesions. Banding patterns were obtained by random amplification of polymorphic DNA (RAPD), and specific D9S50 and D9S52 microsatellites (9p21). D9S50 patterns revealed microsatellite instability (MSI) and/or loss of heterozygosity (LOH) in 36% BCC, 25% SCC, and 57% MM tumors. D9S52 microsatellite showed 28.5%; 42.8%; and 71.4% altered tumors, respectively. No microsatellite alterations were found in MN and AK. On the other hand, genomic rearrangements detected by RAPD were present in 100% tumors. In BCC, the mean number of tumor DNA alterations showed predominant gain of bands. On the contrary, MM samples presented loss, or decreased intensity signal of RAPD bands. Genome alterations in skin cancers would result from chromosomal rearrangements, aneuploidy and/or polysomies. The low-cost and quick RAPD technique may reveal unknown genes or DNA sequences associated with tumor development and progression, and may be easily implemented in clinical diagnosis.     

Multilineage progression of genetically unstable tumor subclones in cutaneous T-cell lymphoma

Molecular analysis of solid malignant tumors has suggested multilineage progression of genetically unstable subclones during early stages of tumorigenesis as a common mechanism of tumor cell evolution. We have investigated whether multilineage progression is a feature of cutaneous T-cell lymphoma (CTCL). To identify individual tumor cell subclones, we determined the pattern of mutations within microsatellite DNA obtained from multiple histomorphologically confined tumor cell nests of mycosis fungoides (MF) and lymphomatoid papulosis (LyP) lesions. Tumor cells were isolated by laser microdissection, and allelotypes were determined at microsatellite markers D6S260, D9S162, D9S171, D10S215, TP53.PCR15, and D18S65. Nine cases of MF and one patient with anaplastic large cell lymphoma (ALCL) originating from LyP were analyzed at 277 different microdissected areas obtained from 31 individual lesions. Three specimens of cutaneous lichen planus microdissected at 26 areas served as the control tissue. Microsatellite instability in microdissected tissue [MSI(md-tissue)] was detected in tumor tissues of all CTCL patients. One hundred and fifty-seven of 469 analyzed polymerase chain reaction (PCR) amplifications contained mutated microsatellite alleles (34%). In lichen planus, MSI(md-tissue) was seen in only four of 76 PCR products (5%) (P < 0.0001). The distribution of allelotypes in tumor cells from different disease stages was consistent with multilineage progression in five MF cases, as well as in the LyP/ALCL patient. Our results suggest that CTCL may evolve by multilineage progression and that tumor subclones in MF can be detected in early disease stages by mutation analysis of microsatellite DNA obtained from multiple microdissected areas.     

Inactivation of tumor suppressor genes p15(INK4b) and p16(INK4a) in primary cutaneous B cell lymphoma

Primary cutaneous B cell lymphomas represent a distinct group of lymphoproliferative disorders that can be distinguished from systemic lymphoma by their good response to local treatment and favorable prognosis. In systemic B cell lymphoma, inactivation of p15(INK4b) and p16(INK4a) is frequently observed and may be associated with a poor prognosis. There have been no comprehensive studies in primary cutaneous B cell lymphomas, however. Mechanisms of p15/p16 inactivation include loss of heterozygosity, homozygous deletion, promotor region hypermethylation, and point mutation. We analyzed DNA from 36 cases of primary cutaneous B cell lymphomas, four systemic B cell lymphomas, and six benign B cell lymphoproliferative infiltrates for abnormalities of p15 and p16 using microsatellite markers for 9p21, methylation specific polymerase chain reaction, and polymerase chain reaction/single stranded conformational polymorphism analysis with exon specific primers. Expression of both p15 and p16 protein was assessed by immunohistochemistry. Loss of heterozygosity at 9p21 was identified in 2 out of 36 primary cutaneous B cell lymphomas. Hypermethylation of p15 and p16 promotor regions was identified in 8 of 35 (23%) and 15 of 35 (43%) cases, respectively. In two cases p16 hypermethylation was identified in recurrent disease but not in the initial tumor. No point mutations were identified. In seven patients, however, a polymorphism was observed in exon 3 of the p16 gene. In primary cutaneous B cell lymphomas with allelic loss or promotor hypermethylation of either p15 or p16, loss of expression in tumor cells was identified in 5 of 8 and 9 of 10 cases, respectively. Our findings suggest that p15(INK4b) and p16(INK4a) biallelic gene abnormalities are common in primary cutaneous B cell lymphomas, most frequently as a result of promotor hypermethylation. The presence of abnormalities in recurrent disease in some cases suggests that inactivation of p15 and p16 may be involved in disease progression.     

神经纤维瘤病2型患者皮肤神经鞘瘤中的基因丢失

目的 应用微卫星多态标志研究神经纤维瘤病2型(NF2)患者的皮肤神经鞘瘤中NF2基因丢失情况,以明确其肿瘤的发生机制及NF2肿瘤抑制基因的特点,为NF2患者的症状前基因诊断提供依据。方法 收集NF2患者的皮肤肿瘤组织及外周血,提取DNA,应用微卫星多态标志进行基因型分析。结果 43例皮肤神经鞘瘤在微卫星多态标志CRYB2,D22S193,NF2CA1,NF2CA3,D22S268,D22S430上显示杂合性丢失的例数分别为18,14,0,13,16,12例。结论 建立了在NF2基因内部及两翼的与NF2基因紧密连锁的多个微卫星多态标志的杂合性丢失探知NF2等位基因丢失的方法,再次证实了NF2基因是一个肿瘤抑制基因。通过对同一患者的多个皮肤神经鞘瘤的研究,发现同一患者的不同肿瘤标本中既有肿瘤存在NF2基因的丢失,又有肿瘤没有NF2基因的丢失,说明了这些患者中肿瘤的发展起源于不同的细胞克隆,各肿瘤的基因变异是独立发生的。     

Sporadic trichoepithelioma demonstrates deletions at 9q22.3

BACKGROUND: Trichoepithelioma (TE) is a benign cutaneous tumor that originates from hair follicles and occurs either in multiple or solitary lesions. Multiple TE is transmitted as an autosomal dominant trait, and a region at 9p21 is thought to be involved in the tumorigenesis. Solitary TE occurs more commonly than multiple TE and is not inherited. Histologically, TE tumors contain horn cysts and abortive hair papillae. A basal cell carcinoma appearance in some or all regions of a TE tumor can happen. In sporadic basal cell carcinoma, frequent deletions at 9q22.3 (Drosophila patched gene) have occurred. The objective of this study is to test whether loss of heterozygosity (LOH) on either 9p21 or on chromosome 9q22.3 could be detected in archival sporadic TE. OBSERVATIONS: We studied 29 randomly selected cases of sporadic TE by microdissection and polymerase chain reaction using paraffin-embedded, formalin-fixed tissue specimens on glass slides. Analysis was performed with the polymorphic markers IFNA and D9S171 (9p21) as well as D9S15, D9S303, D9S287, and D9S252 (9q22.3). RESULTS: The LOH at 9q22.3 was identified in 14 (48%) of 29 cases with at least 1 marker, while LOH could not be demonstrated using the markers IFNA and D9S171 (9p21). CONCLUSIONS: The results show that the Drosophila patched gene LOH can be frequently identified in paraffin-embedded sporadic TE after routine processing and indicates a common gatekeeper mechanism for both TE and basal cell carcinoma.     

p16INK4a expression is frequently decreased and associated with 9p21 loss of heterozygosity in sporadic melanoma

The product of the p16/INK4a/CDKN2/MTS1 tumor-suppressor gene acts as a negative cell cycle regulator by inhibiting G₁ cyclin-dependent kinases that phosphorylate the retinoblastoma protein. p16 is inactivated in a wide range of human malignancies, including familial melanoma. However, its expression and function in sporadic melanoma has not been extensively investigated. We studied p16 expression in 62 archival melanomas and 30 archival nevi and lentigines by immunohistochemistry. Eighteen of 26 (69%) superficial spreading melanomas, 17 of 28 (61%) nodular melanomas, all of three lentigo maligna melanomas, and all of five melanoma metastases were found to harbor less than 10% p16 -positive tumor cells. In contrast, only six of 24 (25%) nevi had less than 10% positive cells. No correlation between tumor thickness and loss of p16 expression was found. Using DNA from micro-dissected tumor and matched normal tissues, five of seven (71%) p16 -negative melanoma cases had 9p21 loss of heterozygosity (LOH), and one of these 9p21 LOH cases had promoter region hypermethylation of the remaining p16 allele. These data demonstrate that partial or complete loss of p16 expression is prevalent in sporadic melanoma and is frequently associated with 9p21 LOH.     

Comparative analysis of loss of heterozygosity and microsatellite instability in adult and pediatric melanoma

Although 0.3% of melanomas occur in children, the incidence has risen in past decades. In adult melanoma, some chromosomal regions in 1p, 6q, 9p, 10q, and 11q are frequently deleted. Microsatellite instability (MSI), which reflects impaired DNA repair, has been found at low levels in adult melanoma and melanocytic nevi. To investigate the molecular changes in pediatric melanoma, a screening for loss of heterozygosity and microsatellite instability was performed and compared with changes found in adult melanoma. Formalin-fixed, paraffin-embedded tissues from 10 adult melanomas, 9 melanocytic nevi, and 8 pediatric melanomas were microdissected and the DNA was extracted. Loss of heterozygosity and microsatellite instability were evaluated using 13 microsatellite repeat polymorphisms located in 1p36, 1q32, 2p12, 2p22-25, 2q33-37, 9p21, 10q23.3, 11q23, 13q14, 17p13, and 17q21. The overall frequency of loss of heterozygosity was 0.09 for nevi, 0.30 for adult melanoma, and 0.43 for pediatric melanoma (nevi vs. adult melanoma, P = 0.0082; nevi vs. pediatric melanoma, P = 0.0092). Pediatric melanoma has more loss of heterozygosity (44%) in 11q23 than adult melanoma (7%, P = 0.046). The microsatellite instability overall frequency was greater in pediatric melanoma (0.24) than nevi (0.05, P = 0.0031) and adult melanoma (0.09, P = 0.0195). Our findings suggest that pediatric melanoma has a different abnormal pattern than adult melanoma. Pediatric melanoma has more microsatellite instability than adult melanoma. 11q23 could contain genes related to the early age onset of melanoma. The high frequency of microsatellite instability is coincidental with the finding of higher levels of microsatellite instability in pediatric brain tumors and could play a role in the pathogenesis of pediatric melanoma.     

Absence of microsatellite instability and lack of evidence for subclone diversification in the pathogenesis and progression of mycosis fungoides

Mutator phenotypes with microsatellite instability (MSI) correlated with defects in the mismatch repair system are characteristic for a subset of solid neoplasms, but are rare in non-Hodgkin lymphomas. In mismatch repair-deficient mice, however, mutator-type non-Hodgkin lymphomas are the most frequent tumors. To determine the role of MSI in mycosis fungoides, we compared the states of the eight dinucleotide microsatellite loci DXS418, DXS453, DXS556, DXS1060, D1S201, D6S260, D9S162, and D10S215 in tumor cells of 12 well-characterized patients at early- and advanced-stage diseases to matched healthy tissue. We did not find any MSI, although all but one patient had progressed to advanced-stage disease within the timeframe of the study. Concordantly, the expression of mismatch repair genes was normal. These results suggest that progressive accumulation of mutations as detected by MS analysis does not play a major role in the pathogenesis or in the progression of mycosis fungoides.     

Molecular alterations at chromosome 9p21 in melanocytic naevi and melanoma

BACKGROUND: The chromosome 9p21 and its CDKN locus, with the p16 tumour suppressor gene (CDKN2A), are recognized as the genomic regions involved in the pathogenesis of melanoma. OBJECTIVES: To elucidate further the role of such regions during the different phases of melanocytic tumorigenesis. METHODS: Tissue sections from naevi, primary and metastatic melanomas were investigated by fluorescence in situ hybridization for allelic loss at the 9p21 chromosome and by immunochemistry for p16CDKN2A expression. RESULTS: Dysplastic naevi and primary or secondary melanomas were found to carry hemizygous deletions within the entire 9p21 region at similar frequencies (varying from 55% to 62%). Allelic deletion spanning the CDKN locus was observed at significantly increased rates moving from early (7%) to advanced (28%) primary melanomas and to secondary melanoma lesions (37%) (P=0.018). Also, inactivation of the p16 gene (CDKN2A) was absent in naevi and present at steadily increasing rates moving from primary melanomas (7% early lesions to 17% advanced lesions) to melanoma metastases (62%) (P=0.004). CONCLUSIONS: Our findings indicate that, in a model of sequential accumulation of genetic alterations, 9p21 deletions may play a role in melanocytic transformation and tumour initiation whereas rearrangements at the CDKN locus, and p16 gene (CDKN2A) inactivation may contribute to tumour progression.     

燃煤型砷中毒皮损中2个DNA微卫星位点的变化

目的 探讨微卫星不稳定性及杂合性丢失在燃煤型砷中毒患者皮肤病变发展中的作用。方法 依据皮肤病理组织学检查结果对燃煤型砷中毒患者进行分组,选取TP53.PCR15、D9S3192个微卫星多态性标记,采用PCR扩增-变性聚丙烯酰胺凝胶电泳-银染法检测其微卫星不稳定性情况。结果 34份燃煤型砷中毒患者皮损组织微卫星不稳定性的发生率为32.4%(11/34),杂合性丢失的发生率为14.7%(5/34),微卫星不稳定性与临床分度、病理分型之间统计学分析差异无显著性(P>0.05)。结论 微卫星不稳定性和杂合性丢失可能在砷中毒皮损癌变的发生发展中起一定的作用。     

Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions

Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a 'halo' SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway. Germline DNA from members of 111 multiple-case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.     

Molecular genetic analysis of the BRCA2 tumor suppressor gene region in cutaneous squamous cell carcinomas

Background:  Germ line mutations of the BRCA2 tumor suppressor gene with subsequent loss of the remaining wild-type BRCA2 allele have been identified in up to 35% of familial breast cancer cases. A high frequency of allelic loss at the BRCA2 gene locus has also been reported in a variety of sporadic epithelial tumors including oesophageal squamous cell carcinomas (SCC), and sporadic head and neck SCC.
Aim:  The present study aimed to examine the integrity of the BRCA2 gene in cutaneous SCC.
Materials and methods:  Allelic imbalance/loss of heterozygosity (AI/LOH) was examined in 22 histologically confirmed cutaneous SCC at two microsatellite markers, D13S260 (centromeric to the BRCA2 gene) and D13S267 (telomeric to the BRCA2 gene). Immunohistochemical analysis of BRCA2 protein expression was also examined in the cutaneous SCC.
Results:  AI/LOH at the D13S260 locus was found in eight of the 19 informative SCC, and AI/LOH at the D13S267 locus was found in 12 of the 18 informative SCC. Seven SCC showed allelic loss at both markers, and six SCC showed retention of heterozygosity at both markers. Expression of BRCA2 protein was only detected in six of the normal epidermises and three of the 21 SCC examined.
Conclusion:  AI/LOH of the BRCA2 gene region was found to be common in the cutaneous SCC.