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Allelic Imbalance at Chromosome 11 in Head and Neck Squamous Cell Carcinoma in an Indian Patient Population

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Allelic Imbalance at Chromosome 11 in Head and Neck Squamous Cell Carcinoma in an Indian Patient Population 512 ORIGINAL ARTICLE J Clin Pathol: first published as 10.1136/jcp.56.7.512 on 1 July 2003. Downloaded from Allelic imbalance at chromosome 11 in head and neck squamous cell carcinoma in an Indian patient population G Mondal, A Tripathi, N Bhattacharya, N Sikdar, A Roy, A Sengupta, B Roy, C K Panda, S Roychoudhury ............................................................................................................................. J Clin Pathol 2003;56:512–518 Background: Genetic instability of chromosome 11 is a frequent event in many solid tumours, includ- See end of article for ing head and neck squamous cell carcinoma (HNSCC). authors’ affiliations Aims: To perform allelic imbalance analysis of cytogenetically mapped altered regions of human chro- ....................... mosome 11 in patients with HNSCC from eastern India. Methods: Correspondence to: Genomic alterations were investigated using highly polymorphic microsatellite markers in Dr S Roychoudhury, both HNSCC and leukoplakia tissues. Human Genetics and Results: Microsatellite markers D11S1758 from 11p13–15 and D11S925 from 11q23.3–24 had the Genomics Division, Indian highest frequency (38% and 32%, respectively) of loss of heterozygosity among all the markers ana- Institute of Chemical lysed. Allelic loss at the marker D11S925 was seen in both leukoplakia and in all stages of HNSCC Biology, 4, Raja S. C. Mullick Road, Kolkata 700 tumour tissues suggesting that it is an early event in HNSCC tumorigenesis. Microsatellite size altera- 032, India; tion was also found to be high (> 20%) in several markers. In leukoplakia samples microsatellite insta- [email protected] bility was seen at a higher frequency than loss of the allele, indicating such alterations might initiate the Accepted for publication process of tumorigenesis in HNSCC. 27 February 2003 Conclusions: The high rate of chromosomal alterations at 11q21–24 in HNSCC suggests the ....................... presence of a putative tumour suppressor gene in this region. ead and neck squamous cell carcinoma (HNSCC) is the mately 40% LOH was found at all the markers in the 11q23 sixth most common human cancer in all parts of the region in colorectal carcinoma.14 Allelotyping studies in world, and it has been estimated that there are around patients with HNSCC have revealed frequent LOH affecting H 1 400 000 new cases each year worldwide. It accounts for about many chromosomal loci, including chromosome 11.15–19 A mic- 2 30–40% of all cancer types in India and in the subcontinent. rosatellite assay covering the region of 11p12–15 showed a http://jcp.bmj.com/ Epidemiological studies have linked chronic exposure to variable amount of LOH and microsatellite size alteration tobacco, betel nut leaf quid, alcohol, and some environmental 15 3 (MA) in 19–45% of tumours. In another report, a microsatel- factors to the occurrence of HNSCC, and the characteristic lite marker flanking the p57KIP2 gene (a cyclin dependent molecular genetic events associated with the initiation and kinase inhibitor) at 11p15.5 showed 33% LOH and loss of progression of HNSCC are beginning to be understood. The imprinting in HNSCC.17 A genetic progression model of karyotypes of HNSCC tumours are complex, often near HNSCC has implicated alteration in chromosomal region triploid, and there are multiple numerical and structural 11q13 in the transition from dysplasia to in situ carcinoma.20 abnormalities, including deletions, balanced and unbalanced on September 30, 2021 by guest. Protected copyright. In addition, it has been reported that the 11q23–24 region is translocations, isochromosomes, dicentric chromosomes, and 19 homogeneously staining regions.4 Classic cytogenetic analysis frequently deleted in nasopharyngeal carcinoma. of HNSCC tumours has identified a gradual increase in chro- mosomal aberrations from premalignant to malignant “Chromosome 11 plays a crucial role in several cancers, lesions.5 In other studies, consistent chromosomal deletions and amplifications in several chromosome arms have been and two regions in particular, one in the short arm reported.6 In addition, centromeric breakage in several (11p13–15) and the other in the long arm (11q21–24), chromosomes has been shown to be important for the devel- have been identified as frequent targets for allelic loss” opment of HNSCC.7 Chromosome 11 plays a crucial role in several cancers, and In our present report, we examine allelic imbalance in two regions in particular, one in the short arm (11p13–15) and HNSCC tumours from the oral cavity, the laryngeal region, and the other in the long arm (11q21–24), have been identified as the orofacial region in eastern Indian patient populations at frequent targets for allelic loss. Allelic deletion at 11p15 has three regions of chromosome 11 (11p15, 11q13, and 11q21–24). been reported to be a common occurrence in oesophageal We present evidence that the 11q21–24 region may harbour a (53.3%) and gastric adenocarcinomas (61.5%).8 Similarly, putative tumour suppressor gene involved in the development anaplastic thyroid carcinoma is associated with a 33% allelic of tumours in these three sites of the head and neck. Our result loss in the 11p13 region.9 Loss of heterozygosity (LOH) at suggests that microsatellite instability is an early event in chromosome 11q23–24 (between loci D11S934 and D11S912) has been reported in 27% of breast cancers in a Chinese population.10 In nasopharyngeal carcinoma, these two loci ............................................................. showed LOH in 46.7% and 23.3% of the tumours, respectively.11 Moreover, comparative genomic hybridisation Abbreviations: H, heterozygosity; HNSCC, head and neck squamous cell carcinoma; LOH, loss of heterozygosity; MA, microsatellite size analysis also revealed frequent loss of 11q21–qter regions in alteration; MSI, microsatellite instability; PBL, peripheral blood leucocyte; 12 nasopharyngeal carcinoma. In addition, 38.8% of cervical PCR, polymerase chain reaction; RFLP, restriction fragment length carcinomas showed LOH at the 11q23.3 region.13 Approxi- polymorphism www.jclinpath.com Allelic imbalance at chromosome 11 in head and neck cancer 513 HNSCC tumorigenesis, and we propose that underlying mecha- nisms responsible for the generation of microsatellite instability Table 1 Clinical data of patients with leukoplakia J Clin Pathol: first published as 10.1136/jcp.56.7.512 on 1 July 2003. Downloaded from could also be responsible for allelic loss. and head and neck squamous cell carcinomas used in the study METHODS AND MATERIALS Age Lymph Tumour (years)/Sex Site Stage Histopathology node Tobacco Tumour samples Sixty freshly operated primary HNSCC tumours and 13 L48 59/F BM – MLD – + L49 52M BM – MOD – + dysplastic leukoplakia tissue samples, along with their corre- L50 64/M BM – MLD – + sponding normal tissues or peripheral blood leucocytes L51 74/M BM – SD – + (PBLs), were collected from the patients before treatment. L52 45/M BM – MOD – + − L53 49/M BM – MOD – + Samples were immediately frozen and stored at 80°C. All L54 44/M BM – MOD – + tumours were histopathologically diagnosed as squamous cell L55 44/M BM – SD – + carcinoma, graded and staged according to the UIC TNM L56 40/M BM – MOD – + classification. Table 1 shows a detailed history of all 73 patients L57 40/M BM – MOD – + 125 35/F BM – SD – – affected with primary HNSCC tumours and leukoplakia. 2024 52/M BM – SD – – Among the 60 patients with HNSCC, there were 49 men and 3037 55/M BM – SD – – 11 women, with a mean age of 49 years. Patients were grouped 1491 58/M BM I WDSCC + + 4119 60/M BM I WDSCC – – on the basis of affected primary sites, namely: oral cavity, lar- 4456 45/M BM I WDSCC + + ynx, and orofacial. Thirty two tumours were from the oral 149 38/M MD II WDSCC – – cavity (three alveolus, 16 buccal mucosa, 10 tongue, two ton- 222 60/F TNG II WDSCC – – 410 57/F TNG II WDSCC + – sil, and one palate), nine tumours were from the larynx, and 558 59/M AL II WDSCC – + 14 tumours were from the orofacial region (13 maxilla and 825 32/M P II PDSCC – – one mandible). Histopathologically, the HNSCC tumours were 939 50/M BM II MDSCC – – 1047 53/M BM II WDSCC – + classified as stage I (six tumours), stage II (13 tumours), stage 1864 45/M MX II MDSCC + + III (17 tumours), or stage IV (19 tumours). Similarly, 13 2030 73/M TNG II MDSCC + + leukoplakia tissues were classified histologically into three 2539 48/M AL II WDSCC U U 3070 48/M AL II WDSCC + + groups, namely: mild (two), moderate (six), and severe (five). 5959 28/M TNG II MDSCC – – Among the 60 tumours, 25 each were lymph node positive and 7216 56/M MX II MDSCC – + negative. In addition, 34 patients were habitual users of 292 48/M LX III MDSCC – + 308 42/M BM III MDSCC – + tobacco by different means (bidi, pan, cigarettes, etc) and 17 326 70/M MX III WDSCC – – did not have a tobacco habit. For four patients no history was 615 45/M TNG III WDSCC – + available (4717b, 4717g, 2917, and 2927). 693 50/M LX III MDSCC – + 4332 54/M BM III WDSCC + + 5090 49/M BM III WDSCC + + Microdissection and DNA isolation 1295 75/M LX III PDSCC – + The normal cells present as contaminants in the primary 1367 60/M TNS III MDSCC – – tumour tissues were removed by a microdissection 2323 62/M MX III WDSCC – + 21 2592 70/M BM III MDSCC + + procedure. More than 50 to 60 serial tumour specimens (10 2772 41/M BM III WDSCC + + http://jcp.bmj.com/ to 20 µm) were sectioned and placed on glass slides using a 4248 36/M BM III MDSCC + + cryostat (model CM 1800; Leica, Heidelberg, Germany). 5325 46/M TNG III WDSCC + + µ 5364 37/M MX III MDSCC + – Representative 5 m tumour specimens from different regions 7428 40/M BM III WDSCC + – of the tumour were stained with haematoxylin and eosin for 7783 45/F TNS III WDSCC + + diagnosis and for marking the tumour rich regions.
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