Cytogenetic and FISH Examination of 3p Abnormalities in Lung Cancer Patients

Year 2024, Volume: 14 Issue: 1, 26 - 39, 24.04.2024

Narmin Bakhshaliyeva , Ayşe Çırakoğlu , Hürrem Gül Öngen , Esin Bil Tuncay , Yelda Argüden

https://doi.org/10.26650/experimed.1408284

Abstract

Objective: Deletions or loss of heterozygosity in chromosome 3p are very common in small-cell lung cancer (SCLC) and lung adenocarcinoma (ADC) cases. These are typically found in tumor cells but rarely observed in lymphocytes. This study aimed to evaluate the frequency of 3p deletions and/or abnormalities in the blood of lung cancer patients using conventional cytogenetics and fluorescence in situ hybridization (FISH), by targeting the fragile histidine triad diadenosine triphosphatase (FHIT) gene located at the commonly deleted region of 3p14.2, in lung cancers.

Materials and Methods: The study examined 24 SCLC patients, 30 ADC patients, and 20 healthy controls. It used standard procedures to perform a 72-h lymphocyte culture, G-banding, and FISH.

Results: All patient group cases showed multiple numerical and structural abnormalities, with numerical abnormalities being more prominent and involving all chromosomes. The following two 3p abnormalities were detected in one patient: del(3)(p22) and t(3;5)(p25;q31). FISH showed positive results regarding FHIT deletion in 9 (30%) ADC, and 7 (29%) SCLC patients.

Conclusion: Regardless of the rarity of 3p abnormalities in lymphocytes, a high frequency of chromosomal aberrations may indicate genomic instability. Nevertheless, due to being a time-consuming and expertise-requiring technique, conventional cytogenetics is not recommended for lung cancer monitoring. However, the FISH results suggested that using FISH to examine FHIT gene status in lymphocytes could be a promising biomarker for lung cancer.

Keywords

Small cell lung carcinoma, FISH technique, adenocarcinoma, cytogenetics, chromosome 3, FHIT

References

• Schwendel A, Langreck H, Reichel M, Schröck E, Ried T, Dietel M, et al. Primary small-cell lung carcinomas and their metastases are characterized by a recurrent pattern of genetic alterations. Int J Cancer 1997; 74(1): 86-93. google scholar
• Graziano SL, Cowan BY, Carney DN, Bryke CR, Mitter NS, Johnson BE, et al. Small cell lung cancer cell line derived from a primary tumor with a characteristic deletion of 3p. Cancer Res 1987; 47(8): 2148-55. google scholar
• Chang JG, Chen CC, Wu YY, Che TF, Huang YS, Yeh KT, et al. Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma. Oncotarget 2016; 7(45): 73664-80. google scholar
• Ashman JN, Brigham J, Cowen ME, Bahia H, Greenman J, Lind M, et al. Chromosomal alterations in small cell lung cancer revealed by multicolour fluorescence in situ hybridization. Int J Cancer 2002; 102(3): 230-6. google scholar
• Iijima H, Tomizawa Y, Dobashi K, Saito R, Nakajima T, Mori M. Allelic losses on chromosome 3p are accumulated in relation to morphological changes of lung adenocarcinoma. Br J Cancer 2004; 91(6): 1143-8. google scholar
• Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P, et al. Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br J Cancer 1997; 75(1): 79-86. google scholar
• Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, et al. The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 1996; 85(1): 17-26. google scholar
• Tarkan-Argüden Y, Hacihanefioglu S, Ongen G, Erk M, Cenani A. 3p abnormalities in peripheral lymphocytes in small cell lung cancer. Tumori 2009; 95(4): 535-7. google scholar
• Zabarovsky ER, Lerman MI, Minna JD. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002; 21(45): 6915-35. google scholar
• Balsara BR, Testa JR. Chromosomal imbalances in human lung cancer. Oncogene 2002; 21(45): 6877-83. google scholar
• Dave BJ, Hopwood VL, King TM, Jiang H, Spitz MR, Pathak S. Genetic susceptibility to lung cancer as determined by lymphocytic chromosome analysis. Cancer Epidemiol Biomarkers Prev 1995; 4(7): 743-9. google scholar
• Mori N, Yokota J, Oshimura M, Cavenee WK, Mizoguchi H, Noguchi M, et al. Concordant deletions of chromosome 3p and loss of heterozygosity for chromosomes 13 and 17 in small cell lung carcinoma. Cancer Res 1989; 49(18): 5130-5. google scholar
• Todd S, Franklin WA, Varella-Garcia M, Kennedy T, Hilliker CE, Jr., Hahner L, et al. Homozygous deletions of human chromosome 3p in lung tumors. Cancer Res 1997; 57(7): 1344-52. google scholar
• Dave B, Hopwood V, Spitz M, Pathak S. Shared cytogenetic abnormalities in lung-tumors and corresponding peripheral-blood lymphocytes. Int J Oncol 1995; 7(6): 1297-305. google scholar
• De Fusco PA, Frytak S, Dahl RJ, Weiland LH, Unni KK, Dewald GW. Cytogenetic studies in 11 patients with small cell carcinoma of the lung. Mayo Clin Proc 1989; 64(2): 168-76. google scholar
• Khan S, Coulson JM, Woll PJ. Genetic abnormalities in plasma DNA of patients with lung cancer and other respiratory diseases. Int J Cancer 2004; 110(6): 891-5. google scholar
• Hurr K, Kemp B, Silver SA, el-Naggar AK. Microsatellite alteration at chromosome 3p loci in neuroendocrine and non-neuroendocrine lung tumors. Histogenetic and clinical relevance. Am J Pathol 1996; 149(2): 613-20. google scholar
• Sozzi G, Pastorino U, Moiraghi L, Tagliabue E, Pezzella F, Ghirelli C, et al. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res 1998; 58(22): 5032-7. google scholar
• Niu Z, Jiang D, Shen J, Liu W, Tan X, Cao G. Potential role of the fragile histidine triad in cancer evo-dev. Cancers (Basel) 2023; 15(4). google scholar
• Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol 2016; 22(44): 9694-705. google scholar
• Karras JR, Paisie CA, Huebner K. Replicative stress and the FHIT gene: roles in tumor suppression, genome stability and prevention of carcinogenesis. Cancers (Basel) 2014; 6(2): 1208-19. google scholar
• Kawanishi M, Kohno T, Otsuka T, Adachi J, Sone S, Noguchi M, et al. Allelotype and replication error phenotype of small cell lung carcinoma. Carcinogenesis 1997; 18(11): 2057-62. google scholar
• Pathak S. Cytogenetics of epithelial malignant lesions. Cancer 1992; 70(6 Suppl): 1660-70. google scholar
• Heng HH, Liu G, Bremer S, Ye KJ, Stevens J, Ye CJ. Clonal and non-clonal chromosome aberrations and genome variation and aberration. Genome 2006; 49(3): 195-204. google scholar
• Burke L, Khan MA, Freedman AN, Gemma A, Rusin M, Guinee DG, et al. Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer. Cancer Res 1998; 58(12): 2533-6. google scholar
• Karras JR, Schrock MS, Batar B, Huebner K. Fragile genes that are frequently altered in cancer: players not passengers. Cytogenet Genome Res 2016; 150(3-4): 208-16. google scholar
• Zhou Q, Chen J, Qin Y, Sun Z, Liu L, Sun Z, et al. [A study on the allelic deletion and mutation of FHIT gene in human non-small cell lung cancer]. Zhongguo Fei Ai Za Zhi 2001; 4(1): 10-4. google scholar
• Saldivar JC, Park D. Mechanisms shaping the mutational landscape of the FRA3B/FHIT-deficient cancer genome. Genes Chromosomes Cancer 2019; 58(5): 317-23. google scholar