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Cancer genetics and cell andmolecular biology: Is this the way forward?
Abstracts
/ Lung
Cancer
COI School, University o/Crete. Heroklion 714 09. Int J Oncol l996;8:1089-93. The purpose of our study was to assess the prevalence and prognostic significance’ofHPV infection as well as K-ras codon 12 point mutations in lung cancez Patients diagnosed with lung carcinoma between 1988 and 1992 @J = 99) were selected. HPV detection and typing was perforined by PCR from pa&in-embedded tissues, while mutations in codon 12 of K-ras gene were detected using the restriction fragment length polymorphism (RFLP) analysis. The prevalence of HPV infection was 15%, while K-ras codon 12 point mutations were found in 18% of the specimens examined. In 50% of the HPV-positive cases, Kras gene mutation coexisted. HPV 18 was the most frequent type. No correlation was found between K-ras mutation and HPV infection with sex, age and clinical outcome of the patient, or the histological type and the differentiation grade of the lumor. An association was found between K-ras codon 12 point mutations and the stage of the tumor, occurring more frequently at stage III (p = 0.037). Infection with potentially oncogenic HPV types could co-operate with K-ras gene activation in the progression of the disease, since K-ras activation by point mutations Seems to bc a late event in lung carcinogenesis. Immunohistochemical examination of fucosylceramide expression in lung adenocarcinomas Yamada H, Kawabata Y. Ohtomo K et al. Deporrment of Pafholoa, Saitamo Medical Centea Saitamo Medical School. Sailorno. Jpn J Lung Cancer 1996:36: 13 1-7. In order to examine whether the antibody PC47H is useful to detect differentiation toward pulmonary adenocarcinoma immunohistcchemical examinations were undertaken comparing the results for antibody for CEA. Furthermore. antibodies for lactoferrin (LF), surfactant apoprotein (SA) and Clara cell 10 kDa antigen were’ used as subtype markers of pulmonary adenocarcinoma. Seventy-one adenocarcinoma (male; 48 cases, female; 23 cases mean age; 62.4, well differentiated; 35 cases, moderately differentiated; 22 cases poorly differentiated; 14 cases) were included. Fucosylceramide was diffusely and granularly stained in cytoplasm in 70/71 (well and moderately differentiated 571 57 in total and poorly differentiated 13114). On the other hand, CEA was recognized in 58/7 1 (well differentiated 3 l/35 and moderately differentiated 21/22, and only 50.0% in poorly differentiated). These results indicate that PC47H is a more useful tumor marker for adenocarcinema than CEA. Genetic abnormality at the 1~32 locus in metastasis of lung cancer Okusaki K. SecondDept. o/lntemalMedicine, Hiroshima Unrv. School ?fMedicine, Hiroshima. Jpn I Lung Cancer 1996;36:99-105. In order to investigate the possibility that some genes related to metastasis of lung cancer are present at the 1~32 locus, where the Lmyc gene is located, primary and metastatic lesions from 17 autopsy zases of lung cancer were studied to determine whether there was loss sf heterozygosity at the 1~32 locus. Four (24%) of the primary and 12 117%) of the metastatic lesions were positive. The positivity ratio was iigniticantly higher (p = 0.0 15) in me&&tic than in primary lesions. jarticularly in cases with the S allele in the L-myc RFLl? It is therefore suggested that some genes related lo metastasis of lung cancer are present tt the 1~32 locus. Expression of vitamin D receptor in lung cancer (a&r U, Schilli M, Wegmann B et al. Zentrum Innere Medizrn, 1bteilung Homotologie/Onkologie, Philipps-Universitat Marburg, Qldinger Strasse, D-35033 MarbuR. J Cancer Res Clin Oncol 1996;122:356-9. The active membolite of vitamin D 1,25-dihydroxycholecalciferol s a hormone-like agent that regulates cell differentiation and PrOhfera-
16 (1996)
105-127
II
tion. Various vitamin D derivatives have been shown to induce diffe entiation in neoplastic cells. The prerequisite for any hormone action the presence of its receptor. We studied the expression of vitamin receptor in human lung cancer cell lines and in primary lung cancf tissue. Employing the polymerase chain reaction, 10 out of 11 cell lint stemming from small-cell lung cancer and I5 out of 15 cell lines sten ming from non-small-cell lung cancer demonstrated vitamin D receptc expression. An immunohistochemical analysis, using a specific mono clonal antibody, demonstrated vitamin D receptor protein expression i 3 1 out of 117 (26%) primary small-cell lung cancer cases tested. Pos tive cells exhibited a nuclear reaction pattern. Twenty-one out of 3 primary non-small-cell lung cancer cases, particularly adenocarcinc mas (9114) and squamous-cell carcinomas (10/15), exhibited vitami D receptor. Results indicate that a subset of lung cancer cases may b susceptible to the differentiating effects of vitamin D analogues.
Cancer genetics and cell and molecular biology: Is this the wa forward? Smyth JF Deportment of Clrnical Oncology, Universiry o/Edinbu@ Western General Hospital, Edinburgh EH4 2XU. Chest 1996;105 Suppl: 125-9. Lung cancer, the most prevalent cancer in the western world, i predominantly caused by smoking and thus perceived as a ‘self-inflicted disease. Nevertheless, only 20% of smokers develop lung cancer. Thi review examines the concept of high-risk populations and screening. I looks at developments in the molecular epidemiology of the diseas that shed new light on genetic changes that may predispose individual to malignancy. Improvements in existing drug therapy are discussed a well as important new therapeutic developments, including antigrowt factors (antagonists G and D), antimetastatic agents (matrix metalla proteinase inhibitors), and natural products, arising from a greater un derstanding of signal transduction pathways anti the process of ccl metastasis.
Human lung cancer cells endogenously expressing mutant ~5: process and present the mutqt epitope and are lysed by mu tant-specific cytotoric T lymphocytes Ciernik IF; Benofsky JA, Corbone DI? Simmons Cancer Cente,: Uni versity of Texas, Southwestern Medico1 Cente,: 5323 Harry Hines Boul evord, Dallas, TX 75235-8593. Clin Cancer Res 1996;2:877-82. The ~53 oncoprotein frequently contains somatically acquired mis sense mutations and is often overexpressed in cancer cells. Missens mutations can give rise to new tumor-specific peptide sequences, whicl can act as targets for T cell-mediated immunotherapy. To investigatl the ability of human lung cancer cells to adequately process and presen a mutant p53derived CTL epitope, we transfcctcd the human cell lint HMy-2.CIR and the p53-null human lung cancer cell lines H358 ant H1299 with an expression vector containing a human mutant ~53 (131 Cys to Tyr). After transfection with the K(d) restriction element, thesl cells were tested as targets for murine mutation-specific CTLs. We shov that these human lung cancer cells effectively process and present thi. endogenous mutant human ~53 epitope, resulting in efficient, mutan epitope-specific lysis by CTLs. In the presence of the appropriate re striction element. human lung cancer cells can be effectively targetec by CTLs specific for somatically acquired, endogenous mutant epitopes supporting targeted immunotherapy efforts in lung cancer. Purification and characterization of a protein that permits early detection of lung cancer: Identification of heterogeneous nuclear ribonucleoprotein-A2/Bl as the antigen for monoclonal antibody 703D4
/ Lung
Cancer
COI School, University o/Crete. Heroklion 714 09. Int J Oncol l996;8:1089-93. The purpose of our study was to assess the prevalence and prognostic significance’ofHPV infection as well as K-ras codon 12 point mutations in lung cancez Patients diagnosed with lung carcinoma between 1988 and 1992 @J = 99) were selected. HPV detection and typing was perforined by PCR from pa&in-embedded tissues, while mutations in codon 12 of K-ras gene were detected using the restriction fragment length polymorphism (RFLP) analysis. The prevalence of HPV infection was 15%, while K-ras codon 12 point mutations were found in 18% of the specimens examined. In 50% of the HPV-positive cases, Kras gene mutation coexisted. HPV 18 was the most frequent type. No correlation was found between K-ras mutation and HPV infection with sex, age and clinical outcome of the patient, or the histological type and the differentiation grade of the lumor. An association was found between K-ras codon 12 point mutations and the stage of the tumor, occurring more frequently at stage III (p = 0.037). Infection with potentially oncogenic HPV types could co-operate with K-ras gene activation in the progression of the disease, since K-ras activation by point mutations Seems to bc a late event in lung carcinogenesis. Immunohistochemical examination of fucosylceramide expression in lung adenocarcinomas Yamada H, Kawabata Y. Ohtomo K et al. Deporrment of Pafholoa, Saitamo Medical Centea Saitamo Medical School. Sailorno. Jpn J Lung Cancer 1996:36: 13 1-7. In order to examine whether the antibody PC47H is useful to detect differentiation toward pulmonary adenocarcinoma immunohistcchemical examinations were undertaken comparing the results for antibody for CEA. Furthermore. antibodies for lactoferrin (LF), surfactant apoprotein (SA) and Clara cell 10 kDa antigen were’ used as subtype markers of pulmonary adenocarcinoma. Seventy-one adenocarcinoma (male; 48 cases, female; 23 cases mean age; 62.4, well differentiated; 35 cases, moderately differentiated; 22 cases poorly differentiated; 14 cases) were included. Fucosylceramide was diffusely and granularly stained in cytoplasm in 70/71 (well and moderately differentiated 571 57 in total and poorly differentiated 13114). On the other hand, CEA was recognized in 58/7 1 (well differentiated 3 l/35 and moderately differentiated 21/22, and only 50.0% in poorly differentiated). These results indicate that PC47H is a more useful tumor marker for adenocarcinema than CEA. Genetic abnormality at the 1~32 locus in metastasis of lung cancer Okusaki K. SecondDept. o/lntemalMedicine, Hiroshima Unrv. School ?fMedicine, Hiroshima. Jpn I Lung Cancer 1996;36:99-105. In order to investigate the possibility that some genes related to metastasis of lung cancer are present at the 1~32 locus, where the Lmyc gene is located, primary and metastatic lesions from 17 autopsy zases of lung cancer were studied to determine whether there was loss sf heterozygosity at the 1~32 locus. Four (24%) of the primary and 12 117%) of the metastatic lesions were positive. The positivity ratio was iigniticantly higher (p = 0.0 15) in me&&tic than in primary lesions. jarticularly in cases with the S allele in the L-myc RFLl? It is therefore suggested that some genes related lo metastasis of lung cancer are present tt the 1~32 locus. Expression of vitamin D receptor in lung cancer (a&r U, Schilli M, Wegmann B et al. Zentrum Innere Medizrn, 1bteilung Homotologie/Onkologie, Philipps-Universitat Marburg, Qldinger Strasse, D-35033 MarbuR. J Cancer Res Clin Oncol 1996;122:356-9. The active membolite of vitamin D 1,25-dihydroxycholecalciferol s a hormone-like agent that regulates cell differentiation and PrOhfera-
16 (1996)
105-127
II
tion. Various vitamin D derivatives have been shown to induce diffe entiation in neoplastic cells. The prerequisite for any hormone action the presence of its receptor. We studied the expression of vitamin receptor in human lung cancer cell lines and in primary lung cancf tissue. Employing the polymerase chain reaction, 10 out of 11 cell lint stemming from small-cell lung cancer and I5 out of 15 cell lines sten ming from non-small-cell lung cancer demonstrated vitamin D receptc expression. An immunohistochemical analysis, using a specific mono clonal antibody, demonstrated vitamin D receptor protein expression i 3 1 out of 117 (26%) primary small-cell lung cancer cases tested. Pos tive cells exhibited a nuclear reaction pattern. Twenty-one out of 3 primary non-small-cell lung cancer cases, particularly adenocarcinc mas (9114) and squamous-cell carcinomas (10/15), exhibited vitami D receptor. Results indicate that a subset of lung cancer cases may b susceptible to the differentiating effects of vitamin D analogues.
Cancer genetics and cell and molecular biology: Is this the wa forward? Smyth JF Deportment of Clrnical Oncology, Universiry o/Edinbu@ Western General Hospital, Edinburgh EH4 2XU. Chest 1996;105 Suppl: 125-9. Lung cancer, the most prevalent cancer in the western world, i predominantly caused by smoking and thus perceived as a ‘self-inflicted disease. Nevertheless, only 20% of smokers develop lung cancer. Thi review examines the concept of high-risk populations and screening. I looks at developments in the molecular epidemiology of the diseas that shed new light on genetic changes that may predispose individual to malignancy. Improvements in existing drug therapy are discussed a well as important new therapeutic developments, including antigrowt factors (antagonists G and D), antimetastatic agents (matrix metalla proteinase inhibitors), and natural products, arising from a greater un derstanding of signal transduction pathways anti the process of ccl metastasis.
Human lung cancer cells endogenously expressing mutant ~5: process and present the mutqt epitope and are lysed by mu tant-specific cytotoric T lymphocytes Ciernik IF; Benofsky JA, Corbone DI? Simmons Cancer Cente,: Uni versity of Texas, Southwestern Medico1 Cente,: 5323 Harry Hines Boul evord, Dallas, TX 75235-8593. Clin Cancer Res 1996;2:877-82. The ~53 oncoprotein frequently contains somatically acquired mis sense mutations and is often overexpressed in cancer cells. Missens mutations can give rise to new tumor-specific peptide sequences, whicl can act as targets for T cell-mediated immunotherapy. To investigatl the ability of human lung cancer cells to adequately process and presen a mutant p53derived CTL epitope, we transfcctcd the human cell lint HMy-2.CIR and the p53-null human lung cancer cell lines H358 ant H1299 with an expression vector containing a human mutant ~53 (131 Cys to Tyr). After transfection with the K(d) restriction element, thesl cells were tested as targets for murine mutation-specific CTLs. We shov that these human lung cancer cells effectively process and present thi. endogenous mutant human ~53 epitope, resulting in efficient, mutan epitope-specific lysis by CTLs. In the presence of the appropriate re striction element. human lung cancer cells can be effectively targetec by CTLs specific for somatically acquired, endogenous mutant epitopes supporting targeted immunotherapy efforts in lung cancer. Purification and characterization of a protein that permits early detection of lung cancer: Identification of heterogeneous nuclear ribonucleoprotein-A2/Bl as the antigen for monoclonal antibody 703D4