Alessandra Renieri1, Maria Antonietta Mencarelli2, Francesco Cetta3, Margherita Baldassarri4, Francesca Mari4, Simone Furini5, Pietro Piu6, Francesca Ariani7, Tommaso A Dragani8, Elisa Frullanti9. 1. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy; Istituto Toscano Tumori, Florence, Italy. Electronic address: alessandra.renieri@unisi.it. 2. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 3. IRCCS MultiMedica, Milan, Italy. 4. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy. 5. Department of Medical Biotechnology, University of Siena, Siena, Italy. 6. Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy. 7. Medical Genetics, University of Siena, Siena, Italy. 8. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 9. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address: elisa.frullanti@dbm.unisi.it.
Abstract
OBJECTIVES: A polygenic model is commonly assumed for the predisposition to common cancers. With respect to lung cancer, Genome Wide Association Studies (GWAS) have identified three loci at 15q25, 5p15.33, and 6p21. However, the relative risks associated with alleles at these loci are low; in addition, the data are limited to smokers, and have not been quite reproducible. MATERIALS AND METHODS: In order to investigate genetic susceptibility we have adopted an entirely novel patient selection strategy. First, we have selected for adenocarcinoma (ADCA) histology only; second, we have selected non-smokers; third we have selected patients who developed ADCA of lung before the age of 60 and who had an older unaffected sib: we have identified 31 such sib-pairs. Among them, we selected two patients with very early age at disease onset (37- and 49-years old), and having a healthy sibling available for genome comparison older than at least 7 years. RESULTS: On germline DNA samples of four subjects of two such pairs we have carried out whole exome sequencing. Truncating mutations were detected in 8 'cancer genes' in one affected, and in 5 cancer genes in the other affected subject: but none in the two healthy sibs (p=0.0026). Some of these mutant genes (such as BAG6, SPEN and WISP3) are recognized as major cancer players in lung tumors; others have been previously identified in other human cancers (JAK2, TCEB3C, NELFE, TAF1B, EBLN2), in mouse models (GON4L, NOP58, and RBMX) or in genome-wide association studies (KIAA2018, ZNF311). CONCLUSIONS: This study identifies for the first time in non-smokers with lung adenocarcinoma specific sets of germline mutations that, together, may predispose to this tumor.
OBJECTIVES: A polygenic model is commonly assumed for the predisposition to common cancers. With respect to lung cancer, Genome Wide Association Studies (GWAS) have identified three loci at 15q25, 5p15.33, and 6p21. However, the relative risks associated with alleles at these loci are low; in addition, the data are limited to smokers, and have not been quite reproducible. MATERIALS AND METHODS: In order to investigate genetic susceptibility we have adopted an entirely novel patient selection strategy. First, we have selected for adenocarcinoma (ADCA) histology only; second, we have selected non-smokers; third we have selected patients who developed ADCA of lung before the age of 60 and who had an older unaffected sib: we have identified 31 such sib-pairs. Among them, we selected two patients with very early age at disease onset (37- and 49-years old), and having a healthy sibling available for genome comparison older than at least 7 years. RESULTS: On germline DNA samples of four subjects of two such pairs we have carried out whole exome sequencing. Truncating mutations were detected in 8 'cancer genes' in one affected, and in 5 cancer genes in the other affected subject: but none in the two healthy sibs (p=0.0026). Some of these mutant genes (such as BAG6, SPEN and WISP3) are recognized as major cancer players in lung tumors; others have been previously identified in other humancancers (JAK2, TCEB3C, NELFE, TAF1B, EBLN2), in mouse models (GON4L, NOP58, and RBMX) or in genome-wide association studies (KIAA2018, ZNF311). CONCLUSIONS: This study identifies for the first time in non-smokers with lung adenocarcinoma specific sets of germline mutations that, together, may predispose to this tumor.
Authors: Alisa M Goldstein; Elizabeth M Gillanders; Melissa Rotunno; Rolando Barajas; Mindy Clyne; Elise Hoover; Naoko I Simonds; Tram Kim Lam; Leah E Mechanic Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-05-28 Impact factor: 4.254