Renieri Alessandra, Mencarelli Maria Antonietta, Cetta Francesco, Baldassarri Margherita, Mari Francesca, Furini Simone, Piu Pietro, Ariani Francesca, Dragani Tommaso A, Frullanti Elisa
Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy; Istituto Toscano Tumori, Florence, Italy.
Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Lung Cancer. 2014 Aug;85(2):168-74. doi: 10.1016/j.lungcan.2014.05.020. Epub 2014 Jun 4.
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.
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.
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).
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.
对于常见癌症的易感性，通常假定为多基因模型。就肺癌而言，全基因组关联研究（GWAS）已在15q25、5p15.33和6p21处确定了三个基因座。然而，与这些基因座上等位基因相关的相对风险较低；此外，数据仅限于吸烟者，且不太具有可重复性。
为了研究遗传易感性，我们采用了一种全新的患者选择策略。首先，我们仅选择腺癌（ADCA）组织学类型的患者；其次，我们选择不吸烟者；第三，我们选择在60岁之前患肺ADCA且有未患病的年长同胞的患者：我们确定了31对这样的同胞对。在其中，我们选择了两名疾病发病年龄非常早（37岁和49岁）且有比其至少大7岁的健康同胞可用于基因组比较的患者。
在两对这样的同胞对中的四名受试者的种系DNA样本上，我们进行了全外显子组测序。在一名患病受试者的8个“癌症基因”中检测到截短突变，在另一名患病受试者的5个癌症基因中检测到截短突变：但在两名健康同胞中均未检测到（p = 0.0026）。其中一些突变基因（如BAG6、SPEN和WISP3）被认为是肺肿瘤中的主要癌症相关基因；其他一些基因先前已在其他人类癌症（JAK2、TCEB3C、NELFE、TAF1B、EBLN2）、小鼠模型（GON4L、NOP58和RBMX）或全基因组关联研究（KIAA2018、ZNF311）中被鉴定出来。
本研究首次在非吸烟的肺腺癌患者中鉴定出特定的种系突变组合，这些突变共同可能易患这种肿瘤。
