Benusiglio Patrick R, Couvé Sophie, Gilbert-Dussardier Brigitte, Deveaux Sophie, Le Jeune Hélène, Da Costa Mélanie, Fromont Gaëlle, Memeteau Françoise, Yacoub Mokrane, Coupier Isabelle, Leroux Dominique, Méjean Arnaud, Escudier Bernard, Giraud Sophie, Gimenez-Roqueplo Anne-Paule, Blondel Christophe, Frouin Eric, Teh Bin T, Ferlicot Sophie, Bressac-de Paillerets Brigitte, Richard Stéphane, Gad Sophie
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Département de Médecine Oncologique, Consultation d'Oncogénétique, Gustave Roussy Cancer Campus, Villejuif, France.
Ecole Pratique des Hautes Etudes, Paris, France Laboratoire de Génétique Oncologique EPHE, INSERM U753, Villejuif, France Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
J Med Genet. 2015 Jun;52(6):426-30. doi: 10.1136/jmedgenet-2014-102912. Epub 2015 Apr 24.
Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC.
We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene.
A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours.
We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.
许多家族性肾细胞癌（RCC）病例无法通过已知的易感基因中的突变或共同的环境因素来解释。因此，还有其他尚未确定的基因参与家族性RCC。PBRM1是一种肿瘤抑制基因，在30%-45%的散发性透明细胞（cc）RCC中发现有体细胞突变。
我们选择了35例无血缘关系的ccRCC患者，他们有无法解释的个人病史且至少有一位患病的一级亲属，并对PBRM1基因进行测序。
在一名患者中发现了一种种系移码突变（c.3998_4005del [p.Asp1333Glyfs]）。该患者的母亲、他的妹妹和一个侄女也患有ccRCC。该突变与疾病共分离，因为这三名患病亲属是携带者，而一名未患病的妹妹不是，符合常染色体显性遗传。体细胞研究支持了这些发现，因为我们在肾肿瘤中观察到了该突变的杂合性缺失和蛋白质表达缺失。
我们首次表明，PBRM1中的遗传性突变易患RCC。有必要进行国际研究，以评估PBRM1对RCC易感性的影响，估计外显率，然后将该基因纳入常规临床实践。
