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J Med Genet. 2015 Jun;52(6):426-30. doi: 10.1136/jmedgenet-2014-102912. Epub 2015 Apr 24.

A germline mutation in PBRM1 predisposes to renal cell carcinoma.

Author information

1
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.
2
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.
3
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Service de Génétique Médicale, CHU de Poitiers, Poitiers, France.
4
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
5
Service d'Anatomie et Cytologie Pathologiques, INSERM UMR1069, CHRU de Tours, Tours, France.
6
Département d'Anatomie et de Cytologie Pathologique, Centre Hospitalier de Niort, Niort, France.
7
Service de Pathologie, CHU Pellegrin de Bordeaux, Bordeaux, France.
8
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Unité d'oncogénétique, CRLC Val-d'Aurelle, Montpellier, France Service de Génétique Médicale, Unité d'Oncogénétique, CHU de Montpellier, Montpellier, France.
9
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Département d'Hématologie, Oncogénétique et Immunologie, CHU de Grenoble site Nord-Institut de biologie et de pathologie, Boulevard de la Chantourne, La Tronche, France.
10
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Service d'Urologie, Hôpital Européen Georges-Pompidou, AP-HP,  Paris, France Université Paris-Descartes, 12 Rue de l'École de Médecine, Paris, France.
11
Département de Médecine Oncologique, Consultation des tumeurs rénales, et INSERM U753, Villejuif, France.
12
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Génétique Moléculaire et Clinique, Hôpital Edouard Herriot, Lyon, France.
13
Département de Génétique Moléculaire, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
14
Département de Biopathologie, Service de Génétique, Gustave Roussy Cancer Campus, Villejuif, France.
15
Service d'Anatomie et de Cytologie Pathologiques, CHU de Poitiers, Poitiers, France.
16
NCCS-VARI Translational Research Laboratory, Division of Medical Sciences, National Cancer Centre, Singapore, Singapore Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, Singapore, Singapore.
17
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, France Service d'Anatomie Pathologique, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France.
18
Centre Expert National Cancers Rares PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin Bicêtre, 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.

Abstract

BACKGROUND:

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.

METHODS:

We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Cancer: urological; Molecular genetics; PBRM1; predisposing genes

PMID:
25911086
DOI:
10.1136/jmedgenet-2014-102912
[Indexed for MEDLINE]

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