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Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma
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| Zeitschriftentitel: | Cancer Discovery |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , |
| In: | Cancer Discovery, 5, 2015, 7, S. 723-729 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Jafri, Mariam Wake, Naomi C. Ascher, David B. Pires, Douglas E.V. Gentle, Dean Morris, Mark R. Rattenberry, Eleanor Simpson, Michael A. Trembath, Richard C. Weber, Astrid Woodward, Emma R. Donaldson, Alan Blundell, Tom L. Latif, Farida Maher, Eamonn R. Jafri, Mariam Wake, Naomi C. Ascher, David B. Pires, Douglas E.V. Gentle, Dean Morris, Mark R. Rattenberry, Eleanor Simpson, Michael A. Trembath, Richard C. Weber, Astrid Woodward, Emma R. Donaldson, Alan Blundell, Tom L. Latif, Farida Maher, Eamonn R. |
|---|---|
| author |
Jafri, Mariam Wake, Naomi C. Ascher, David B. Pires, Douglas E.V. Gentle, Dean Morris, Mark R. Rattenberry, Eleanor Simpson, Michael A. Trembath, Richard C. Weber, Astrid Woodward, Emma R. Donaldson, Alan Blundell, Tom L. Latif, Farida Maher, Eamonn R. |
| spellingShingle |
Jafri, Mariam Wake, Naomi C. Ascher, David B. Pires, Douglas E.V. Gentle, Dean Morris, Mark R. Rattenberry, Eleanor Simpson, Michael A. Trembath, Richard C. Weber, Astrid Woodward, Emma R. Donaldson, Alan Blundell, Tom L. Latif, Farida Maher, Eamonn R. Cancer Discovery Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma Oncology |
| author_sort |
jafri, mariam |
| spelling |
Jafri, Mariam Wake, Naomi C. Ascher, David B. Pires, Douglas E.V. Gentle, Dean Morris, Mark R. Rattenberry, Eleanor Simpson, Michael A. Trembath, Richard C. Weber, Astrid Woodward, Emma R. Donaldson, Alan Blundell, Tom L. Latif, Farida Maher, Eamonn R. 2159-8274 2159-8290 American Association for Cancer Research (AACR) Oncology http://dx.doi.org/10.1158/2159-8290.cd-14-1096 <jats:title>Abstract</jats:title> <jats:p>Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.</jats:p> <jats:p>Significance: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease. Cancer Discov; 5(7); 723–9. ©2015 AACR.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 681</jats:p> Germline Mutations in the <i>CDKN2B</i> Tumor Suppressor Gene Predispose to Renal Cell Carcinoma Cancer Discovery |
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| title |
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_unstemmed |
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_full |
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_fullStr |
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_full_unstemmed |
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_short |
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_sort |
germline mutations in the <i>cdkn2b</i> tumor suppressor gene predispose to renal cell carcinoma |
| topic |
Oncology |
| url |
http://dx.doi.org/10.1158/2159-8290.cd-14-1096 |
| publishDate |
2015 |
| physical |
723-729 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.</jats:p>
<jats:p>Significance: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease. Cancer Discov; 5(7); 723–9. ©2015 AACR.</jats:p>
<jats:p>This article is highlighted in the In This Issue feature, p. 681</jats:p> |
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| author | Jafri, Mariam, Wake, Naomi C., Ascher, David B., Pires, Douglas E.V., Gentle, Dean, Morris, Mark R., Rattenberry, Eleanor, Simpson, Michael A., Trembath, Richard C., Weber, Astrid, Woodward, Emma R., Donaldson, Alan, Blundell, Tom L., Latif, Farida, Maher, Eamonn R. |
| author_facet | Jafri, Mariam, Wake, Naomi C., Ascher, David B., Pires, Douglas E.V., Gentle, Dean, Morris, Mark R., Rattenberry, Eleanor, Simpson, Michael A., Trembath, Richard C., Weber, Astrid, Woodward, Emma R., Donaldson, Alan, Blundell, Tom L., Latif, Farida, Maher, Eamonn R., Jafri, Mariam, Wake, Naomi C., Ascher, David B., Pires, Douglas E.V., Gentle, Dean, Morris, Mark R., Rattenberry, Eleanor, Simpson, Michael A., Trembath, Richard C., Weber, Astrid, Woodward, Emma R., Donaldson, Alan, Blundell, Tom L., Latif, Farida, Maher, Eamonn R. |
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| description | <jats:title>Abstract</jats:title> <jats:p>Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.</jats:p> <jats:p>Significance: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease. Cancer Discov; 5(7); 723–9. ©2015 AACR.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 681</jats:p> |
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| spelling | Jafri, Mariam Wake, Naomi C. Ascher, David B. Pires, Douglas E.V. Gentle, Dean Morris, Mark R. Rattenberry, Eleanor Simpson, Michael A. Trembath, Richard C. Weber, Astrid Woodward, Emma R. Donaldson, Alan Blundell, Tom L. Latif, Farida Maher, Eamonn R. 2159-8274 2159-8290 American Association for Cancer Research (AACR) Oncology http://dx.doi.org/10.1158/2159-8290.cd-14-1096 <jats:title>Abstract</jats:title> <jats:p>Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.</jats:p> <jats:p>Significance: Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease. Cancer Discov; 5(7); 723–9. ©2015 AACR.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 681</jats:p> Germline Mutations in the <i>CDKN2B</i> Tumor Suppressor Gene Predispose to Renal Cell Carcinoma Cancer Discovery |
| spellingShingle | Jafri, Mariam, Wake, Naomi C., Ascher, David B., Pires, Douglas E.V., Gentle, Dean, Morris, Mark R., Rattenberry, Eleanor, Simpson, Michael A., Trembath, Richard C., Weber, Astrid, Woodward, Emma R., Donaldson, Alan, Blundell, Tom L., Latif, Farida, Maher, Eamonn R., Cancer Discovery, Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma, Oncology |
| title | Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_full | Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_fullStr | Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_full_unstemmed | Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_short | Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| title_sort | germline mutations in the <i>cdkn2b</i> tumor suppressor gene predispose to renal cell carcinoma |
| title_unstemmed | Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma |
| topic | Oncology |
| url | http://dx.doi.org/10.1158/2159-8290.cd-14-1096 |