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Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome
Cancer Letters 247 (2007) 353–355 www.elsevier.com/locate/canlet
Letter to the Editor Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome q We read with interest the article ‘‘The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families’’ by Achatz and colleagues [1]. The authors sequenced the TP53 genes of 45 unrelated patients from south Brazil whose families fulfilled the clinical criteria for Li-Fraumeni syndrome (LFS) (10 families) or Li-Fraumeni-like (LFL) syndrome (35 families). Among the 13 carriers of TP53 mutations, six carried the TP53 R337H mutation. However, despite the article’s title, none of these carriers’ families met the criteria for classic LFS [2]. Similarly, we found no instance of LFS in carriers of the TP53 R337H mutation among 30 kindreds (40 families; 695 individuals tested in the carrier parental line) of index cases of childhood adrenocortical tumor (ACT) [3]. In two smaller studies in southern Brazil, none of 26 children and 6 adults with ACT and the germline TP53 R337H mutation had families that fulfilled the criteria for LFS [4,5]. Therefore, the available data compellingly indicate that the TP53 R337H mutation is not associated with LFS. This fact is not surprising, considering that the function of the mutant TP53 in such cases is relatively well preserved [6,7], and consequently the spectrum and the age of onset of associated cancers should differ from those of mutations that substantially abrogate TP53 function. The issue then becomes whether the TP53 R337H mutation is associated with LFL syndrome in Brazilian families. The authors included 35 q Supported in part by Cancer Center Support Grants CA21765 and CA-71907 from the National Institutes of Health (U.S. Department of Health and Human Services); a Center of Excellence grant from the State of Tennessee; the Conselho Nacional de Pesquisa (CNPq) of Brazil; Fundacao Araucaria, Curitiba, Parana, Brazil (01/2001), and the American Lebanese Syrian Associated Charities (ALSAC).
families that fulfilled the criteria of either Birch et al. [2] or Eeles et al. [2] for LFL syndrome. Cancer patients from six of the 35 families with LFL syndrome (17.1%) carried the TP53 R337H mutation. Twenty-three of these 35 families (65.7%) harbored no constitutional TP53 mutations, implicating other, still unidentified genetic or environmental factors in their increased predisposition to cancer. Therefore, factors other than the TP53 R337H mutation may also be associated with increased cancer susceptibility among families carrying the TP53 R337H mutation. In our study, seven (23%) of 30 kindreds in which one parental line carried the TP53 R337H mutation fulfilled the criteria of Birch et al. [2] for LFL syndrome. Remarkably, the remaining 23 kindreds (77%) with this mutation showed no evidence of increased predisposition to cancer. Our results are similar to those described by Latronico et al. [4] and Sandrini et al. [5]. Taken together, these findings clearly demonstrate that the TP53 R337H mutation is not sufficient to establish LFS or LFL syndrome. Why were our findings [3] and those of other investigators [4,5] different from those reported by Achatz et al.? We believe that the explanation lies in the criteria used to select the participating families. In our study, we first identified families of a proband with ACT and subsequently detected the germline TP53 R337H mutation. In each case, either the proband’s mother or father carried the mutation. The history of cancer was then ascertained for this side of the family. Conversely, Achatz et al. selected families that fulfilled the criteria for LFS or LFL syndrome. However, if we had applied the same selection criteria used by Achatz et al., we would have excluded from our study the 23 kindreds with one parental line carrying the TP53 R337H mutation where ACT has occurred, but failed to meet the criteria for LFS or LFL. Consequently, we would have concluded, on the basis of the remaining 7 families that fulfilled Birch’s criteria
0304-3835/$ - see front matter Ó 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2006.04.008
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Letter to the Editor / Cancer Letters 247 (2007) 353–355
for LFL syndrome, that the TP53 R337H is associated with LFL syndrome. Our hypothesis has been that the TP53 R337H mutation has a narrow, age-dependent organ specificity and relatively low penetrance for the development of cancers. Children carrying this mutation have a 10% cumulative incidence of ACT during the first decade of life [3]. However, Achatz et al. suggest that the age, gender, and tumor spectrum observed in carriers of the TP53 R337H are similar to those observed in LFS or LFL family members carrying other TP53 mutations. A careful inspection of Table 1 in their article argues against this conclusion. For example, the median age of individuals with soft-tissue sarcomas was 44 years among carriers of the TP53 R337H mutation but 17.5 years among with those with other TP53 mutations. Analysis of Fig. 1 in the same article showed other important differences in the spectrum of cancers between carriers of the R337H and carriers of other TP53 mutations. In addition to the high frequency of ACT (8.9% vs. 3.3% in carriers of other TP53 mutations) and stomach cancer (8.9% vs. 3.3%), no cases of bone tumor (0% vs. 11.4%), or leukemia/lymphoma (0% vs. 4.7%) were noted among carriers of the TP53 R337H. Therefore, except for the well-documented contribution of the TP53 R337H mutation to the excess frequency of pediatric ACT in southern Brazil, the role of this mutation in other tumor types remains to be conclusively determined. Finally, the authors suggest that the penetrance of pediatric ACT (approximately 10%) in carriers of the TP53 R337H mutation should be re-evaluated in view of their finding of other types of cancer typical of LFS/LFL syndrome in these carriers. It is not clear how the presence of other tumors would be relevant to the penetrance of pediatric ACT in carriers of the TP53 R337H. The observation of an apparent excess of cancer among certain families that include carriers of the TP53 R337H and the implication of this mutation in the development of breast cancer in a young woman is intriguing. Our data and available published data suggest that breast, brain, and stomach cancer may cluster within affected families. However, extensive epidemiologic investigation would be required to determine whether the penetrance of breast, brain, stomach, or other cancers is increased in carriers of the TP53 R337H mutation. If indeed this is the case, the TP53 R337H mutant most likely does so in combination with
other cooperating genetic factors that lead to a broader spectrum of tumors. Nevertheless, what is clear from our findings [3,6] and those of Latronico [4] and Sandrini [5], is that the TP53 R337H mutant is not sufficient to establish LFS or LFL syndrome, but strongly predisposes carriers to ACT. References [1] M.I.W. Achatz, M. Olivier, F. Le Calvez, et al., The TP53 mutation, R337H, is associated with Li-Fraumeni and LiFraumeni-like syndromes in Brazilian families, Cancer Lett. (2006) 1–7. [2] M. Olivier, D.E. Goldgar, N. Sodha, et al., Li-Fraumeni and related syndromes. Correlations between tumor type, family structure and TP53 genotype, Cancer Res. 63 (2003) 6643–6650. [3] B.C. Figueiredo, R. Sandrini, G.P. Zambetti, et al., Penetrance of adrenocortical tumors associated with the germline TP53 R337H mutation, J. Med. Genet. 43 (2006) 91–96. [4] A.C. Latronico, E.M. Pinto, S. Domenice, et al., An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors, J. Clin. Endocrinol. Metab. 86 (2002) 4970–4973. [5] F. Sandrini, D.P. Villani, S. Tucci, et al., Inheritance of R337H gene mutation in children with sporadic adrenocortical tumor, Horm. Metab. Res. 37 (2005) 231–235. [6] R.C. Ribeiro, F. Sandrini, B. Figueiredo, et al., An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma, Proc. Natl. Acad. Sci. USA 98 (2001) 9330–9335. [7] E.L. DiGiammarino, A.S. Lee, C. Cadwell, et al., A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer, Natl. Struct. Biol. 9 (2002) 12–16.
Raul C. Ribeiro * Carlos Rodriguez-Galindo Department of Hematology-Oncology, International Outreach Program, St. Jude Children’s Research Hospital, Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN, USA E-mail address: [email protected] (R.C. Ribeiro) Bonald C. Figueiredo Center for Molecular Genetics and Cancer Research in Children CEGEMPAC, Federal University of Parana´, Curitiba PR 80060-90, Brazil
*
Corresponding author. Tel.: +1 901 495 3694; fax: +1 901 495 3122.
Letter to the Editor / Cancer Letters 247 (2007) 353–355
Maria Jose Mastellaro Centro Infantil Boldrini, Campinas, SP, Brazil Alina Nico West Department of Interdisciplinary Science, University of Tennessee Health Science Center, Memphis, TN 38163, USA Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
355
Richard Kriwacki Department of Structural Biology, St. Jude Children’s Research Hospital, College of Medicine, University of Tennessee, Memphis, TN, USA Gerard P. Zambetti Department of Biochemistry, St. Jude Children’s Research Hospital, College of Medicine, University of Tennessee, Memphis, TN, USA Received 25 April 2006; accepted 28 April 2006
Letter to the Editor Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome q We read with interest the article ‘‘The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families’’ by Achatz and colleagues [1]. The authors sequenced the TP53 genes of 45 unrelated patients from south Brazil whose families fulfilled the clinical criteria for Li-Fraumeni syndrome (LFS) (10 families) or Li-Fraumeni-like (LFL) syndrome (35 families). Among the 13 carriers of TP53 mutations, six carried the TP53 R337H mutation. However, despite the article’s title, none of these carriers’ families met the criteria for classic LFS [2]. Similarly, we found no instance of LFS in carriers of the TP53 R337H mutation among 30 kindreds (40 families; 695 individuals tested in the carrier parental line) of index cases of childhood adrenocortical tumor (ACT) [3]. In two smaller studies in southern Brazil, none of 26 children and 6 adults with ACT and the germline TP53 R337H mutation had families that fulfilled the criteria for LFS [4,5]. Therefore, the available data compellingly indicate that the TP53 R337H mutation is not associated with LFS. This fact is not surprising, considering that the function of the mutant TP53 in such cases is relatively well preserved [6,7], and consequently the spectrum and the age of onset of associated cancers should differ from those of mutations that substantially abrogate TP53 function. The issue then becomes whether the TP53 R337H mutation is associated with LFL syndrome in Brazilian families. The authors included 35 q Supported in part by Cancer Center Support Grants CA21765 and CA-71907 from the National Institutes of Health (U.S. Department of Health and Human Services); a Center of Excellence grant from the State of Tennessee; the Conselho Nacional de Pesquisa (CNPq) of Brazil; Fundacao Araucaria, Curitiba, Parana, Brazil (01/2001), and the American Lebanese Syrian Associated Charities (ALSAC).
families that fulfilled the criteria of either Birch et al. [2] or Eeles et al. [2] for LFL syndrome. Cancer patients from six of the 35 families with LFL syndrome (17.1%) carried the TP53 R337H mutation. Twenty-three of these 35 families (65.7%) harbored no constitutional TP53 mutations, implicating other, still unidentified genetic or environmental factors in their increased predisposition to cancer. Therefore, factors other than the TP53 R337H mutation may also be associated with increased cancer susceptibility among families carrying the TP53 R337H mutation. In our study, seven (23%) of 30 kindreds in which one parental line carried the TP53 R337H mutation fulfilled the criteria of Birch et al. [2] for LFL syndrome. Remarkably, the remaining 23 kindreds (77%) with this mutation showed no evidence of increased predisposition to cancer. Our results are similar to those described by Latronico et al. [4] and Sandrini et al. [5]. Taken together, these findings clearly demonstrate that the TP53 R337H mutation is not sufficient to establish LFS or LFL syndrome. Why were our findings [3] and those of other investigators [4,5] different from those reported by Achatz et al.? We believe that the explanation lies in the criteria used to select the participating families. In our study, we first identified families of a proband with ACT and subsequently detected the germline TP53 R337H mutation. In each case, either the proband’s mother or father carried the mutation. The history of cancer was then ascertained for this side of the family. Conversely, Achatz et al. selected families that fulfilled the criteria for LFS or LFL syndrome. However, if we had applied the same selection criteria used by Achatz et al., we would have excluded from our study the 23 kindreds with one parental line carrying the TP53 R337H mutation where ACT has occurred, but failed to meet the criteria for LFS or LFL. Consequently, we would have concluded, on the basis of the remaining 7 families that fulfilled Birch’s criteria
0304-3835/$ - see front matter Ó 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2006.04.008
354
Letter to the Editor / Cancer Letters 247 (2007) 353–355
for LFL syndrome, that the TP53 R337H is associated with LFL syndrome. Our hypothesis has been that the TP53 R337H mutation has a narrow, age-dependent organ specificity and relatively low penetrance for the development of cancers. Children carrying this mutation have a 10% cumulative incidence of ACT during the first decade of life [3]. However, Achatz et al. suggest that the age, gender, and tumor spectrum observed in carriers of the TP53 R337H are similar to those observed in LFS or LFL family members carrying other TP53 mutations. A careful inspection of Table 1 in their article argues against this conclusion. For example, the median age of individuals with soft-tissue sarcomas was 44 years among carriers of the TP53 R337H mutation but 17.5 years among with those with other TP53 mutations. Analysis of Fig. 1 in the same article showed other important differences in the spectrum of cancers between carriers of the R337H and carriers of other TP53 mutations. In addition to the high frequency of ACT (8.9% vs. 3.3% in carriers of other TP53 mutations) and stomach cancer (8.9% vs. 3.3%), no cases of bone tumor (0% vs. 11.4%), or leukemia/lymphoma (0% vs. 4.7%) were noted among carriers of the TP53 R337H. Therefore, except for the well-documented contribution of the TP53 R337H mutation to the excess frequency of pediatric ACT in southern Brazil, the role of this mutation in other tumor types remains to be conclusively determined. Finally, the authors suggest that the penetrance of pediatric ACT (approximately 10%) in carriers of the TP53 R337H mutation should be re-evaluated in view of their finding of other types of cancer typical of LFS/LFL syndrome in these carriers. It is not clear how the presence of other tumors would be relevant to the penetrance of pediatric ACT in carriers of the TP53 R337H. The observation of an apparent excess of cancer among certain families that include carriers of the TP53 R337H and the implication of this mutation in the development of breast cancer in a young woman is intriguing. Our data and available published data suggest that breast, brain, and stomach cancer may cluster within affected families. However, extensive epidemiologic investigation would be required to determine whether the penetrance of breast, brain, stomach, or other cancers is increased in carriers of the TP53 R337H mutation. If indeed this is the case, the TP53 R337H mutant most likely does so in combination with
other cooperating genetic factors that lead to a broader spectrum of tumors. Nevertheless, what is clear from our findings [3,6] and those of Latronico [4] and Sandrini [5], is that the TP53 R337H mutant is not sufficient to establish LFS or LFL syndrome, but strongly predisposes carriers to ACT. References [1] M.I.W. Achatz, M. Olivier, F. Le Calvez, et al., The TP53 mutation, R337H, is associated with Li-Fraumeni and LiFraumeni-like syndromes in Brazilian families, Cancer Lett. (2006) 1–7. [2] M. Olivier, D.E. Goldgar, N. Sodha, et al., Li-Fraumeni and related syndromes. Correlations between tumor type, family structure and TP53 genotype, Cancer Res. 63 (2003) 6643–6650. [3] B.C. Figueiredo, R. Sandrini, G.P. Zambetti, et al., Penetrance of adrenocortical tumors associated with the germline TP53 R337H mutation, J. Med. Genet. 43 (2006) 91–96. [4] A.C. Latronico, E.M. Pinto, S. Domenice, et al., An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors, J. Clin. Endocrinol. Metab. 86 (2002) 4970–4973. [5] F. Sandrini, D.P. Villani, S. Tucci, et al., Inheritance of R337H gene mutation in children with sporadic adrenocortical tumor, Horm. Metab. Res. 37 (2005) 231–235. [6] R.C. Ribeiro, F. Sandrini, B. Figueiredo, et al., An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma, Proc. Natl. Acad. Sci. USA 98 (2001) 9330–9335. [7] E.L. DiGiammarino, A.S. Lee, C. Cadwell, et al., A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer, Natl. Struct. Biol. 9 (2002) 12–16.
Raul C. Ribeiro * Carlos Rodriguez-Galindo Department of Hematology-Oncology, International Outreach Program, St. Jude Children’s Research Hospital, Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN, USA E-mail address: [email protected] (R.C. Ribeiro) Bonald C. Figueiredo Center for Molecular Genetics and Cancer Research in Children CEGEMPAC, Federal University of Parana´, Curitiba PR 80060-90, Brazil
*
Corresponding author. Tel.: +1 901 495 3694; fax: +1 901 495 3122.
Letter to the Editor / Cancer Letters 247 (2007) 353–355
Maria Jose Mastellaro Centro Infantil Boldrini, Campinas, SP, Brazil Alina Nico West Department of Interdisciplinary Science, University of Tennessee Health Science Center, Memphis, TN 38163, USA Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
355
Richard Kriwacki Department of Structural Biology, St. Jude Children’s Research Hospital, College of Medicine, University of Tennessee, Memphis, TN, USA Gerard P. Zambetti Department of Biochemistry, St. Jude Children’s Research Hospital, College of Medicine, University of Tennessee, Memphis, TN, USA Received 25 April 2006; accepted 28 April 2006