Cancer genetics
COMMUNICATIONS
Transmission of germline TP53 mutations from male carriers to female partners Gestational choriocarcinoma (CC) represents the most aggressive form of gestational tumours. In Europe and North America, gestational CC occurs in approximately 1/50 000 deliveries.1 We report the detection, in a gestational CC developed in a female partner of a patient with Li-Fraumeni syndrome (LFS) (MIM #151623), of the germline TP53 mutation initially detected in this LFS patient. In the French LFS series, we identified 78 fathers who were carriers of a germline TP53 mutation. Among the 213 corresponding pregnancies, we found two other cases of gestational CC in their partners. We estimate that gestational CC occurs in approximately 1% of the deliveries in female partners of TP53 mutation carriers. Gestational trophoblastic disease (GTD), which can occur after either abnormal or normal fertilisation, is characterised by the uncontrolled proliferation of trophoblastic cells normally producing the placenta. GTD includes premalignant (complete and partial hydatidiform moles) and malignant (invasive mole, gestational CC, placentalsite trophoblastic and epithelioid trophoblastic tumours) lesions.1 We considered the diagnosis of LFS, a remarkable cancer predisposition characterised by the extent of tumour spectrum,2 in the family described in figure 1. The male index case had developed a cholangiocarcinoma at 37 years of age, his brother a choroid plexus carcinoma at age 23 and his father a leiomyosarcoma at age 54. The diversity of the tumour spectrum within this family fulfilling the Chompret criteria for LFS3 led us to analyse TP53 in the index case, and we
identified a canonical heterozygous germline TP53 mutation within exon 7 (c.743 G>A, p.(Arg248Gln), NM_000546.5), confirming the diagnosis of LFS (figure 2A). The index case’s second child presented at 5 months of age with a metastatic CC and was shown to carry the paternal
TP53 mutation (figure 2B). Remarkably, in the mother, a metastatic CC was diagnosed 13 months after the delivery. Microsatellite genotyping of metastases developed in the child and the mother had confirmed in both cases the biparental genetic contribution and transplacental transmission of the
Figure 2 Sequencing analysis of TP53. Sanger chromatograms from (A) father’s blood, (B) child’s non-tumoural tissue, (C) mother’s blood, (D) mother’s brain metastasis and (E) child’s hepatic metastasis. The arrows indicate the position of the mutated nucleotide (c.743 G>A, NM_000546.5). Note that there was a clear loss of heterozygosity (LOH) in the child’s hepatic metastasis (figure 2E). In contrast, the wild-type TP53 peak in the mother’s brain metastasis (D) is probably explained by the fact that the tumour sample contained necrotic tumour cells and inflammatory cells.
Figure 1 Pedigree of the Li-Fraumeni syndrome family. The arrow indicates the proband. Affected subjects are shown as filled symbols and asymptomatic subjects as open symbols. Deceased subjects are depicted with oblique lines. For each affected subject, the tumour type and age at diagnosis are indicated (y, years; m, months). Germline genotypes are indicated (wt, wild-type TP53; c.743G>A, mutant TP53).
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Cancer genetics CC.4 We sequenced TP53 in the mother’s peripheral blood cells and brain metastasis (figure 2C, D). As shown on the Sanger chromatograms, the metastasis in the mother, like the hepatic metastasis in the child (figure 2E), contained the germline TP53 mutation identified in the father. This constitutes a strong argument supporting the contribution of the germline TP53 mutation to the development of this gestational CC. To explore the contribution of germline TP53 mutations transmitted by the fathers to the risk of gestational CC in the mothers, we reviewed the French LFS cohort including 415 TP53 mutation carriers derived from 214 families. Among the 78 fathers who were carriers of a germline TP53 mutation and totalling 213 pregnancies, we found two other cases of gestational CC occurring in their female partners; in one LFS family, the female proband had developed breast cancer at the age of 36 and harboured a germline TP53 mutation (c.761T>C, p.(Ile254Thr), exon 7), which was shown to be from paternal origin. Her mother who had a germline wild-type TP53 genotype had presented at 22 years of age, several months after a normal pregnancy, with a metastatic gestational CC (tumour DNA was not available). In the other LFS family, the female partner of a TP53 mutation carrier (c.817C>G, p. (Arg273Gly), exon 7) had developed a gestational CC, but also in this case, absence of tumour DNA hampered molecular analyses within the tumour.5 In conclusion, we can estimate that gestational CC occurs approximately in 1/100 of the deliveries in female partners of TP53 mutation carriers. This 500-fold increased risk, as compared with the general population, is probably underestimated since we have not systematically recorded medical data concerning female partners of TP53 mutation male carriers. The low incidence of the LFS syndrome
146
(the French series including 415 TP53 mutation carriers is, to our knowledge, the largest series worldwide) and an estimated risk of 1/100 in female partners of germline TP53 mutation carriers explain why the observations of gestational CC in the context of LFS are exceptional. Nevertheless, clinicians should be aware of the increased risk of gestational CC in female partners of TP53 mutation carriers. This report also highlights the contribution of TP53 mutations to the development of gestational CC. TP53 normally acting as an antioncogene,2 it is likely that, in the context of GTD characterised by an uncontrolled proliferation of trophoblastic cells, germline TP53 mutations will act as permissive mutations and will favour the malignant transformation and therefore the occurrence of gestational CC. Gestational CC linked to LFS represents an exceptional situation of a transmission of a germline mutation from male carriers to female partners.
Acknowledgements This work was supported by the INCa, the French National Cancer Institute. Contributors Data collection: SP-S, GB, SB-D and FG. Laboratory investigations: GB, AL and J-MF. Genetic counselling and patient care: LM, MB, CL and LB. Obtained funding: TF. Data interpretation and drafting of the manuscript: TF, SP-S and GB. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
To cite Patrier-Sallebert S, Bougeard G, BaertDesurmont S, et al. J Med Genet 2015;52:145–146. Received 27 October 2014 Revised 22 December 2014 Accepted 6 January 2015 Published Online First 22 January 2015 J Med Genet 2015;52:145–146. doi:10.1136/jmedgenet-2014-102853
REFERENCES 1
Sophie Patrier-Sallebert,1 Gaëlle Bougeard,2 Stéphanie Baert-Desurmont,2,3 Aude Lamy,1 Jean-Michel Flaman,2 Ludovic Mansuy,4 Myriam Bronner,5 Christine Lasset,6 Laurence Brugières,7 François Golfier,8 Thierry Frebourg2,3 1 Department of Pathology, University Hospital, Rouen, France 2 Inserm U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France 3 Department of Genetics, University Hospital, Rouen, France 4 Department of Pediatric Oncology, University Hospital, Nancy, France 5 Department of Genetics, University Hospital, Nancy, France 6 Department of Genetics, Comprehensive Cancer Centre Léon Bérard, Lyon, France 7 Department of Pediatrics, Gustave Roussy Institute, Villejuif, France 8 French Trophoblastic Disease Reference Centre, University Hospital, Lyon, France
2
3
4
5
Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C ESMO Guidelines Working Group. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi39–50. Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 2014;35:654–62. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaïti-Pellié C, Stoppa-Lyonnet D, Frebourg T. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108–9. Bolze PA, Weber B, Fisher RA, Seckl MJ, Golfier F. First confirmation by genotyping of transplacental choriocarcinoma transmission. Am J Obstet Gynecol 2013;209:e4–6. Brugières L, Gardes M, Moutou C, Chompret A, Meresse V, Martin A, Poisson N, Flamant F, Bonaïti-Pellié C, Lemerle J, Feunteun J. Screening for germ line p53 mutations in children with malignant tumours and a family history of cancer. Cancer Res 1993;53:452–5.
Correspondence to Professor Thierry Frebourg, Inserm U1079, Faculty of Medicine, 22 boulevard Gambetta, 76183 Rouen cedex 1, France; frebourg@ chu-rouen.fr/[email protected]
J Med Genet March 2015 Vol 52 No 3
COMMUNICATIONS
Transmission of germline TP53 mutations from male carriers to female partners Gestational choriocarcinoma (CC) represents the most aggressive form of gestational tumours. In Europe and North America, gestational CC occurs in approximately 1/50 000 deliveries.1 We report the detection, in a gestational CC developed in a female partner of a patient with Li-Fraumeni syndrome (LFS) (MIM #151623), of the germline TP53 mutation initially detected in this LFS patient. In the French LFS series, we identified 78 fathers who were carriers of a germline TP53 mutation. Among the 213 corresponding pregnancies, we found two other cases of gestational CC in their partners. We estimate that gestational CC occurs in approximately 1% of the deliveries in female partners of TP53 mutation carriers. Gestational trophoblastic disease (GTD), which can occur after either abnormal or normal fertilisation, is characterised by the uncontrolled proliferation of trophoblastic cells normally producing the placenta. GTD includes premalignant (complete and partial hydatidiform moles) and malignant (invasive mole, gestational CC, placentalsite trophoblastic and epithelioid trophoblastic tumours) lesions.1 We considered the diagnosis of LFS, a remarkable cancer predisposition characterised by the extent of tumour spectrum,2 in the family described in figure 1. The male index case had developed a cholangiocarcinoma at 37 years of age, his brother a choroid plexus carcinoma at age 23 and his father a leiomyosarcoma at age 54. The diversity of the tumour spectrum within this family fulfilling the Chompret criteria for LFS3 led us to analyse TP53 in the index case, and we
identified a canonical heterozygous germline TP53 mutation within exon 7 (c.743 G>A, p.(Arg248Gln), NM_000546.5), confirming the diagnosis of LFS (figure 2A). The index case’s second child presented at 5 months of age with a metastatic CC and was shown to carry the paternal
TP53 mutation (figure 2B). Remarkably, in the mother, a metastatic CC was diagnosed 13 months after the delivery. Microsatellite genotyping of metastases developed in the child and the mother had confirmed in both cases the biparental genetic contribution and transplacental transmission of the
Figure 2 Sequencing analysis of TP53. Sanger chromatograms from (A) father’s blood, (B) child’s non-tumoural tissue, (C) mother’s blood, (D) mother’s brain metastasis and (E) child’s hepatic metastasis. The arrows indicate the position of the mutated nucleotide (c.743 G>A, NM_000546.5). Note that there was a clear loss of heterozygosity (LOH) in the child’s hepatic metastasis (figure 2E). In contrast, the wild-type TP53 peak in the mother’s brain metastasis (D) is probably explained by the fact that the tumour sample contained necrotic tumour cells and inflammatory cells.
Figure 1 Pedigree of the Li-Fraumeni syndrome family. The arrow indicates the proband. Affected subjects are shown as filled symbols and asymptomatic subjects as open symbols. Deceased subjects are depicted with oblique lines. For each affected subject, the tumour type and age at diagnosis are indicated (y, years; m, months). Germline genotypes are indicated (wt, wild-type TP53; c.743G>A, mutant TP53).
J Med Genet March 2015 Vol 52 No 3
145
Cancer genetics CC.4 We sequenced TP53 in the mother’s peripheral blood cells and brain metastasis (figure 2C, D). As shown on the Sanger chromatograms, the metastasis in the mother, like the hepatic metastasis in the child (figure 2E), contained the germline TP53 mutation identified in the father. This constitutes a strong argument supporting the contribution of the germline TP53 mutation to the development of this gestational CC. To explore the contribution of germline TP53 mutations transmitted by the fathers to the risk of gestational CC in the mothers, we reviewed the French LFS cohort including 415 TP53 mutation carriers derived from 214 families. Among the 78 fathers who were carriers of a germline TP53 mutation and totalling 213 pregnancies, we found two other cases of gestational CC occurring in their female partners; in one LFS family, the female proband had developed breast cancer at the age of 36 and harboured a germline TP53 mutation (c.761T>C, p.(Ile254Thr), exon 7), which was shown to be from paternal origin. Her mother who had a germline wild-type TP53 genotype had presented at 22 years of age, several months after a normal pregnancy, with a metastatic gestational CC (tumour DNA was not available). In the other LFS family, the female partner of a TP53 mutation carrier (c.817C>G, p. (Arg273Gly), exon 7) had developed a gestational CC, but also in this case, absence of tumour DNA hampered molecular analyses within the tumour.5 In conclusion, we can estimate that gestational CC occurs approximately in 1/100 of the deliveries in female partners of TP53 mutation carriers. This 500-fold increased risk, as compared with the general population, is probably underestimated since we have not systematically recorded medical data concerning female partners of TP53 mutation male carriers. The low incidence of the LFS syndrome
146
(the French series including 415 TP53 mutation carriers is, to our knowledge, the largest series worldwide) and an estimated risk of 1/100 in female partners of germline TP53 mutation carriers explain why the observations of gestational CC in the context of LFS are exceptional. Nevertheless, clinicians should be aware of the increased risk of gestational CC in female partners of TP53 mutation carriers. This report also highlights the contribution of TP53 mutations to the development of gestational CC. TP53 normally acting as an antioncogene,2 it is likely that, in the context of GTD characterised by an uncontrolled proliferation of trophoblastic cells, germline TP53 mutations will act as permissive mutations and will favour the malignant transformation and therefore the occurrence of gestational CC. Gestational CC linked to LFS represents an exceptional situation of a transmission of a germline mutation from male carriers to female partners.
Acknowledgements This work was supported by the INCa, the French National Cancer Institute. Contributors Data collection: SP-S, GB, SB-D and FG. Laboratory investigations: GB, AL and J-MF. Genetic counselling and patient care: LM, MB, CL and LB. Obtained funding: TF. Data interpretation and drafting of the manuscript: TF, SP-S and GB. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
To cite Patrier-Sallebert S, Bougeard G, BaertDesurmont S, et al. J Med Genet 2015;52:145–146. Received 27 October 2014 Revised 22 December 2014 Accepted 6 January 2015 Published Online First 22 January 2015 J Med Genet 2015;52:145–146. doi:10.1136/jmedgenet-2014-102853
REFERENCES 1
Sophie Patrier-Sallebert,1 Gaëlle Bougeard,2 Stéphanie Baert-Desurmont,2,3 Aude Lamy,1 Jean-Michel Flaman,2 Ludovic Mansuy,4 Myriam Bronner,5 Christine Lasset,6 Laurence Brugières,7 François Golfier,8 Thierry Frebourg2,3 1 Department of Pathology, University Hospital, Rouen, France 2 Inserm U1079, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France 3 Department of Genetics, University Hospital, Rouen, France 4 Department of Pediatric Oncology, University Hospital, Nancy, France 5 Department of Genetics, University Hospital, Nancy, France 6 Department of Genetics, Comprehensive Cancer Centre Léon Bérard, Lyon, France 7 Department of Pediatrics, Gustave Roussy Institute, Villejuif, France 8 French Trophoblastic Disease Reference Centre, University Hospital, Lyon, France
2
3
4
5
Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C ESMO Guidelines Working Group. Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl 6):vi39–50. Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 2014;35:654–62. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaïti-Pellié C, Stoppa-Lyonnet D, Frebourg T. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108–9. Bolze PA, Weber B, Fisher RA, Seckl MJ, Golfier F. First confirmation by genotyping of transplacental choriocarcinoma transmission. Am J Obstet Gynecol 2013;209:e4–6. Brugières L, Gardes M, Moutou C, Chompret A, Meresse V, Martin A, Poisson N, Flamant F, Bonaïti-Pellié C, Lemerle J, Feunteun J. Screening for germ line p53 mutations in children with malignant tumours and a family history of cancer. Cancer Res 1993;53:452–5.
Correspondence to Professor Thierry Frebourg, Inserm U1079, Faculty of Medicine, 22 boulevard Gambetta, 76183 Rouen cedex 1, France; frebourg@ chu-rouen.fr/[email protected]
J Med Genet March 2015 Vol 52 No 3
