INTRODUCTION
The clinical diagnosis of Li-Fraumeni Syndrome (LFS) is associated with a high lifetime risk of cancer, approaching > 80%, often with early onset.1,2 The connection between LFS and pathogenic variants (PVs) in the tumor suppressor gene TP53 was first identified in 1990 along with an autosomal dominant inheritance pattern.3 Studies have demonstrated that comprehensive screening may improve outcomes for individuals with LFS; therefore, the identification of family members who carry the mutation is important.4-6 While the majority of TP53 PVs are inherited, up to 20% arise de novo.7 We describe a family in which 2 siblings with LFS inherited the same TP53 PV as a result of germ cell mosaicism in the father. Germ cell mosaicism is a rare cause of disease recurrence in families, and this case report highlights the importance of testing all siblings for an identified PV, even when the PV is not detected in the blood or saliva of the parents.
CASE
An 18-month-old female first presented with virilization and was subsequently diagnosed with an adrenocortical carcinoma (ACC). The tumor was treated by complete surgical resection, after which the patient’s hormone levels normalized. Children with ACC have a germline TP53 mutation in 50% of cases.8 The diagnosis of ACC met the criterion for rare tumors by the revised Chompret criteria and the National Comprehensive Cancer Network guidelines for genetic screening for LFS.8,9 Clinical next-generation sequencing (NGS) and gross deletion/duplication analysis of the TP53 gene from a blood sample were performed at Ambry Genetics (Aliso Viejo, CA) and revealed the missense variant c.797G>A (p.Gly266Glu). This variant is classified as pathogenic by the testing laboratory and likely pathogenic by 3 additional sources in ClinVar.
FAMILY SCREENING
A detailed family history of cancer was obtained (Fig 1). Neither parent had a personal history of cancer. Other than the proband’s diagnosis of an ACC, the rest of the family history did not meet LFS clinical or genetic testing criteria. Other family members had Clinical Laboratory Improvement Amendments (CLIA) genetic-testing and the TP53 c.797G>A PV was not detected in blood samples from either parent or from an older sibling.
FIG 1.
Case of LFS germline mosaicism pedigree. Family pedigree for an 18-month old with adrenocortical carcinoma and a TP53 pathogenic variant that shows cases of cancer in the family as well as TP53 sequencing results. ACC, adrenocortical carcinoma.
Another child was born to the family several years later. Testing for the known TP53 PV was recommended because of the possibility of germ cell mosaicism. At 4 months of age, the child was tested for TP53 c.797G>A, and found to be positive. Review of laboratory NGS data from the family members confirmed parentage.
Germ cell mosaicism was suspected as the cause of the second sibling’s positive test result. Because the mother’s germ cells were not readily accessible for evaluation, testing was pursued from a paternal semen sample. Clinical Sanger sequencing of the semen sample detected c.797G>A variant at levels lower than would be expected for a heterozygote. This result, in conjunction with his blood sample analysis, suggested germ cell mosaicism, but mosaicism in other tissues could not be ruled out. To quantify the level of the variant in the semen for the research investigation, an in-house droplet digital polymerase chain reaction with a TaqMan assay specific for c.797G>A (#C_190324006_10; Thermo Fisher Scientific, Waltham, MA) was performed on semen and blood samples from the father as well as on blood samples from both affected children. The assay detected the c.797G>A PV in the semen sample at an allele frequency of 5.6% compared with 50.7% and 49.8% in the samples from the affected children. Semen analysis was performed in this case for research purposes as a non–CLIA-approved test. Investigators obtained informed consent to publish information from each participant/participant’s guardian in this article. The appropriate clinical diagnostic procedure would include CLIA testing of blood samples from all offspring for the TP53 PV in the case of an apparent de novo PV.
DISCUSSION
This case most likely represents gonadal mosaicism, although mosaic involvement of tissues beyond the germ cells cannot be ruled out in the absence of multitissue testing. However, the presence of the mutation in the paternal germ cells at low levels and absence in the blood suggest that the TP53 c.797G>A variant arose exclusively in those cells rather than earlier in the father’s embryologic development.
In cases with apparent de novo or low levels of TP53 PVs in blood, clonal hematopoiesis of indeterminate potential is a known possibility and should be ruled out.9,10 This family demonstrates that recurrence of LFS can occur as a result of germ cell mosaicism in cases that originally seem to be of de novo origin. We were able to establish that the TP53 PV was of paternal origin by semen analysis. Paternal germline mosaicism was investigated first because it is far more invasive and costly to evaluate maternal germ cells. However, both cases of maternal and paternal mosaicism have been reported in other conditions, including familial adenomatous polyposis, neurofibromatosis, and Duchenne muscular dystrophy.11,12 Therefore, when evaluating for germ cell mosaicism, if semen analysis is nondiagnostic, the possibility of maternal inheritance should be considered.
While data on the frequency of germ cell mosaicism are still lacking, somatic mosaicism has been reported in probands with LFS.13,14 In addition, a case of TP53 PV inheritance was previously found from a parent with suspected germ cell mosaicism.15 In this case, we show that even the presence of a PV at a low level in parental germ cells can have implications for other siblings. This case demonstrates the importance of sibling testing of apparent de novo germline PVs because despite negative parental testing, there are scenarios where siblings are at risk. Once identified, siblings found positive for a PV can begin critical cancer screening protocols proven to improve early cancer detection, provide significant survival benefits, and present the most cost-effective clinical management strategy for these high-risk patients.4,5,16
Families with severe autosomal dominant hereditary cancer disorders like LFS and who are planning for more children should be offered reproductive planning counseling. Discussions with parents on the many options available, is an ethical way to aid their decision making to fit their family’s values. Pre-implantation genetic diagnosis, an evolving field within precision medicine, to look for the known PV is a possible route and can be included in patient education.17 Recommendations should also include prompt blood testing for the PV in all current and future children.
To our knowledge, this is the first reported case of germ cell mosaicism as the cause of recurrence of LFS in siblings. While rare, consideration of germ cell mosaicism should be part of genetic counseling for LFS as well as for other autosomal dominate genetic conditions. Current cancer predisposition and surveillance guidelines should consider the recommendation of additional testing of future siblings in cases of autosomal dominant cancer predisposition syndromes.18,19
Presented at the 4th International Li-Fraumeni Symposium, Toronto, Ontario, Canada, April 25-29, 2018.
SUPPORT
Support for the use of genetic counseling and biorepository and molecular pathology shared resources by National Cancer Institute under award number P30CA042014 to the Huntsman Cancer Institute and the Huntsman Cancer Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
AUTHOR CONTRIBUTIONS
Conception and design: Wendy Kohlmann, Luke Maese
Collection and assembly of data: Wendy Kohlmann, Luke Maese
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Lauren N. Donovan
Employment: Willamette ENT (I)
Wendy Kohlmann
Employment: BioFire Diagnostics (I)
Angela K. Snow
Stock and Other Ownership Interests: Arbor Vita
Research Funding: Janssen Pharmaceuticals
Deborah W. Neklason
Consulting or Advisory Role: Recursion Pharmaceuticals
Research Funding: Janssen Pharmaceuticals (Inst)
Joshua D. Schiffman
Employment: PEEL Therapeutics
Leadership: PEEL Therapeutics.
Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics, Inc.
Honoraria: Affymetrix
Consulting or Advisory Role: N-of-One, Fabric Genomics
Luke Maese
Honoraria: Jazz Pharmaceuticals
Consulting or Advisory Role: Jazz Pharmaceuticals
No other potential conflicts of interest were reported.
REFERENCES
- 1.McBride KA, Ballinger ML, Killick E, et al. Li-Fraumeni syndrome: Cancer risk assessment and clinical management. Nat Rev Clin Oncol. 2014;11:260–271. doi: 10.1038/nrclinonc.2014.41. [DOI] [PubMed] [Google Scholar]
- 2.Amadou A, Achatz MIW, Hainaut P. Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: Temporal phases of Li-Fraumeni syndrome. Curr Opin Oncol. 2018;30:23–29. doi: 10.1097/CCO.0000000000000423. [Erratum: Curr Opin Oncol 31:52, 2019] [DOI] [PubMed] [Google Scholar]
- 3.Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233–1238. doi: 10.1126/science.1978757. [DOI] [PubMed] [Google Scholar]
- 4.Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17:1295–1305. doi: 10.1016/S1470-2045(16)30249-2. [DOI] [PubMed] [Google Scholar]
- 5.Ballinger ML, Best A, Mai PL, et al. Baseline surveillance in Li-Fraumeni syndrome using whole-body magnetic resonance imaging: A meta-analysis. JAMA Oncol. 2017;3:1634–1639. doi: 10.1001/jamaoncol.2017.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ballinger ML, Mitchell G, Thomas DM. Surveillance recommendations for patients with germline TP53 mutations. Curr Opin Oncol. 2015;27:332–337. doi: 10.1097/CCO.0000000000000200. [DOI] [PubMed] [Google Scholar]
- 7.Schneider K, Zelley K, Nichols K, et al. Li-Fraumeni Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle, WA; University of Washington: 2019. [Google Scholar]
- 8.Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li‐Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33:2345–2352. doi: 10.1200/JCO.2014.59.5728. [DOI] [PubMed] [Google Scholar]
- 9.National Comprehensive Cancer Network doi: 10.6004/jnccn.2021.0001. NCCN clinical practice guidelines in oncology V.1.2020: Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, 2020. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. [DOI] [PubMed]
- 10.Batalini F, Peacock EG, Stobie L, et al. Li-Fraumeni syndrome: Not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis. Breast Cancer Res. 2019;21:107. doi: 10.1186/s13058-019-1193-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Erickson RP. Somatic gene mutation and human disease other than cancer: An update. Mutat Res. 2010;705:96–106. doi: 10.1016/j.mrrev.2010.04.002. [DOI] [PubMed] [Google Scholar]
- 12.Schwab AL, Tuohy TM, Condie M, et al. Gonadal mosaicism and familial adenomatous polyposis. Fam Cancer. 2008;7:173–177. doi: 10.1007/s10689-007-9169-1. [DOI] [PubMed] [Google Scholar]
- 13.Behjati S, Maschietto M, Williams RD, et al. A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing. PLoS One. 2014;9:e96531. doi: 10.1371/journal.pone.0096531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Prochazkova K, Pavlikova K, Minarik M, et al. Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome. Am J Med Genet A. 2009;149A:206–211. doi: 10.1002/ajmg.a.32574. [DOI] [PubMed] [Google Scholar]
- 15.Renaux-Petel M, Charbonnier F, Théry JC, et al. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet. 2018;55:173–180. doi: 10.1136/jmedgenet-2017-104976. [DOI] [PubMed] [Google Scholar]
- 16.Tak CR, Biltaji E, Kohlmann W, et al. Cost-effectiveness of early cancer surveillance for patients with Li-Fraumeni syndrome. Pediatr Blood Cancer. 2019;66:e27629. doi: 10.1002/pbc.27629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sullivan-Pyke C, Dokras A. Preimplantation genetic screening and preimplantation genetic diagnosis. Obstet Gynecol Clin North Am. 2018;45:113–125. doi: 10.1016/j.ogc.2017.10.009. [DOI] [PubMed] [Google Scholar]
- 18.Druker H, Zelley K, McGee RB, et al. Genetic counselor recommendations for cancer predisposition evaluation and surveillance in the pediatric oncology patient. Clin Cancer Res. 2017;23:e91–e97. doi: 10.1158/1078-0432.CCR-17-0834. [DOI] [PubMed] [Google Scholar]
- 19.National Cancer Institute . Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version, 2019. https://www.cancer.gov/about-cancer/causes-prevention/genetics/risk-assessment-pdq. [PubMed] [Google Scholar]