Original Article

CME Article: Identification and Management of TP53 Gene Carriers Detected Through Multigene Panel Testing

Authors: Tuya Pal, MD, Jennifer Brzosowicz, MS, CGC, Ailyn Valladares, BS, Georgia L. Wiesner, MD, MS, Christine Laronga, MD

Abstract

Objectives: The increasing use of multigene panel tests may reveal an unexpected pathogenic variant in the tumor protein p53 (TP53) gene among individuals who do not meet clinical criteria for Li-Fraumeni syndrome (LFS). Among a registry-based sample of individuals with a pathogenic (P) or likely pathogenic (LP) variant in TP53, we sought to characterize the original clinical context in which genetic testing was performed, the personal and family history and whether they met clinical LFS criteria, and the follow-up care following diagnosis among those in whom this information was available.

Methods: Among individuals with multigene panel testing (inclusive of the TP53 gene) who were part of either the Inherited Cancer Registry or the Vanderbilt Hereditary Cancer Registry protocols and were confirmed to have a P/LP variant in TP53, pedigree was reviewed to characterize personal and family history, including original clinical context for genetic testing and whether they met clinical diagnostic criteria for TP53. Subsequent cancer risk management options were documented through information collected in the study questionnaire and medical records.

Results: Among the 10 participants enrolled in one of the two registries with a germline TP53 P/LP variant detected through a multigene panel test, the most frequent clinical contexts for testing were genetic risk recognized in the survivorship care setting (50%) and a newly diagnosed breast cancer (40%). No participants met classic LFS diagnostic criteria and 6 of 10 met Chompret criteria (60%) at the time of testing. Among the seven participants in whom results of total body magnetic resonance imaging were available, only three had completely negative findings. The remaining four had findings, three of which were likely benign/incidental requiring additional follow-up, and one was consistent with metastatic disease in the vertebrae.

Conclusions: Our findings suggest that individuals identified with a germline P/LP variant in TP53 through multigene panel tests have substantial variations in clinical phenotypes not previously recognized when only those with striking family histories suggestive of LFS were tested through targeted TP53 testing. The expansion of the clinical phenotype among carriers of a P/LP in TP53 in the era of multigene testing should be considered when making cancer risk management recommendations, which were developed based on patients with classic LFS.

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References

1. Li FP, Fraumeni JF, Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969;71:747-752.
 
2. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:5358-5362.
 
3. Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 2001;38:43-47.
 
4. Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108-e110.
 
5. Bougeard G, Sesboue R, Baert-Desurmont S, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 2008;45:535-538.
 
6. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977;74:5463-5467.
 
7. Ray T. With $999 whole-genome sequencing service, Veritas embarks on goal to democratize DNA information. https://www.genomeweb.com/sequencing-technology/999-whole-genome-sequencing-service-veritas-embarks-goal-democratize-dna. Published March 6, 2016. Accessed July 27, 2017.
 
8. Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 2014;35:654-662.
 
9. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast and ovarian. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed September 19, 2016.
 
10. Cragun D, Besharat AD, Lewis C, et al. Educational needs and preferred methods of learning among Florida practitioners who order genetic testing for hereditary breast and ovarian cancer. J Cancer Educ 2013;28:690-697.
 
11. Cragun D, Pal T. Identification, evaluation, and treatment of patients with hereditary cancer risk within the United States. ISRN Oncol 2013;2013:260847.
 
12. Cragun D, Lewis C, Camperlengo L, et al. Hereditary cancer: example of a public health approach to ensure population health benefits of genetic medicine. Healthcare (Basel) 2016;4:pii: E6.
 
13. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 2015;33:2345-2352.
 
14. Axilbund JE. Panel testing is not a panacea. J Clin Oncol 2016;34:1433-1435.
 
15. Axilbund JE. Reply to M.J. Hall et al and K.N. Maxwell et al. J Clin Oncol 2016;34:4187.
 
16. Hall MJ, Obeid E, Daly MB. Multigene panels to evaluate hereditary cancer risk: reckless or relevant? J Clin Oncol 2016;34:4186-4187.
 
17. Tung NM, Garber JE. Reply to S.M. Sorscher and M.J. Hall et al. J Clin Oncol 2016;34:4187-4188.
 
18. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2015;33:3660-3667.
 
19. King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA 2014;312:1091-1092.
 
20. Yurgelun MB, Hiller E, Garber JE. Population-wide screening for germline BRCA1 and BRCA2 mutations: too much of a good thing? J Clin Oncol 2015;33:3092-3095.
 
21. Chompret A, Brugieres L, Ronsin M, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer 2000;82:1932-1937.
 
22. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 1995;57:1233-1241.
 
23. Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011;12:559-567.
 
24. 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.
 
25. Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol 2016;13:581-588.
 
26. Henry E, Villalobos V, Million L, et al. Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome. J Natl Compr Canc Netw 2012;10:939-942.
 
27. Kast K, Krause M, Schuler M, et al. Late onset Li-Fraumeni syndrome with bilateral breast cancer and other malignancies: case report and review of the literature. BMC Cancer 2012;12:217.