“N of 1” Case Reports in the Era of Whole-Genome Sequencing
Total Page:16
File Type:pdf, Size:1020Kb
“N of 1” case reports in the era of whole-genome sequencing A. Rose Brannon, Charles L. Sawyers J Clin Invest. 2013;123(11):4568-4570. https://doi.org/10.1172/JCI70935. Commentary Prostate cancer has a range of clinical outcomes, from complete remission in response to treatment to death as a result of aggressive metastasis. Prognosis for individuals with prostate cancer is not readily predictable, and new diagnostics will be useful for treatment strategy determination. In this issue of the JCI, Haffner and colleagues use comprehensive tumor genome sequencing to investigate the origin of genetic mutations underlying a case of lethal prostate cancer. Surprisingly, the lethal clone in this individual arose from a tumor focus that is typically considered very low risk based on histology. Their report highlights the need to collect and curate “N of 1” cases to develop a database that can be used for clinical decision making. Find the latest version: https://jci.me/70935/pdf commentaries 1. Nikiforov YE, Nikiforova MN. Molecular genetics tion-induced and sporadic thyroid papillary carcino- 15. Nikiforova MN, Stringer JR, Blough R, Medve- and diagnosis of thyroid cancer. Nat Rev Endocrinol. mas in children. Cancer Res. 1997;57(9):1690–1694. dovic M, Fagin JA, Nikiforov YE. Proximity of 2011;7(10):569–580. 9. Bongarzone I, et al. Age-related activation of the chromosomal loci that participate in radiation- 2. Williams D. Radiation carcinogenesis: lessons from tyrosine kinase receptor protooncogenes RET and induced rearrangements in human cells. Science. Chernobyl. Oncogene. 2008;27(suppl 2):S9–S18. NTRK1 in papillary thyroid carcinoma. J Clin Endo- 2000;290(5489):138–141. 3. Santoro M, Carlomagno F. Drug insight: Small- crinol Metab. 1996;81(5):2006–2009. 16. Gandhi M, Medvedovic M, Stringer JR, Nikiforov molecule inhibitors of protein kinases in the treat- 10. Fenton CL, Lukes Y, Nicholson D, Dinauer CA, YE. Interphase chromosome folding determines ment of thyroid cancer. Nat Clin Pract Endocrinol Francis GL, Tuttle RM. The ret/PTC mutations are spatial proximity of genes participating in car- Metab. 2006;2(1):42–52. common in sporadic papillary thyroid carcinoma cinogenic RET/PTC rearrangements. Oncogene. 4. Rabes HM, Klugbauer S. Molecular genetics of of children and young adults. J Clin Endocrinol 2006;25(16):2360–2366. childhood papillary thyroid carcinomas after irra- Metab. 2000;85(3):1170–1175. 17. Gandhi M, Evdokimova V, Nikiforov YE. Frequency diation: high prevalence of RET rearrangement. 11. Kumagai A, et al. Low frequency of BRAFT1796A of close positioning of chromosomal loci detected Recent Results Cancer Res. 1998;154:248–264. mutations in childhood thyroid carcinomas. J Clin by FRET correlates with their participation in car- 5. Nikiforova MN, et al. Low prevalence of BRAF Endocrinol Metab. 2004;89(9):4280–4284. cinogenic rearrangements in human cells. Genes mutations in radiation-induced thyroid tumors in 12. Ricarte-Filho JC, et al. Identification of kinase Chromosomes Cancer. 2012;51(11):1037–1044. contrast to sporadic papillary carcinomas. Cancer fusion oncogenes in post-Chernobyl radia- 18. Roccato E, et al. Proximity of TPR and NTRK1 Lett. 2004;209(1):1–6. tion-induced thyroid cancers. J Clin Invest. 2013; rearranging loci in human thyrocytes. Cancer Res. 6. Lima J, et al. BRAF mutations are not a major event 123(11):4935–4944. 2005;65(7):2572–2576. in post-Chernobyl childhood thyroid carcinomas. 13. Cetinbas N, et al. Mutation of the salt bridge-form- 19. Cardis E, et al. Risk of thyroid cancer after expo- J Clin Endocrinol Metab. 2004;89(9):4267–4271. ing residues in the ETV6 SAM domain interface sure to 131I in childhood. J Natl Cancer Inst. 2005; 7. Ito T, et al. In vitro irradiation is able to cause blocks ETV6-NTRK3 induced cellular transfor- 97(10):724–32. RET oncogene rearrangement. Cancer Res. 1993; mation [published online ahead of print June 24, 20. Leeman-Neill RJ, et al. RET/PTC and PAX8/PPARγ 53(13):2940–2943. 2013]. J Biol Chem. doi:10.1074/jbc.M113.475301. chromosomal rearrangements in post-Cherno- 8. Nikiforov YE, Rowland JM, Bove KE, Monforte- 14. Ciampi R, et al. Oncogenic AKAP9-BRAF fusion is byl thyroid cancer and their association with Munoz H, Fagin JA. Distinct pattern of ret oncogene a novel mechanism of MAPK pathway activation in iodine-131 radiation dose and other characteris- rearrangements in morphological variants of radia- thyroid cancer. J Clin Invest. 2005;115(1):94–101. tics. Cancer. 2013;119(10):1792–1799. “N of 1” case reports in the era of whole-genome sequencing A. Rose Brannon1,2 and Charles L. Sawyers2,3 1Department of Pathology, 2Human Oncology and Pathogenesis Program, and 3Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Prostate cancer has a range of clinical outcomes, from complete remission primary tumor? How did this constella- in response to treatment to death as a result of aggressive metastasis. Prog- tion of mutations evolve over time as the nosis for individuals with prostate cancer is not readily predictable, and patient suffered multiple relapses (with new diagnostics will be useful for treatment strategy determination. In this accompanying tissue biopsies) during 17 issue of the JCI, Haffner and colleagues use comprehensive tumor genome years of treatment with various interven- sequencing to investigate the origin of genetic mutations underlying a case tions? Answering these questions offered of lethal prostate cancer. Surprisingly, the lethal clone in this individual the potential for new insights into pros- arose from a tumor focus that is typically considered very low risk based tate cancer progression, drug resistance on histology. Their report highlights the need to collect and curate “N of 1” mechanisms, and perhaps opportunities cases to develop a database that can be used for clinical decision making. to develop molecular diagnostics. Histological examination of the primary The case of the lethal clone genome sequencing of metastatic tumor tumor revealed multiple regions of high- Scientists are detectives at heart. When deposits recovered at autopsy. This analy- grade (Gleason 4) tumor, a small focus Haffner and colleagues learned about a sis yielded evidence of mutations in several of lower-grade (Gleason 3) disease, and case of lethal metastatic prostate cancer well-documented prostate cancer genes, a single lymph node metastasis (1). It is with evidence dating back 17 years, they such as tumor suppressor PTEN, tumor well established that patients with high- had to take the case (1). Using an approach protein p53 (TP53), speckle-type POZ volume, high-grade primary disease have similar to one previously employed to fol- protein (SPOP), ATP-dependent helicase an increased risk of recurrence; therefore, low pancreatic cancer progression (2), (ATRX), and androgen receptor (AR) (1), this patient’s subsequent clinical course of the authors began with comprehensive all of which are known to be recurrently metastatic prostate cancer is not surpris- altered in end-stage, castration-resistant ing. It was surprising that the lethal clone, prostate cancer. Because this patient’s defined by the presence of the same PTEN, Conflict of interest: Charles L. Sawyers serves on the primary tumor had been surgically TP53, and SPOP mutations recovered at Board of Directors of Novartis Pharmaceuticals and on excised (and saved) 17 years earlier, the autopsy, originated from the small, low- the Scientific Advisory Boards of Agios, Beigene, Blue- print, Housey Pharmaceuticals, Nextech, and Tracon. authors had a unique opportunity to ask grade Gleason 3 focus, and not from the Citation for this article: J Clin Invest. 2013; the “whodunit” question. Which, if any, much more substantial, high-volume Glea- 123(11):4568–4570. doi:10.1172/JCI70935. of these mutations were present in the son 4 tumors, which did not harbor PTEN, 4568 The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 11 November 2013 commentaries Figure 1 The potential for “N of 1” studies to benefit clinical practice will require collection of these cases into databases. Genomics is a powerful tool for mapping tumor progression/evolution with great precision in individuals. Collecting these “N of 1” cases into a common database will help identify common patterns and enable more robust conclusions about cancer diagnosis and progression. TP53, and SPOP mutations. Furthermore, on the molecular profile obtained from everolimus treatment. Despite the small the lymph node metastasis removed at the the biopsy of a single tumor focus, know- number of patients, this report provided initial surgery was also negative for these ing that an entirely different profile might enough evidence for the commercial mutations. Thus, this patient died from be seen from the biopsy of an adjacent sponsor to initiate a new clinical trial disease that, based on widely used (and val- lesion? Of course, it is impossible to make of everolimus in TSC1 mutant cancers, idated) histologic criteria, would be consid- any such conclusions from a single case. regardless of histology. Such biomarker- ered low risk for metastasis. Indeed, the academic community typically based clinical trials (called “basket stud- frowns upon clinical anecdotes, and for ies”) are becoming increasingly common Case closed? good reason: attempts to generalize lack in oncology and reflect growing confi- We can certainly credit the authors for scientific validity. Therefore, it is notori- dence