Childhood Cancer Genomics (PDQ®)–Health Professional Version
Melanoma
Melanoma-related conditions with malignant potential that arise in the pediatric population can be classified into the following three general groups:[1]
- Large/giant congenital melanocytic nevus.
- Spitzoid melanocytic tumors ranging from atypical Spitz tumors to spitzoid melanomas.
- Melanoma arising in older adolescents that shares characteristics with adult melanoma (i.e., conventional melanoma).
The genomic characteristics of each tumor are summarized in Table 5.
The genomic landscape of conventional melanoma in children is represented by many of the genomic alterations that are found in adults with melanoma.[1] A report from the Pediatric Cancer Genome Project observed that 15 cases of conventional melanoma had a high burden of somatic single-nucleotide variations, TERT promoter mutations (12 of 13), and activating BRAF V600 mutations (13 of 15), as well as a mutational spectrum signature consistent with ultraviolet (UV) light damage. In addition, two-thirds of the cases had MC1R variants associated with an increased susceptibility to melanoma. An Australian study compared the whole-genome sequencing of melanomas in adolescents and young adults (age range, 15–30 years) with the sequencing of melanomas in older adults.[2] The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the adolescent and young adult cohort were double the rates observed in the adult cohort. Adolescent and young adult melanomas contained a higher proportion of mutation signatures unrelated to UV radiation than did mature adult melanomas, as a proportion of total mutation burden.
The genomic landscape of spitzoid melanomas is characterized by kinase gene fusions involving various genes, including RET, ROS1, NTRK1, ALK, MET, and BRAF.[3-5] These fusion genes have been reported in approximately 50% of cases and occur in a mutually exclusive manner.[1,4] TERT promoter mutations are uncommon in spitzoid melanocytic lesions and were observed in only 4 of 56 patients evaluated in one series. However, each of the four cases with TERT promoter mutations experienced hematogenous metastases and died of their disease. This finding supports the potential of TERT promoter mutations in predicting aggressive clinical behavior in children with spitzoid melanocytic neoplasms, but additional study is needed to define the role of wild-type TERT promoter status in predicting clinical behavior in patients with primary site spitzoid tumors.
(Refer to the PDQ summary on Unusual Cancers of Childhood Treatment for information about the treatment of childhood melanoma.)
References
- Lu C, Zhang J, Nagahawatte P, et al.: The genomic landscape of childhood and adolescent melanoma. J Invest Dermatol 135 (3): 816-23, 2015. [PUBMED Abstract]
- Wilmott JS, Johansson PA, Newell F, et al.: Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility. Int J Cancer 144 (5): 1049-1060, 2019. [PUBMED Abstract]
- Wiesner T, He J, Yelensky R, et al.: Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 5: 3116, 2014. [PUBMED Abstract]
- Lee S, Barnhill RL, Dummer R, et al.: TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. Sci Rep 5: 11200, 2015. [PUBMED Abstract]
- Yeh I, Botton T, Talevich E, et al.: Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat Commun 6: 7174, 2015. [PUBMED Abstract]
- Charbel C, Fontaine RH, Malouf GG, et al.: NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J Invest Dermatol 134 (4): 1067-74, 2014. [PUBMED Abstract]
- Kinsler VA, Thomas AC, Ishida M, et al.: Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J Invest Dermatol 133 (9): 2229-36, 2013. [PUBMED Abstract]
Thyroid Cancer
(Refer to the Molecular Features section of the PDQ summary on Childhood Thyroid Cancer Treatment for information about the genomics of childhood thyroid cancer.)
(Refer to the PDQ summary on Childhood Thyroid Cancer Treatment for information about the treatment of childhood thyroid cancer.)
Multiple Endocrine Neoplasia Syndromes
The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 6.
- Multiple endocrine neoplasia type 1 (MEN1) syndrome (Wermer syndrome): MEN1 syndrome is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two endocrine tumors listed in Table 6 are present.A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients.[2] Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.
- Primary hyperparathyroidism. Primary hyperparathyroidism, the most common symptom, was found in 75% of patients, usually only in those with biological abnormalities. Primary hyperparathyroidism diagnosed outside of a screening program is extremely rare, most often presents with nephrolithiasis, and should lead the clinician to suspect MEN1.[2,3]
- Pituitary adenomas. Pituitary adenomas were discovered in 34% of patients, occurred mainly in females older than 10 years, and were often symptomatic.[2]
- Pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors were found in 23% of patients. Specific diagnoses included insulinoma, nonsecreting pancreatic tumor, and Zollinger-Ellison syndrome. The first case of insulinoma occurred before age 5 years.[2]
- Malignant tumors. Four patients had malignant tumors (two adrenal carcinomas, one gastrinoma, and one thymic carcinoma). The patient with thymic carcinoma died before age 21 years from rapidly progressive disease.
Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors.[4] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[5]Clinical practice guidelines recommend that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[6-8] - Multiple endocrine neoplasia type 2A (MEN2A) and multiple endocrine neoplasia type 2B (MEN2B) syndromes:A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN2A and MEN2B syndromes.[9-11] Table 7 describes the clinical features of MEN2A and MEN2B syndromes.
- MEN2A: MEN2A is characterized by the presence of two or more endocrine tumors (refer to Table 6) in an individual or in close relatives.[12] RET mutations in these patients are usually confined to exons 10 and 11.
- MEN2B: MEN2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[12-14] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[15] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid body habitus.
A retrospective analysis identified 167 children with RET mutations who underwent prophylactic thyroidectomy; this group included 109 patients without a concomitant central node dissection and 58 patients with a concomitant central node dissection. Children were classified into risk groups by their specific type of RET mutation (refer to Table in the PDQ summary on Childhood Thyroid Cancer Treatment for more information).[17]- In the highest-risk category, medullary thyroid carcinoma was found in five of six children (83%) aged 3 years or younger.
- In the high-risk category, medullary thyroid carcinoma was present in 6 of 20 children (30%) aged 3 years or younger, 16 of 36 children (44%) aged 4 to 6 years, and 11 of 16 children (69%) aged 7 to 12 years (P = .081).
- In the moderate-risk category, medullary thyroid carcinoma was seen in one of nine children (11%) aged 3 years or younger, 1 of 26 children (4%) aged 4 to 6 years, 3 of 26 children (12%) aged 7 to 12 years, and 7 of 16 children (44%) aged 13 to 18 years (P = .006).
- Familial Medullary Thyroid Carcinoma: Familial medullary thyroid carcinoma is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases.The most-recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria includes families of at least two generations with at least two, but less than ten, patients with RET germline mutations; small families in which two or fewer members in a single generation have germline RET mutations; and single individuals with a RET germline mutation.[16,19]
(Refer to the PDQ summary on Unusual Cancers of Childhood Treatment for information about the treatment of childhood MEN syndromes.)
References
- Thakker RV: Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab 83 (8): 2617-20, 1998. [PUBMED Abstract]
- Goudet P, Dalac A, Le Bras M, et al.: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 100 (4): 1568-77, 2015. [PUBMED Abstract]
- Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014. [PUBMED Abstract]
- Farnebo F, Teh BT, Kytölä S, et al.: Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 83 (8): 2627-30, 1998. [PUBMED Abstract]
- Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43 (4): 219-29, 2007. [PUBMED Abstract]
- Thakker RV: Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 24 (3): 355-70, 2010. [PUBMED Abstract]
- Vannucci L, Marini F, Giusti F, et al.: MEN1 in children and adolescents: Data from patients of a regional referral center for hereditary endocrine tumors. Endocrine 59 (2): 438-448, 2018. [PUBMED Abstract]
- Thakker RV, Newey PJ, Walls GV, et al.: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97 (9): 2990-3011, 2012. [PUBMED Abstract]
- Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002. [PUBMED Abstract]
- Alsanea O, Clark OH: Familial thyroid cancer. Curr Opin Oncol 13 (1): 44-51, 2001. [PUBMED Abstract]
- Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004. [PUBMED Abstract]
- Puñales MK, da Rocha AP, Meotti C, et al.: Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid 18 (12): 1261-8, 2008. [PUBMED Abstract]
- Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996. [PUBMED Abstract]
- Brauckhoff M, Gimm O, Weiss CL, et al.: Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28 (12): 1305-11, 2004. [PUBMED Abstract]
- Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008. [PUBMED Abstract]
- Waguespack SG, Rich TA, Perrier ND, et al.: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7 (10): 596-607, 2011. [PUBMED Abstract]
- Machens A, Elwerr M, Lorenz K, et al.: Long-term outcome of prophylactic thyroidectomy in children carrying RET germline mutations. Br J Surg 105 (2): e150-e157, 2018. [PUBMED Abstract]
- Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009. [PUBMED Abstract]
- Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015. [PUBMED Abstract]
Changes to this Summary (09/09/2019)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Tran et al. as reference 119 in the Acute Lymphoblastic Leukemia (ALL) subsection.
Added Prognosis (genomic and molecular factors) as a new subsection in the Juvenile Myelomonocytic Leukemia (JMML) subsection.
The Medulloblastomas subsection was comprehensively reviewed and reformatted.
The Nonmedulloblastoma Embryonal Tumors subsection was comprehensively reviewed and reformatted.
Added Pineoblastoma as a new subsection.
The Ependymomas subsection was comprehensively reviewed and extensively revised.
Added text to the Ewing Sarcoma subsection to state that undifferentiated small blue round cell sarcomas with the EWSR1-NFATc2 fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with EWSR1-NFATc2 fusions, which clearly segregated them from the more common form of Ewing sarcoma with EWS-ETS translocations (cited Koelsche et al. as reference 27).
Added text to the Ewing Sarcoma subsection to state that some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported. Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis (cited Schaefer et al. as reference 32).
Added text to the Ewing Sarcoma subsection to state that other undifferentiated round cell sarcomas are characterized by a CIC-DUX4 fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas (cited Antonescu et al. as reference 33).
The Rhabdomyosarcoma subsection was comprehensively reviewed.
This section was comprehensively reviewed.
Added text to the Melanoma section about the results of an Australian study that compared the whole-genome sequencing of melanomas in adolescents and young adults with the sequencing of melanomas in older adults (cited Wilmott et al. as reference 2).
Added text to the Multiple Endocrine Neoplasia Syndromes section about a retrospective analysis that identified 167 children with RET mutations who underwent prophylactic thyroidectomy and were classified into risk groups by their specific type of RET mutation (cited Machens et al. as reference 17).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genomics of childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Childhood Cancer Genomics is:
- Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Cancer Genomics. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/pediatric-genomics-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 27466641]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
No hay comentarios:
Publicar un comentario