Download Free Medical Inherited Cancer Syndromes of Childhood PowerPoint Presentation

Inherited Cancer Syndromes of Childhood PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical presentation on Childhood Cancer, which is titled "Inherited Cancer Syndromes of Childhood", to know about “inherited cancer syndromes” and its common clinical features, the contribution of heredity to pediatric cancer with attention to genes involved in cancer development, the clinical features and mechanistic biology of some established pediatric cancer syndromes, and general guidelines for the identification and management of children with identified cancer syndromes.

Tags : Childhood Cancer, Inherited Cancer Syndromes, Childhood, clinical features, heredity, pediatric cancer, genes

Published on : May 13, 2021 | Views : 2174 | Downloads : 4

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Inherited Cancer Syndromes of Childhood John D’Orazio, M.D., Ph.D. Department of Pediatrics Hematology/Oncology Kentucky Children’s Hospital jdorazio@uky.edu There are no financial or other conflicts of interest to disclose relevant to this presentation.
Slide 2-

Objectives Define what is meant by “inherited cancer syndromes” and describe common clinical features. Outline the contribution of heredity to pediatric cancer with attention to genes involved in cancer development. Describe the clinical features and mechanistic biology of some established pediatric cancer syndromes. Discuss general guidelines for the identification and management of children with identified cancer syndromes.
Slide 3-

Pediatric Cancer ~15,000 US children diagnosed with cancer each year in the US 6-10% of new pediatric cancer patients have an identifiable cancer syndrome. Zhang, J. et. al., 2015, NEJM. Grobner, S. et. al., 2018, Nature. Each year, > 900 US children with cancer have an inherited cancer syndrome. Curesearch.org; American Cancer Society Facts and Figures (2014)
Slide 4-

So why should we care about familial cancer syndromes? To the 10% or so of cancer patients affected by them and to the doctors taking care of them, they matter a great deal! Disease management Surveillance Prophylaxis Genetic counseling implications Financial/insurance considerations
Slide 5-

much of what we know about cancer genetics has come from studying cancer-prone families. Implications for all cancers Many of the very same familial cancer genes drive sporadic cancers as well
Slide 6-

Oncogenes Tumor Suppressors Genes whose products drive cellular progression to cancer Genes whose products work to prevent development of cancer. There are two basic kinds of genes that are involved in carcinogenesis.
Slide 7-

familial cancer syndromes Not enough of a tumor suppressor. Too much of an oncogene.
Slide 8-

Case 1: “something in her eye” 1 year old with opacity of the left eye. “leukocoria” Possibilities (differential) Tumor Congenital malformation Vascular disease Inflammatory disease Trauma Phakomatosis
Slide 9-

Retinoblastoma Most common pediatric ocular tumor 1 in 20,000 children ~200 new U.S. cases/year. Arises from primitive neural elements of the retina. May directly invade CNS. Can metastasize bone marrow Two distinct clinical patterns: Older children (1-4 yrs.) Only one eye involved Only one tumor Young age (infants) Both eyes involved Many simultaneous tumors Parent frequently affected ~2/3 of cases ~1/3 of cases Affected eye, in cross section. Multiple tumors in a predisposed infant RB pathology: note the Flexner-Wintersteiner rosettes!
Slide 10-

Alfred Knudson (1922-2016) Knudson’s Novel Idea Geneticist who considered retinoblastoma’s two distinct clinical patterns. In 1971, Knudson proposed a novel concept: He reasoned that for retinoblastoma to occur, both alleles of the same retinoblastoma-relevant gene must be inactivated. Predicted the existence of tumor-suppressor genes that suppress cancer cell growth. The “2-hit hypothesis” is now widely accepted and relevant to many cancers. Two-Hit Hypothesis Familial vs. Sporadic
Slide 11-

Pathogenesis of retinoblastoma Loss-of-function of both alleles of RB are needed in the same retinal cell for cancer to develop. Familial form: all somatic cells inherit one mutant RB gene from a carrier parent second mutation inactivates the remaining RB locus in one or more retinal cells. Sporadic form: both RB alleles must independently be inactivated in the same retinal cell Adapted from Kumar, Robbins and Cotran: Pathologic Basis of Disease Familial form Sporadic form Parental somatic cells Parental germ cells Zygote Child’s somatic cells Child’s Retinal cells Retinoblastoma Normal Rb mutant
Slide 12-

Rb and the Cell Cycle All cells – even cancer cells – divide by an orderly progression through the cell cycle. The Rb protein controls whether a cell will proceed into a proliferative cycle. Rb functions at the G1/S cell cycle “checkpoint” Rb prevents proliferation by binding to and inactivating E2F transcription factors. Phosphorylation of Rb releases E2F transcription factors. E2F’s activate genes that drive cell-cycle progression
Slide 13-

Cancer Biology Implications RB mutation accounts for only 1-2% of all pediatric cancers. Studying the greater RB signaling pathway has facilitated landmark insights into the “rules” of cell division. Every human cancer demonstrates some defect in the extended RB pathway! www.researchgate.net
Slide 14-

Back to the patient with retinoblastoma: Knowing whether there is inherited RB deficiency is important Increased risk of second tumors More retinoblastomas Pineoblastoma (trilateral RB) Osteosarcoma * Brain tumors* Sarcomas * Melanoma Lung cancer Implications for future children especially after radiation
Slide 15-

Hereditary RB management Early diagnosis and treatment of tumors Preserve vision Monthly eye exams until age 1y, then q6-8 wks until 3y q6 month brain MRI’s through age 5y (pineal tumors) Prompt evaluation of persistent/unusual pain or lumps Avoid carcinogens Ionizing radiation u/s, mri > ct, plain films protons vs. photons UV radiation Avoid direct sunlight, no tanning beds, sunblock Detailed and regular mole surveillance Genetic testing for family Prenatal diagnosis available “Bragg Peak” of proton energy
Slide 16-

7 year-old female, well-known to the Pediatric Oncology Service Choroid plexus carcinoma, 6 months old Osteosarcoma, 5 years old AML, 7 years old Referred for genetic evaluation somatic inactivation of one p53 allele this discovery guided therapeutic approach “Why does this kid have cancer again?!”
Slide 17-

Li-Fraumeni Syndrome Cancer predisposition syndrome caused by loss of p53 tumor suppressor function Generations of cancer in family Multiple primary tumors Early age of onset Characteristic cancers: Bone and soft tissue sarcomas Breast cancer Brain tumors Leukemias Adrenocortical carcinoma
Slide 18-

Fred Li, MD 1940 – 2015 Joseph Fraumeni, MD National Cancer Institute Li, FP and Fraumeni, JF (1969). Soft-tissue sarcomas, breast cancer and other neoplasms. A familial syndrome? Ann Intern Med 71:747-52. 90% lifetime risk of cancer (♀) 70% lifetime risk of cancer (♂) 50% risk of cancer by age 35 yrs.
Slide 19-

p53: “guardian of the genome” most common target for genetic alteration in human tumors. >50% of human cancers have p53 mutations! LFS = inheritance of 1 mutant TP53 allele Currently > 62,000 published papers about p53 and cancer
Slide 20-

p53 and the Cell Cycle p53 halts cell division at the G2/M phase www.genecopoeia.com
Slide 21-

Zhang, J. et. al., 2015, “Germline mutations in predisposition genes in pediatric cancer”, NEJM, 373: 2336-46. P53 mutations are the most frequent identified cause of AD cancer syndromes in children (1120 oncology patients younger than 20 years of age: whole exome or whole genome sequencing)
Slide 22-

LFS – Cancer Surveillance Annual physical examination including careful skin and neurologic examinations. Prompt evaluation of any unexplained symptoms. Breast cancer monthly breast self-examination clinical examination by a health care provider twice a year beginning at age 18-20 yrs diagnostic imaging (annual mammography or MRI) beginning at age 20 to 25 yrs prophylactic mastectomy may be considered Colorectal cancer colonoscopy beginning at age 25 years and then every two to five years Annual whole body MRI imaging – efficacy studies underway National Comprehensive Cancer Network (NCCN) guidelines
Slide 23-

Child with abnormal vision School-age boy Several pigmented skin macules. Abnormal visual field testing. Significant temporal field cut Head MR shows mass in optic nerve. (hemianopsia) R L
Slide 24-

Neurofibromatosis Type I 1 in 2,500 incidence 100% penetrance Diagnostic Criteria (>2) “von Recklinghausen disease” Café-au-lait spots (>6) > 5 mm (pre-pubertal) >15 mm (post-pubertal) Neurofibromas (>2) or >1 plexiform neurofibroma Axillary/inguinal freckling Optic pathway glioma Lisch nodules Iris melanocytic hamartomas Bony lesions (sphenoid dysplasia) 1st degree relative with NF1 Original illustration from von Recklinghausen’s descriptive paper: “Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen”, Berlin, Hirschwald, 1882
Slide 25-

Café-au-lait spots Sphenoid dysplasia Neurofibromas Lisch Nodules Axillary freckling Inguinal freckling CNS gliomas - optic pathway and others Leukemias, especially AML Pheochromocytoma Rhabdomyosarcoma Malignant peripheral nerve sheath tumor “malignant schwannoma” NF1 physical stigmata associated malignancies
Slide 26-

NF-1 Molecular Biology Germline loss-of-function of “neurofibromin” tumor suppressor Neurofibromin regulates Ras signaling in neuronal cells Ras signals “on” through MAP kinase cascade when bound by GTP Neurofibromin mediates hydrolysis of the GTP into GDP to turn off Ras signaling With loss of NF, Ras signaling stays “on”, promoting cell proliferation.
Slide 27-

Optic Glioma Low-grade astrocytoma ~50% occur in patients with neurofibromatosis type 1 (NF1) Usually diagnosed in children < 10y May develop in any part of the visual pathway Try not to radiate in children with NF1 Secondary malignancy risk Pilocytic astrocytoma of the optic nerve in a child http://www.uic.edu/depts/mcpt/eyepath/specon.htm
Slide 28-

12 y/o with hypertension daily headaches x 6 mo flushing, palpitations 25% loss of body weight Pediatrician’s office: P)120, BP) 205/160 right-sided contrast-enhancing suprarenal mass (with calcifications) displacing both the kidney and the liver Case Rep Genet. 2014: 273423
Slide 29-

Sky-high Catecholamines!
Slide 30-

MIBG nuclear scan showing uptake by the adrenal mass. Case Rep Genet. 2014: 273423 pheochromocytoma Patient admitted for sympathetic blockade: phenoxybenzamine, hydralazine, propanolol. Progressive decreases in hypertension and tachycardia. Symptomatic relief Removal of suprarenal mass Pathology confirmed pheochromocytoma
Slide 31-

Pheochromocytoma Rare tumor of sympathetic ganglia or adrenals Often secrete catecholamines Hypertension, headache, flushing, sweating, tachycardia, palpitations, pallor, anxiety Associated cancer syndromes Von Hippel Lindau (VHL) Multiple endocrine neoplasia type 2 (RET) Neurofibromatosis type 1 (NF1) Familial paraganglioma syndromes: Type 1 : succinate dehydrogenase D gene (SDHD) Type 2: SDHAF2/SDH5 Type 3: SDHC Type 4: SDHB www.medical-institution.com Positive family history a third of the time First tumors present at an average age of 30 years Tumors often extra-adrenal (abdominal), have a propensity to metastasize.
Slide 32-

Personalized Surveillance  risk for thyroid, renal, or gastrointestinal stromal tumors (GISTs) Anticipatory guidance Flushing, palpitations, headache, diaphoresis Hematuria New lumps/bumps Q6 month clinic visit: History and physical CBC with differential CMP Serum/urine catecholamines Serum/urine metanephrines Annual MRI abd/pelvis www.liveclinic.com/
Slide 33-

Cancer syndromes: clinical clues specific constellation of tumors family history of similar tumor type cancers at a young age multiple primary tumors of same type over time “too much cancer” in the family multiple cancers in the same individual bilateral tumors cancer syndrome stigmata
Slide 34-

Consider screening in any child diagnosed with cancer with ≥ 1 of the following: European Journal of Medical Genetics 59 (2016) 116-125 Being diagnosed with ≥ 2 malignancies in childhood 1st-degree relative diagnosed with cancer < 45 y ≥ 2 second degree relatives (same side) diagnosed with cancer < 45 y Parental consanguinity Excessive toxicity from DNA damaging agents Physical or developmental features of known syndrome Characteristic tumors Adrenocortical carcinoma JMML Pleuropulmonary blastoma ATRT Low hypodiploid ALL Pituitary blastoma Cerebellar gangliocytoma MPNST Pineoblastoma Choroid plexus carcinoma Medullary thyroid carcinoma Retinoblastoma Endolymphatic sac tumor Medulloblastoma Osteosarcoma Hemangioblastoma Optic pathway glioma Schwannoma Hepatoblastoma Ovarian Sertoli-Leydig cell tumor Subependymal giant cell tumor Congental anomalies Facial dysmorphism Intellectual disability Aberrant growth Skin abnormalities Hematologic disorders Immunodeficiency
Slide 35-

Cancer Predisposition Caveats What do you do with the information? Is there effective cancer screening? Are there prophylactic interventions? Adverse psychological outcomes Fragile child syndrome Disruption of family dynamics Issues of confidentiality, insurance coverage Important issue of informed consent Implication of diagnosis on other family members.
Slide 36-

Surveillance matters! ~ 100 LFS patients 2 groups: Recommended cancer surveillance 40 asymptomatic tumors found No surveillance 5 year overall survival: 88.8% (surveillance group) 59.6% (no surveillance) Villani, A, et. al., Lancet Oncology, 2016
Slide 37-

Continued identification of genetic modifiers of cancer risk Appreciation of “continuum” of cancer risk Berger, AH, AG Knudson and PP Pandolfi. 2011. A continuum model for tumour suppression, Nature, 476: 163-9 More uniformity in clinical management Epigenetic predisposition syndromes? microRNA’s? Development of agents to “treat” molecular defects I can see the future! http://cutcaster.com/photo/100464712-Cartoon-Fortune-Teller/
Slide 38-

UK Pediatric Inherited Cancer Program Multidisciplinary & Comprehensive Oncology Genetics Cancer Genetics Nursing Endocrinology Surgical Services Radiology Neurology Gastroenterology Surveillance School Intervention Child Life Social Work Anticipatory guidance Research opportunities Pathology Precision screening Personalized therapy Financial/Insurance support Registry identification Cardiology Nephrology Pulmonology Palliative Care Adolescent Medicine Dietary Fertility Please call UK MDs (859-257-5522) or the Pediatric Heme/Onc Clinic (859-257-4554) for patient referrals
Slide 39-

Thank you! Questions? Comments? www.wordle.com
Slide 40-

Resources Useful websites https://www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-fact-sheet www.genetests.org http://www.cancer.gov/cancertopics/genetics http://ukhealthcare.uky.edu/Markey/medical/geneticcounseling.asp http://cancergenetics.uchicago.edu/clinic/index.html Articles Jongmans MC, Loeffen JL, Waanders E, Hoogerbrugge PM, Ligtenberg MJ, Kuiper RP, et al. Recognition of genetic predisposition in pediatric cancer patients: an easy-to-use selection tool. Eur J Med Genet 2016;59:116–25. Druker H, Zelley K, McGee RB, Scollon S, Kohlmann W, Schneider KA, et al. Genetic counselor recommendations for cancer predisposition evaluation and surveillance in the pediatric oncology patient. Clin Cancer Res 2017;23. Parsons DW, Roy A, Yang Y, Wang T, Scollon S, Bergstrom K, et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol 2016. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 2015;373:2336–46. Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, 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;17:1295–305. Sherborne AL, Lavergne V, Yu K, Lee L, Davidson PR, Mazor T, et al. Somatic and germline TP53 alterations in second malignant neoplasms from pediatric cancer survivors. Clin Cancer Res 2017;23:1852–61. Ripperger T, Bielack SS, Brokhardt A, et al. Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. Am J Med Genet A. 2017;173:1017-1037. Brodeur GM, Nichols KE, Plon SE, et al. Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr.. Clin Cancer Res. 2017;23:e1-e5.