Are we ready to predict who will get what kind of cancer? Nothing to disclose Endocrine JE Gosnell MD Assoc Prof of Clinical Surgery 3/6/15 2 Genetics in endocrine surgery 3/6/15 Thyroid cancer Genetics in endocrine disease � Identified risk factors: family � Thyroid history and radiation exposure RET • Papillary, follicular and RET/PTC � Historical factors: local BRAF medullary thyroid cancer symptoms in the neck (pain, RAS hoarseness, dyspnea). Other � Parathyroid endocrine disorders (!) • Hyperparathyroidism, cancer HRTP2 � Signs: fixed mass, adenopathy CASR � Adrenal � US characteristics • Pheochromocytoma, SDH � Biopsy: cytology, gene VHL paraganglioma expression NF1 � Pancreas � Germline and Somatic • PNET TP53 mutations: RET, RET/PTC IGF2gene mutations 3 Genetics in endocrine surgery 3/6/15 4 Genetics in endocrine surgery 3/6/15 1 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Ideal disease for genetic testing Prophylactic surgery � You et al. 2007 World J Surg. Prophylactic surgery � Diseases that are autosomal dominant with high penetrance � Diseases for which there are prophylactic treatment when 1) the genetic mutation causing the hereditary malignancy must have discovered early a very high penetrance and be expressed regardless of environmental factors; � Diseases for which there is an accurate screening test 2) there must be a highly reliable test to identify patients who have inherited the mutated gene; 3) the organ must be removed with minimal morbidity and virtually no mortality; 4) there must be a suitable replacement for the function of the removed organ; and 5) there must be a reliable method of determining over time that the patient has been cured by "prophylactic surgery” M Sara Rosenthal, ATA Satellite Symposium at ENDO 2015 Pediatric Ethics guidelines, 2010 International J Ped Endocril 5 Genetics in Endocrine Surgery 3/6/15 6 Genetics in Endocrine Surgery 3/6/15 Medullary thyroid cancer Medullary thyroid cancer 1959: Hazard, Hawk and Crile � Specific genetic test-direct DNA analysis “Medullary (solid) carcinoma of the � Essentially 100% of affected Thyroid: clinico pathological entity” patients develop disease � Age-related progression � Genotype-phenotype (J Clin Endocrinol Metab;19:152-161) correlation � Prophylactic/preclinical surgery for cure (www.whonamedit.com) 7 Genetics in endocrine surgery 3/6/15 8 Genetics in endocrine surgery 3/6/15 2 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Medullary thyroid cancer Medullary thyroid cancer 1966: Descriptions of parafollicular C cells 1961: John H. Sipple, MD Williams et al. American Pulmonologist Johns Hopkins, Syracuse ( J Clin Pathology 1966;9:103-13 ) Calcitonin is a sensitive and specific tumor Marker (purified by Copp and Cheney 1962, but only later attributed to c-cells (www.whonamedit.com) 9 Genetics in endocrine surgery 3/6/15 10 Genetics in endocrine surgery 3/6/15 Medullary thyroid cancer Medullary thyroid cancer 1990s: AD, chromosome 10 1965-6: ED Williams and DJ Pollock 1993: RET proto-oncogene first description of MEN 2b as a syndrome (Mulligan et al, 1993) (Donis-Keller et al, 1993) (J Path Bact;1966) Up to 10% of apparent “sporadic” cases of MTC will be found to have RET mutation (Lips et al, N Eng J Med, 1994) 11 Genetics in endocrine surgery 3/6/15 12 Genetics in endocrine surgery 3/6/15 3 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Medullary thyroid cancer Medullary thyroid cancer 1990s: RET proto-oncogene encodes for transmembrane Importance of early diagnosis: tyrosine kinase Wells et al. 192 patients 634 “aggressive screening with Pentagastrin-stimulated 918 609 Calcitonin levels” 611 618 -correlation of Ct levels with LN involvement 620 -better prognosis when patients treated earlier, with 804 disease confined to the thyroid (Ann Surg 1982;95:595) 13 Genetics in endocrine surgery 3/6/15 14 Genetics in endocrine surgery 3/6/15 Medullary thyroid cancer: 804 kindred Surgical treatment of a disease based on a genetic test 15 Genetics in endocrine surgery 3/6/15 16 Genetics in endocrine surgery 3/6/15 4 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
Genetics in thyroid carcinogenesis Genotype-phenotype correlation Prophylactic thyroidectomy in 22 pts in MEN-2a family (c804Y) MTC, CCH= CCH= 5 pts HPT= 5 pts 15 pts normal thyroid glands in 2 pts, no patients had metastases in central lymph nodes, pheochromocytoma in 1 pt (Gosnell, ANZJS 2006) 17 Surgical management of MTC 3/6/15 18 Genetics in endocrine surgery (Mitsiades and Fagin,2010) 3/6/15 MTC over 50 years….. Genetics of sporadic and familial hyperparathyroidism Clinical observations-> genetic cause -> genetic test-> prophylactic surgery Parathyroid disorder Gene (s) involved Sporadic parathyroid adenoma Cyclin D1; MEN1 (somatic) Sporadic parathyroid carcinoma HRPT2 (somatic and germline) MEN 1 MEN1 (germline) MEN 2 RET (germline) HPR-JT (jaw tumor syndrome) HRPT2 (germline) Familial hypercalcuric hypercalcemia CASR and unidentified genes Neonatal severe hyperparathyroidism CASR and unidentified genes Familial isolated hyperparathyroidism MEN1, HRPT2, CASR, unidentified genes ( Arnold and Lauter, 2010) 19 Genetics in endocrine surgery 3/7/2015 20 Genetics in endocrine surgery 3/6/15 5 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
HRTP2 gene Genetics of adrenal disease Pheochromocytomas and extra-adrenal paragangliomas are tumors derived from the neural crest � Encodes for parafibromin � Acts as a tumor suppressor gene � Pheochromocytoma • Tumor arising from chromaffin cells � Associated with HPT-Jaw tumor syndrome (mutations in about 70%) of the adrenal medulla (sympathetic) � Associated with sporadic and • Associated with MEN 2 syndromes hereditary parathyroid cancer (75%) � Paraganglioma • Extra-adrenal tumors originating from either sympathetic or parasympathetic nervous system • Associated with paraganglioma syndromes Both are associated with constellation of symptoms, including episodic tachycardia, diaphoresis and headaches ( Harari, 2010) 21 Genetics in endocrine surgery 3/6/15 22 Genetics in endocrine surgery 3/6/15 Genetics of pheochromocytoma and Succinate dehyrogenase genes (SDH) paraganglioma � Encode for mitochondrial complex enzyme � Proposed as an oxygen sensor � Mutation results in little or no enzyme activity (Pagan RA et al. Gene Reviews) (Pagan RA et al. Gene Reviews) 23 Genetics in endocrine surgery 3/7/2015 24 Genetics in endocrine surgery 3/7/2015 6 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
SDHB mutations Conclusions � There have been tremendous advancements in our understanding of the genetic causes of endocrine disease � Most common mutation in patients with pheochromocytomas and paragangliomas � MTC a prototype disease for genetic testing and early treatment. Genetic testing should be offered to most if not all patients with � Over 150 mutations identified even apparent sporadic MTC � Associated risk of malignancy is 34-97% (the highest among the � Parathyroid carcinoma is associated with mutations in the HRPT2 SDH mutations) gene; genetic counselling and testing should be offered � Associated with renal cell carcinoma and Cowden’s disease � Pheochromocytomas and paragangliomas may be associated with mutations in the SDH genes; genetic testing should be offered. � Identified mutations allow tailored approach to individual patients Carriers should undergo more aggressive surveillance and treatment AND allow us to better predict disease in other endocrine organs and presence of disease in gene+ kindred (Pagan RA et al. Gene Reviews) 25 Genetics in endocrine surgery 3/7/2015 26 Genetics in endocrine surgery 3/6/15 Limitations � Not very good at predicting de-novo mutations � Genotype-phenotype correlation is imperfect � Ethical landscape is changing Thank you Jessica E. Gosnell MD Associate Professor of Clinical Surgery 28 27 Genetics in endocrine surgery 3/6/15 7 3/7/2015 [ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS]
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