1. Introduction to Cancer Genetics and Genomics Apostolos Psychogios, MD, FACMG Associate Professor of Pediatrics LeeAnne Brown Chair of Clinical Excellence Division of Medical Genetics and Genomic Medicine

2. Disclosure Statement of Financial Interest I, Apostolos Psychogios, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. I, Apostolos Psychogios, DO NOT anticipate discussing the unapproved/investigative use of a commercial product/device during this activity or presentation.

3. Learning Objectives Identify the genetic syndromes associated with breast, ovarian, colon and other types of cancer and the genes associated with these syndromes. Use and understand the models available to predict risk of breast and colon cancer. Understand the principles of genetic testing for individuals and families where hereditary cancer predisposition is suspected. Recognize when to refer an individual or family for cancer genetics evaluation Understand the management options for individuals who are carriers of deleterious gene mutations

5. Inherited Predisposition to Cancer Inherited cancers range from 1-60%. For most tumor types, e.g. breast, the inherited fraction fall in the range of 1-10%. Several rare tumors, adrenocortical carcinoma, retinoblastoma, and optic gliomas have very high inherited fraction (40-60%). Autosomal dominant inheritance

6. Inheritance Patterns

7. >10% Germline Mutations and Tumors

8. Multiple Mechanisms: Wilm’s Tumor

9. Multiple Mechanisms: Renal Cell Cancer Von Hippel Lindau Syndrome (VHL) – almost always clear cell histology 80% of sporadic RCC has somatic VHL mutations. Balanced translocation carriers involving chromosome 3 Papillary renal carcinoma – due to activating mutations in c-MET oncogene Hereditary leiomyomatosis RCC: mutations in fumarate hydratase; autosomal dominant uterine fibroids and cutaneous leiomyomata Birt-Hogg-Dubé Syndrome – chromophobe/oncocytic

10. Multiple Cancers: Birt-Hogg-Dubé Syndrome Chromophobe/oncocytic histology RCC Benign fibrofolliculomas Colonic polyps Medullary thyroid cancer Spontaneous pneumothorax BHD tumor suppressor gene

11. NEJM 359;7 August 14, 2008 Chromosomal Abnormalities in Human Cancer

12. Example of Imprecise Translocation: t(8;14) in Burkitt’s Lymphoma

13. Example of Precise Translocation: Philadelphia Chromosome in CML

14. Precise Translocation: t(11;22) in Ewings’ sarcoma Large destructive lesion in the diaphysis or metaphysis with a moth-eaten appearance periosteal lifting may give "onion skin" or "sunburst" appearance

16. N Engl J Med 2008;359:2143-53. Genes and Common Cancers

17. Breast-Cancer Susceptibility Loci and Genes N Engl J Med 2008;359:2143-53.

18. N Engl J Med 2007;357:154-62.

19. “Red Flags” for HBOC Syndrome Breast cancer diagnosed < 50 years Ovarian cancer Male breast cancer Two primary breast cancers “Triple-negative” breast cancer Ashkenazi Jewish ancestry Familial BRCA gene mutation

22. Risk Prediction Models There are well established computer models to predict: –Risk of developing breast cancer for someone of “average” risk – Gail Model. –Risk of developing breast cancer based on family history – Claus Tables. –Likelihood that genetic testing will yield a mutation in BRCA1 or BRCA2 – BRCAPro (US model) and BOADICEA (UK model).

23. N Engl J Med 2007;357:154-62.

25. http://www.afcri.upenn.edu/itacc/penn2/

26. Professional Societies Guidelines

27. N Engl J Med 2007;357:154-62.

28. Other Syndromes with Increased Risk for Breast Cancer Li-Fraumeni – average diagnosis 32 in p53 carriers Cowden’s syndrome – PTEN mutations assoc. with thyroid cancer, hamartomas, skin lesions Peutz-Jeghers – 32% by age 60 Ataxia telangiectasia (ATM) heterozygotes.

29. Li-Fraumeni Syndrome (LFS)

30. Cowden Syndrome (CS) Breast Cancer risk (30% lifetime risk). Thyroid cancer (10% lifetime risk). Cerebellar dysplastic gangliocytoma Mucocutaneous lesions Trichilemmomas (facial) Papillomatous lesions

31. Colorectal Cancer (CRC) Risks

32. HNPCC Family Pedigree

33. Hereditary Non-Polyposis Colon Cancer Lynch Syndrome Autosomal dominant CRC without polyposis associated with endometrial cancer, bile duct, ovarian, ureteral and gliomas. ~70% lifetime risk of CRC 50-70% endometrial cancer in classic Lynch. Right-sided CRC cancer is more frequent. Better prognosis of CRC stage for stage. Patients with 2 or 3 different primary HNPCC-related tumors.

34. “Red Flags” for an Affected Individual with HNPCC

35. Family History (Unaffected Individual) Criteria for HNPCC Amsterdam Criteria (CRC based) - Exclude FAP I.At least one CRC < age 50 II.Two affected generations III.Three affected relatives, two are FDR relatives of other one

36. HNPCC Genes

38. Polyposis Syndromes

39. “Red Flags” for Polyposis Syndromes More than 10 cumulative colorectal adenomas Colorectal cancer associated with multiple adenomas Familial mutation for hereditary polyposis syndrome

40. HNPCC vs. AFAP vs. MAP

41. Polyposis Associated with FAP

43. MYH-Associated Polyposis ACMG Genetics Review Course

44. Colorectal Cancer Management

45. “Red Flags” for Hereditary Melanoma Two or more melanomas in the proband or family (FDR) Melanoma and pancreatic cancer in the proband or family Family history of p16 gene mutation

46. Hereditary Melanoma

47. Genomics and the Continuum of Cancer Care

48. NEJM 2011;364:340-50.

49. N Engl J Med 2011;364:340-50.

50. N Engl J Med 2008;358:1148-59

53. Quillen Genomic Medicine Program Research

54. LeeAnne Brown Research Project In collaboration with Mayo Clinic (Dr. Eric Wieben) 2012- 2015 Whole Exome Sequencing/Methylation Analysis of patients with: –Unknown syndromes –Autism, intellectual disability –Neurologic disorders (MS, ALS, AD) –Tumors (Multiplex families with breast, prostate, bladder cancer)

56. Questions?