INTRODUCTION TO CLINICAL CANCER GENETICS. SHERLY PARDO, MD Assistant Professor Depts Biochemistry & Pediatrics UPR-School of Medicine
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1 INTRODUCTION TO CLINICAL CANCER GENETICS SHERLY PARDO, MD Assistant Professor Depts Biochemistry & Pediatrics UPR-School of Medicine
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3 Top Ten Incidence Cancer Sites, * Males (N=32,714) Prostate 40.2 Colon and Rectum 13.4 Lung and Bronchus 6.4 Urinary Bladder 4.1 Oral Cavity and Pharynx 4.0 Non-Hodgkin Lymphoma 3.4 Stomach 2.9 Liver and Intrahepatic Bile 2.8 Kidney and Renal Pelvis 2.1 Leukemia 2.1 Other Locations 18.4 % Females (N=27,935) % *Statistics are from an average of the years /statistics that presents the year 2009 are preliminary. Cases with age unknown were included/ Statistics were generated from malignant cases only Rates are per 100,000 and age-adjusted to the 2000 PR population Data Source: Puerto Rico Central Cancer Registry, Preliminary Puerto Rico Cancer Incidence File (December, 2011) Breast 30.6 Colon and Rectum 14.0 Thyroid 8.1 Corpus and Uterus 7.1 Lung and Bronchus 4.2 Non-Hodgkin Lymphoma 3.8 Cervix Uteri 3.7 Stomach 2.6 Ovary 2.6 Leukemia 1.9 Other Locations 21.3
4 Top Ten Mortality Cancer Sites, * Males (N=5,653) % Females (N=4,319) % Prostate 18.4% Lung and Bronchus 13.2% Colon and Rectum 12.8% Liver and Intrahepatic Bile Duct 6.4% Stomach 4.8% Oral Cavity and Pharynx 3.8% Pancreas 3.7% Esophagus 3.6% Lymphoma 3.6% Leukemia 3.3% Other Locations 26.5% Breast 19.3% Colon and Rectum 12.8% Lung and Bronchus 10.2% Liver and Intrahepatic Bile Duct 5.5% Pancreas 5.3% Corpus and Uterus, NOS 4.6% Ovary 4.2% Lymphoma 3.9% Stomach 3.8% Leukemia 3.5% Other Locations 26.9% *Cases with age unknown were included/ Statistics were generated from malignant cases only/ Statistics are an average of the years Rates are per 100,000 and age-adjusted to the 2000 PR population Data Source: Puerto Rico Department of Health and National Center for Health Statistics using the Medical Mortality Data System (MMDS) for the years
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7 Ultra Violet Radiation 3 types of UV light: UVA ( nm), UVB ( nm), UVC ( nm) UVB is the most effective carcinogen. Conjugated double bonds in the N base rings of DNA absorb UV radiation. UVB-induced UV photoproducts: 1. Cyclobutane pyrimidine dimers, Causes a bend in the DNA helix. When DNA polymerase cannot read the DNA template, it incorporates an A. Therefore, TT dimers can be restored, but TC and CC dimers end up as TT. 2. pyrimidine-pyrimidone photo products: mimics an abasic site, can be repaired. UV light causes skin cancer
8 Chemical Mutagens Carcinogens: Polyacrylic aromatic hydrocarbons (cigarette smoke), aromatic amines (cooking meat), azo dyes, nitrosoamines and nitrosoamides (tobacco), hyrazo and azoxy compounds, carbamates, halogenated compounds, natural products, inorganic carcinogens, alkylating agents (mustard gas), aldehydes, phenolics, etc. Cigarette smoke: DMBA, dimethyl benzanthracine Benzyl pyrene (BP) is converted by cyt p450 to BP diol epoxide that results in G to T transversions. Nitrosamines are converted to methylate guanine that is incorporated into DNA.
9 Viruses can cause cancer by integration of viral genes into host chromosomes
10 KNUDSON HYPOTHESIS
11 Characteristics the pathologist looks for when diagnosing a tumor as malignant
12 CANCER PROGRESSION tulane.edu The Principles of Clinical Cytogenetics. 1 st Ed. SL. Gersen
13 The Principles of Clinical Cytogenetics. 1 st Ed. SL. Gersen
14 The Principles of Clinical Cytogenetics. 1 st Ed. SL. Gersen
15 Not all genomic alterations are the same AJHG. Vol 90(2) Pages
16 Gene categories commonly affected.
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19 What are the chances of developing cancer? NCI
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22 Hereditary breast and ovarian cancer (HBOC) syndrome. Data from Myriad Genetics Laboratory.
23 HEREDITARY CANCER SYNDROMES NCI
24 Hereditary Cancer Syndromes Basal Cell Nevus Syndrome, Gorlin Syndrome (Skin Cancer). Bloom Syndrome (Skin Cancer). Xeroderma Pigmentosum (Skin Cancer). Melanoma, Hereditary (Skin Cancer). Fanconi Anemia (Skin Cancer). Breast/Ovarian Cancer, Hereditary (Breast and Ovarian Cancer). Cowden Syndrome (Breast and Ovarian Cancer; Colorectal Cancer). Li-Fraumeni Syndrome (Breast and Ovarian Cancer). Peutz-Jeghers Syndrome (Colorectal Cancer; Breast and Ovarian Cancer). Hyperparathyroidism, Familial (Endocrine and Neuroendocrine Neoplasias). Medullary Thyroid Cancer, Familial (Endocrine and Neuroendocrine Neoplasias). Multiple Endocrine Neoplasia Type 1 (Endocrine and Neuroendocrine Neoplasias). Multiple Endocrine Neoplasia Type 2A, 2B (Endocrine and Neuroendocrine Neoplasias). Polyposis, Familial Adenomatous Polyposis (Colorectal Cancer). Colon Cancer, Hereditary Nonpolyposis or Lynch Syndrome (Colorectal Cancer). Polyposis, Familial Juvenile (Colorectal Cancer). Polyposis, MYH-Associated (Colorectal Cancer). Prostate Cancer, Hereditary (Prostate Cancer).
25 Classification based on inheritance patterns.
26 Cancers in Classic FAP Cancer Lifetime Risk Colon 100% Duodenal 5-11% Pancreatic 2% Thyroid 2% Brain (medulloblastoma) < 1% Hepatoblastoma <1% (< 5y/o)
27 Cancers in Lynch Syndrome Cancer Lifetime Risk (%) Colon 80 Endometrial Stomach 13 Ovarian <5 Ureters/renal <5 Brain (glioblastoma) <5
28 Cancer Risk in Breast Cancer Syndromes Cancer Lifetime Risk Ovarian 27% Uterine 5-11% Colon 8% Prostate 8% Pancreas 7% Thyroid,Brain (medulloblastoma), sarcoma <1%
29 Autosomal Dominant Inheritance
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31 Incomplete Penetrance
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35 When to suspect a HCS? In the individual patient: Multiple primary tumors in the same organ. Multiple primary tumors in different organs. Bilateral primary tumors in paired organs. Multifocality within a single organ (e.g., multiple tumors in the same breast, all of which have risen from one original tumor). Early age at tumor diagnosis. Tumors with rare histology. Tumors occurring in the sex not usually affected (e.g., breast cancer in men). Tumors associated with other genetic traits. Tumors associated with congenital defects. In the patient s family: One first-degree relative with the same or a related tumor. Two or more first-degree relatives with tumors of the same site. Two or more first-degree relatives with tumor types belonging to a known familial cancer syndrome. Two or more first-degree relatives with rare tumors. Three or more relatives in two generations with tumors of the same site or etiologically related sites.
36 Clinical Cancer Genetics: Risk assessment
37 Gail Model Claus Model Data derived from Family history characteristics Other characteristics Strengths Breast Cancer Detection Demonstration Project Study FDRs with breast cancer Current age Age at menarche Age at first live birth Number of breast biopsies Atypical hyperplasia in breast biopsy Race (included in the most current version of the Gail model) Incorporates: Risk factors other than family history Cancer and Steroid Hormone Study FDRs or SDRs with breast cancer Age of onset in relatives Current age Incorporates: Risk factors other than family history. Limitations Best application Underestimates risk in hereditary families. Number of breast biopsies without atypical hyperplasia may cause inflated estimates. Does not incorporate: Paternal family history of breast cancer or any family history of ovarian cancer. Age at onset of breast cancer in relatives. All known risk factors for breast cancer. For individuals with no family history of breast cancer or one FDR with breast cancer, aged 50 y. For determining eligibility for chemoprevention studies. May underestimate risk in hereditary families May not be applicable to all combinations of affected relatives Does not include risk factors other than family history For individuals with no more than two FDRs or SDRs with breast cancer
38 Clinical Cancer Genetics Goals
39 IDENTIFY individuals at risk
40 Recommend Genetic TESTS
41 Prevention & Early detection
42 Guide Management: NCCN guidelines for HBOC WOMEN Breast self-exam starting at age 18y Clinical breast exam, q6-12 months, starting at age 25y. Annual mammogram and breast MRI screening starting at age 25y. Transvaginal ultrasound and CA-125 every 6 mo starting at age 35y (or 10y before the earliest age of ovarian cancer in the family). Discuss risk-reducing mastectomy and salpingo-oophorectomy (between 35-40y, and upon completion of child bearing). Consider chemoprevention. MEN Breast self-exam starting at age 35y Clinical breast exam, q6-12 months, starting at age 25y. Annual mammograms starting at age 40y. Adhere to NCCN guidelines for prostate and other cancer screening.
43 Clinical Cancer Genetics: Benefits to patients and their families. If a HCS is confirmed Life-saving management implications. Specific interventions aimed at reducing risk. Information about familial cancer risk allows planning for the future (lifestyle and health care decisions, family planning, or other decisions). If negative Psychological effects (reduced worry, guilt) and lower health care costs.
44 Post-Test Question Which of the following statements in regards to Hereditary Cancer Syndromes (HCS) is incorrect? a) Most HCS show an autosomal dominant inheritance pattern. b) An affected individual can pass along the causative gene to their progeny with a 50% chance. c) Hereditary breast-ovarian cancer syndrome (HBOC) only affects females. d) Genetic tests could provide valuable information to guide management and preventive measures. e) Genetic counseling should be an integral component to the management of HCS patients and their families.
45 Thanks!!! Sherly Pardo, MD Assistant Professor Depts Biochemistry & Pediatrics UPR- School of Medicine , x1623
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