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1 Overview Biology and Introduction to the Genetics of Cancer Denise Jones, MS, CGC Certified Genetic Counselor Virginia Piper Cancer Service Line I. Our understanding of cancer the historical perspective II. Development of cancer on a cellular level on a genetic level on an organismal level III. Cancer treatment IV. Hereditary cancers 2 Historical Perspective Questions along the way Is cancer an infectious disease? (i.e. can it be spread from one person to another) Historical Perspective Current Understanding: cancer arises as a result of changes in the DNA within a cell Does cancer arise from chronic irritation of tissues? Is cancer hereditary? 3 4 Cancer at a Cellular Level The Cell Cycle How do cancer cells differ from normal cells? How do tumors grow? G2 Mitosis Irreversibly) out of cell cycle (terminal maturation Synthesis Cell Death G1 Reversibly out of cell cycle Transition from one phase of the cycle to the next occurs in response to external signals and is under the control of multiple genes 5 6 1
2 Normal Cell vs Cancer Cell Proliferation Why do Cancers Grow? Cell Death Cell Proliferation 7 8 The rate of cell division exceeds the rate of cell death Cancer at the Molecular (Genetic) Level Each Cell has 23 Pairs of Chromosomes What happens to genes that are involved in carcinogenesis? This will require a little background information 9 10 One chromosome out of each pair is inherited from our father, and the other is inherited from our mother Chromosomes Contain our Genes DNA Double Helix 11 Our genes are made of Deoxyribonucleic Acid (DNA) 12 2
3 Genes Are Instructions for Producing Proteins Back to Current Theory Cancer arises as a result of changes in the DNA within a cell The human genome includes approximately 20,000 genes, some of which are involved in controlling cell growth, division and maturation Mutation Definition: A change in the sequence of the DNA that causes a gene not to work properly How it occurs: DNA damage + cell division without adequate DNA repair = mutation Sources of DNA Damage Spontaneous Environmental (Inherited) Multiple genes within a single cell must be mutated for a cancer to develop Spontaneous DNA Damage Occur as the result of natural processes within a cell DNA replication errors Natural or man made substances which can damage DNA Chemicals Mimic DNA bases Alter the overall structure of the DNA helix Radiation Thymine dimers (UV radiation) Free radical production (ionizing radiation) Single or double strand DNA breaks, crosslinks Viruses Examples of Carcinogens (agents that cause DNA damage) Chemicals Environmental (tobacco, alcohol) Occupational (benzene, asbestos) Radiation Radon, UV rays, Ionizing radiation Viruses Human papilloma virus (HPV) cervical cancer Hepatitis B and C liver cancer Epstein Barr virus Burkitt s lymphoma Other may promote cell proliferation certain hormones inflammatory agents
4 DNA Repair DNA damage is constantly occurring in our cells Cancer on Both a Cellular and Genetic Level We have mechanisms in place to identify and repair the vast majority of this damage When these mechanisms fail, and a cell replicates, the DNA damage becomes permanent a mutation is born Carcinogenesis is a Multi-step Process Cancer on an Organismal Level: Invasion and Metastasis Initiation Promotion Invasion & Metastasis Tumor Progression How Do We Classify Cancers? Tissue Type: histology where did the cancer originate? Cellular Grade: degree of differentiation or how abnormal the cells appear Tumor Stage: how big is the tumor?, how far has it spread?, how big are the metastases? Tumor Classification: Tissue of Origin Epithelial skin, lining of organs (80% of all tumors) carcinomas squamous (flat), adeno (glandular) Connective Tissue cartilage, muscle, bone sarcomas fibro (fibrous), lipo (fat), osteo (bone) Hematologic blood or lymph components leukemias, lymphomas Central Nervous System brain or spinal cord Include astrocytomas, meningiomas, etc
5 Tumor Classification: Cellular Grade CELLULAR GRADE reflects how abnormal the cells appear under the microscope compared to normal cells. Grade also differs based on the type of cancer The pathologist determines grade using specific criteria and a scoring system (G1 G3) The higher the grade, the poorer the prognosis (all other factors being equal) Tumor Classification: Tumor Stage 1. Based on tumor size and degree of metastasis 2. Used to determine prognosis and treatment 3. Facilitates data collection and comparisons Staging of Cancers Anatomic staging (TNM classification) T = tumor size and location N = nodal involvement M = metastasis Staging by extent of spread (0 IV) 0= in situ IV= distant metastases Example: Colon Cancer Treatment by Stage Stage 0 local excision, polypectomy Stage 1 wide excision, anastomosis Stage 2 wide resection, anastomosis, + or chemotherapy Stage 3 wide resection, anastomosis, adjuvant chemotherapy Stage 4 palliative surgery, curative resection of metastases, palliative chemotherapy Current Methods of Treatment LOCAL THERAPY: Surgery physical removal of cancer cells Radiation Therapy targets dividing cells SYSTEMIC THERAPY: Chemotherapy targets dividing cells Immunotherapy targets specific proteins that may be expressed on cancer cells Hormone Therapy blocks the production or the effect of a hormone on cancer cell Anti angiogenesis starves cancer cells by limiting their blood supply Sporadic vs Hereditary Cancers Sporadic cancers (vast majority) DNA damage is acquired over time Hereditary cancers (5 10%) some DNA damage is inherited in the form of a mutated tumor suppressor gene or proto oncogene Hereditary Breast & Ovarian Cancer BRCA1 or BRCA2 (tumor suppressor genes) Lynch Syndrome MLH1, MHS2, MSH6, PMS2 (mismatch repair genes)
6 Hereditary Cancer is Rare Sporadic vs Hereditary Cancer Tumor Develops In hereditary cancer, one damaged gene is inherited. Sporadic Cancer Hereditary Cancer Tumor Develops Family History Characteristics that Can Indicate Hereditary Cancer Indications for a Hereditary Cancer Syndrome: Cancer in two or more close relatives on the same side of the family with the same or possibly related cancers Early age at diagnosis (i.e. <50 yrs old) Multiple primary tumors in the same individual Bilateral or multiple rare cancers Constellation of tumors in a given family consistent with a specific cancer syndrome Evidence of an autosomal dominant inheritance pattern What do Genetic Counselors Do? BEFORE TESTING: Gather three generation family tree Confirm diagnoses through medical records Assess hereditary cancer risk Discuss possible genetic syndromes/educate Address the option of genetic testing Discuss insurance coverage and reassure about insurance discrimination AFTER TESTING: Interpret test result Discuss continuing care with screening/surgeries Encourage conversation with family members Address psychosocial issues for both patient and family GOAL: Eliminate the burden of cancer in our patient and their family members
7 Assessing Inherited Cancer Risk The family history of cancer is our main tool in identifying an inherited risk for cancer Limitations: small family size, non paternity, adoption Sometimes a patient s personal history alone is enough to consider the possibility of an inherited risk Rare cancer diagnosis, unusually young age at diagnosis, etc. Hereditary Breast and Ovarian Cancer Syndrome (HBOC) BRCA1 and BRCA2 genes Tumor suppressor genes Breast cancer risk up to 40 85% Heightened surveillance Alternate mammogram and MRI every 6 months Bilateral mastectomy Tamoxifen? Ovarian cancer risk up to 25 55% BSO by age Hereditary Breast and Ovarian Cancer Syndrome (HBOC) Prostate cancer risk up to 33 35% Earlier onset Biologically more aggressive Screening by age 40 Male breast cancer risk of about 5 10% Clinical breast exams by age 35 Baseline mammogram by age 40 Lynch Syndrome Also known as Hereditary Non Polyposis Colorectal Cancer (HNPCC) Mutations in the MLH1, MSH2, MSH6, PMS2 or EPCAM genes Mismatch repair genes All colon and uterine tumors removed at an Allina facility routinely tested for Lynch Syndrome Lynch Syndrome Cancer Risks Risk Depends on Gene! Lynch Syndrome Management depends on gene and family history: Colonoscopy by age 20 25, every 1 2 years TAH/BSO by age 40 Upper endoscopy for some Annual physical exam and urinalysis Prostate screening by age 40 Annual dermatology exams Aspirin
8 Risk Assessment Other Breast Cancer Genes For those not appropriate for genetic testing or negative for genetic testing: Assess risk based on family history NCCN guidelines Breast, >20% lifetime risk of breast cancer=breast MRI candidate Colon Breast cancer risk assessment models: Claus IBIS Gail Other Colon Cancer Genes Multi-gene panel testing Lots of information! Will identify mutation carriers who may otherwise have been missed Multi-gene Panel Testing Not all panels are the same Turn around time is longer (months) May obtain unexpected results Not all information will be clinically useful Variants of uncertain significance A negative result still cannot exclude genetic risk! Common Myths Hereditary cancer is common most cancers run in families If my mother had breast cancer, I am automatically at an increased risk for breast cancer I cannot inherit breast cancer risk from my father s side of the family
9 Common Myths There is nothing I can do about it if I am at high risk for cancer, so why find out? If I go see a genetic counselor, they will pressure me into genetic testing and/or make medical decisions that I am not comfortable with I have already had cancer, so genetic testing is not appropriate for me it is only appropriate for my family members Common Myths A negative test result means I do not have an increased risk for breast cancer or other cancers Insurance won t cover the cost of genetic counseling or genetic testing If I have a genetic test, my health insurance company will drop my coverage or raise my rates Summary Some families have a significant inherited risk for cancer Genetic testing is appropriate for high risk families Identification of high risk families can lead to: Very effective screening and prevention for those who have inherited the risk Reassurance and appropriate screening for those who have not inherited the risk Not all family histories of cancer indicate a significant cancer risk Screening and prevention is important and can still be tailored THANK YOU!! Questions?? 51 9
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Disclosure I have no financial relationships to disclose Biology and Introduction to the Genetics of Cancer Vickie Matthias Hagen, MS, CGC Certified Genetic Counselor Virginia Piper Cancer Service Line
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