Cancer Genomics 101 BCCCP 2015 Annual Meeting
Objectives Identify red flags in a person s personal and family medical history that indicate a potential inherited susceptibility to cancer Develop a systematic way of identifying individuals at increased risk and low risk of hereditary cancer that involves collecting personal and family medical history information and using evidence-based guidelines and risk assessment tools Recognize the importance of identifying individuals at increased risk of hereditary cancer in terms of providing access to genetic counseling and possible testing, and tailored medical management
Background- Clinical Cancer Genetics
Cancer is fundamentally a genetic disease.* * However, even though all cancers are genetic, only a small percentage of cancers are inherited.
Cancer In Families Most people have at least one relative with cancer, but most are not at increased risk based on family history Determining which patients have an increased risk of cancer requires a three-four generation genetic pedigree The first step in risk assessment is to try to classify a family history in one of the following three ways: Sporadic (Average Risk) Familial (Moderate Risk) Hereditary (High Risk)
Sporadic Cancer (Average Risk) Single occurrence of a specific type of cancer in a family Typical age of onset Single primary tumor Relatives generally not at increased risk of cancer Etiology-chance or environmental exposure Dxd. 70 Medical management: population screening.
Hereditary Cancer (High Risk) Dxd. 35 Dxd. 42 Dxd. 45 Dxd. 48 Medical management: Specific to syndrome, but increased surveillance if available, starting at an earlier age than usual, may be multiple organs at risk, discuss preventative measures if appropriate. Consider genetic testing to clarify risks. Red Flags Two or more relatives in the same lineage with the same or related cancers Early age of onset Multifocal or bilateral cancers Evidence of a specific inheritance pattern (usually dominant) Predisposition is due to a single gene defect If dominant, first degree relatives of have 50% risk of inheriting mutation
Familial Cancer (Moderate Risk) Two close relatives with a specific type of cancer Typical age of onset Single primary tumor Other relatives at moderately increased risk of cancer Etiology-multiple possibilities Dxd. 70 Dxd. 65 Increased surveillance generally starting at standard age of onset. Discussion of preventative measures balancing risks of cancer versus risk of intervention.
Difference Between Sporadic and Hereditary Cancer Explained by Knudson s two hit hypothesis Hypothesis developed from observations of retinoblastoma cases 40% of retinoblastoma is hereditary, 60% is sporadic Hereditary cases tend to be associated with earlier age of onset, two or more retinoblastomas, bilaterality, increased risk of other tumors Both caused by mutations in the RB1 tumor suppressor gene
Knudson s Hypothesis
Autosomal Dominant
Summary-Two Hit Hypothesis Sporadic cases Both copies of the RB1 gene have to be mutated (in the same cell) to start the process of tumorigenesis Mutations only present in cancer cells, not transmitted to offspring, (all are acquired) Hereditary cases A person has a germ-line mutation in one copy of the RB1 gene, so only one additional event required to start the process, (one is inherited, the rest are acquired) Mutation can be transmitted to offspring
Two-Hit Hypothesis Explains earlier age of onset in hereditary cases (one less event required for tumor to develop) Explains increased incidence of bilateral and/or multifocal cancers (all cells start with one hit, not just a single cell) Explains reduced penetrance (having a germline mutation is not enough to cause cancer-other mutations must be acquired) Explains why genetic testing (blood sample) is primarily beneficial to those whose history is suggestive of hereditary but not sporadic cancer
Sporadic vs Hereditary Cancer Sporadic cancer- one hit Hereditary cancer- one hit Two normal copies One normal & one mutated copy Two mutated copies
Etiology of Familial Cases- Heterogeneous Multifactorial influences (multiple genes and environment together) Shared environmental risk factors Chance clustering of sporadic cases Under-reporting of cancer history or small family size that masks hereditary family Liability Threshold Affected
Summary Cancer Genetics All cancers are genetic but most are not inherited. Can classify cancer in families as sporadic, familial, hereditary The first step in classifying a family history to take a three-generation pedigree Classifying the family history is important in identifying those who may benefit from genetic testing and in tailoring management. Genetic counseling and testing is most beneficial to those whose family history is classified as hereditary.
Self-Assessment What are the red flags you want to look for in determining if a patient is at risk of hereditary cancer? For which family history type is genetic testing most beneficial? Sporadic Familial Hereditary For which family history type is genetic testing least beneficial? Why? If a parent has a mutation that increases his/her risk of cancer that is passed on as an autosomal dominant trait, what is the risk that a child will inherit the mutation?
How would you classify this family history? English, Irish Colon Cancer dxd. 75 60 62 65 65 70 72 1. Sporadic 2. Familial 3. Hereditary 4. Cannot determine Breast cancer dxd. 60 45 43
How would you classify this history? Scottish, German Breast cancer @ 50, ovarian cancer @ 62 60 62 65 65 70 Breast cancer dxd. 32 Breast cancer dxd. 45 42 45 43 1. Sporadic 2. Familial 3. Hereditary 4. Cannot assess
How would you classify this history? Irish, Italian Colon Cancer dxd. 75 60 62 70 70 75 80 1. Sporadic colon cancer 2. Familial colon cancer 3. Familial breast cancer 4. Hereditary colon cancer 5. Cannot assess Breast cancer dxd. 60 2 45 43 62 3 Colon Cancer dxd. 62
Inherited Breast Cancer Syndromes
Breast Cancer Genetics All Breast Cancers Hereditary Breast Cancers 7% hereditary 10-15% familial 78-87% sporadic * From A J Hum Genetics, 62:676-689, 1998 52% BRCA1* 32% BRCA2* 13% Other*
Most Common Hereditary Breast Cancer Syndromes Gene BRCA1 & BRCA p53 PTEN CDH1 Syndrome Hereditary breast ovarian cancer syndrome (HBOC): Breast, ovarian, male BC, prostate cancers, and pancreatic cancer, melanoma Li-Fraumeni syndrome: Breast, sarcoma, lung, leukemia, colon, adrenal cortical tumor Cowden syndrome: Breast, thyroid, endometrial cancers; less often brain, renal cancers. Skin manifestations, thyroid abnormalities, polyps, macrocephaly Hereditary diffuse gastric cancer: Lobular breast cancer and diffuse gastric cancer.
Characteristics of Hereditary Breast Cancer Syndromes Significantly increased risk of breast cancer (up to 85% with BRCA1/2) Early age of onset (avg. 30-40 s) Associated with risks of other specific cancers (syndrome-dependent) Increased risk of developing 2 or more primary cancers
Age-Related Penetrance Estimates BRCA1 & 2 Mutation Carriers TAKE HOME MESSAGE: Women who have a BRCA1/2 mutation have a significant risk of developing breast cancer <40, i.e., before population screening starts. So need to identify at risk women to screen appropriately.
BRCA1/2 Mutations and Ethnicity ~1 in 400 people in the general population have a BRCA1 or BRCA2 mutation 1 in 40 in Ashkenazi (Northern European) Jewish individuals Three common mutations Account for at least 90% of mutations in these genes in AJ population What does this mean for assessing risk of hereditary cancer? This means that Ashkenazi Jewish ancestry by itself is a risk factor for having a BRCA1/2 mutation
Genetic Testing Hereditary Breast Cancer Available on a gene-bygene basis or as part of a panel for multiple (5-50+) genes When a mutation is identified in a family, can test other relatives for that specific mutation, with their consent Identifies who in the family is at increased risk and who is not
Management Hereditary Breast Cancer Syndromes Breast Cancer Starts early (25-30 yrs) MRI s and mammograms Clinical breast exam every 6-12 months Option: risk reducing mastectomy Chemoprevention Other Cancers HBOC: Ovarian Cancer Recommend: Risk reducing bilateral salpingo-oophorectomy, 35-40 Screening available but does not significantly improve outcomes Cowden: Educate about attention to endometrial symptoms Thyroid ultrasounds Colonoscopy at 35
Hereditary Colon Cancer Syndromes
Colorectal Cancer Genetics All colon cancer Hereditary colon cancer 5% hereditary 10-30% familial 65-85% sporadic Polyposis syndromes Non-polyposis syndrome 80% HNPCC (Lynch) 15% FAP 5% Rare CRC syndromes
Colon Cancer Risks Average Risk of Colon Cancer Age > 50 No history of adenoma or colorectal cancer No history of inflammatory bowel disease Negative family history (sporadic) Increased Risk of Colon Cancer Personal history of adenoma or sessile serrated polyp, colorectal cancer or inflammatory bowel disease Positive family history (degree of risk varies based on the extent of history) High Risk Syndromes (Hereditary) Lynch syndrome (also called hereditary nonpolyposis colorectal cancer) Polyposis syndromes Classic familial adenomatous polyposis (FAP) Attenuated FAP (AFAP) MUTYH-Associated polyposis (MAP) Peutz-Jeghers Juvenile Polyposis Serrated Polyposis
Classic Familial Adenomatous Polyposis (FAP) 100 s-1000 s of adenomatous polyps Polyps develop at average age of 16 Without colectomy, near 100% will develop colon cancer Average age of cancer diagnosis is 39 Also increased risk of other specific cancers including thyroid, small bowel, stomach, and hepatoblastoma (children) Can have polyps in gastric fundus, duodenum, and desmoid tumors Autosomal dominant Due to mutations in the APC gene
Gardner Syndrome & Attenuated FAP Gardner: FAP + specific extracolonic signs Osteomas Dental anomalies Congenital hypertrophy of the retinal pigment epithelium Benign cutaneous lesions (e.g., epidermoids) Attenuated FAP: 10-~100 polyps Both can be due to mutations in the APC gene Attenuated FAP can also be due to MUTYH gene (recessive gene)
Lynch Syndrome Increased risk of Colorectal cancer Endometrial cancer Ovarian cancer Stomach cancer Others Features Early age of onset (avg. in the 40 s) Colon cancers tend to be right-sided Lifetime cancer risk up to 80-90% Autosomal dominant Caused by mutations in one of 5 genes called mismatch repair genes
Sample Lynch Pedigree Uterine ca @ 49; CRC @ 54 Stomach ca @ 58 CRC @ 44; CRC @ 56; Liver ca @ 62 Ovarian ca @ 57
Screening for Hereditary Colon Cancer Syndromes Colon Cancer Colonoscopy every 1-2 years, starting at 20-25 yrs for Lynch Colonoscopy or sigmoidoscopy starting at 10-15 for FAP. Polypectomy until polyp burden too high then colectomy. Other Cancers Endometrial and ovarian cancer- Lynch No good screening Educate about symptoms Option: Risk reducing surgery Stomach- Lynch Consider upper endoscopy
Self-Assessment Women with a BRCA mutation are at increased risk for what types of cancers? What about men? Women with Lynch syndrome are at risk for what types of cancers? Why is it important to identify women and men at risk for these conditions?
Eliciting a Comprehensive Family History
Step 1: Know How to Construct a Pedigree Generally a three-four generation pedigree is ideal in cancer genetics.
Standardized Pedigree Symbols
Step 2. Know What General Family History Questions to Ask Ages Illnesses and ages at diagnosis Information regarding prior genetic testing Information about pregnancies including infertility, losses, and complications Information about half siblings Ages and cause of death for deceased relatives Relevant conditions Contributing risk factors Consanguinity Ethnic background
Step 3: Know What Targeted Questions to Ask Targeted questions are those specific to the symptoms of the condition you are assessing in the family history. Helps identify people in the family who may have been affected (unbeknownst to your patient) or may be at risk. Targeted question make family history risk assessment more robust.
Targeted Cancer Family History Questions Questions to Ask About All Relatives Age Personal history of benign or malignant tumors? Major illnesses Hospitalizations Surgeries (including risk-reducing ones) Biopsy history Reproductive history* *Especially important for women at increased risk of breast, ovarian, or endometrial cancer. Questions to Ask About Relatives Who Have Had Cancer Organ in which tumor developed Age at time of diagnosis Number of tumors* Pathology, stage, and grade of malignant tumor Pathology of benign tumors Treatment regimen (surgery, chemotherapy, radiation) *Primary or recurrence?
Step 4: Prepare Patient Explain what you are doing and why Explain what type of information you are looking for When possible, notify patients ahead of time that you will be requesting family history information so they can prepare Ask patients what questions or concerns they have before you get started
Step 5: Finishing Your Pedigree End with some summary questions Anyone else with any cancer, benign tumors, surgeries to reduce cancer risk Any other concerns in the family history Remember, you are never really finished with a family history Dynamic, needs to be updated regularly
Pedigree Practice
Risk Assessment
Who should be referred for genetic counseling? Jan Ann d. 70 d. 75 d. 80 d. 70 Ovarian ca d. 75 d. 80 @ 68 70 67 67 70 72 60 67 67 70 Breast ca @ 65 Ovarian ca @ 54 Breast ca @ 50 37 35 45 English Irish No consanguinity 42 Breast ca @ 35 37 35 45 Russian/Polish Ashkenazi Jewish Ancestry No consanguinity
Risk Assessment Guidelines United States Preventive Services Task Force, 2005, 2014 Evidence-based For women without a personal history of cancer, referral should be made if family history of: Breast cancer diagnosis <50 Bilateral breast cancer Family history of breast and ovarian cancer Breast cancer in >1 males Multiple cases of breast cancer >1relative with w/ 2 primary types of BRCA-related cancer Jewish ancestry Familial mutation Recommends against referral for low risk women (harms outweigh benefits) National Comprehensive Cancer Network NCCN.org Guidelines based on available evidence and expert opinion Has guideline for those without a history of cancer, similar to USPSTF Also has guideline for those with cancer
Risk Assessment Tools: Family History Guide Developed by the Michigan Department of Community Health to help identify patients with HBOC and Lynch Syndrome If significant family history reported, tool indicates 1) referral to genetics indicated, 2) increased screening appropriate Evaluates family history ONLY so not meant to assess risk in people who already have a cancer diagnosis.
Red Flags in People with Cancer (Family History Guide Card) HBOC Breast <50 or ovarian cancer at any age Ovarian cancer & close relative with breast or ovarian cancer Bilateral breast cancer or >1 primary cancer Breast or ovarian cancer and Ashkenazi Jewish ancestry Male with breast cancer Lynch Colon cancer or uterine cancer <50 10+ gastrointestinal polyps Multiple cancer diagnoses (e.g. colon and uterine cancer, 2 primary colon cancers)
Using the Family History Tool Start with outermost wheel Line up appropriate arrow for each ring on the guide Select cancer type from colored sectionsdo separate assessment for each type Outer wheel- # of affected relatives Middle wheel-# earliest age at diagnosis (< or > 50) Inner wheel- are all affected relatives first degree (parent, sibling, child) yes or no?
Results of Assessment Red- TAKE ACTION Referral to genetics specialist to further evaluate history Yellow- Proceed with Caution Prior to referral, patient should discuss history with affected relative who is most appropriate for consultation Green- Population Screening
Other Family History Factors If family history has any of the following, referral is indicated (see back of the wheel) Both breast and ovarian cancer on the same side of the family A male relative with breast cancer at any age Three or more relatives with related cancers at any age (i.e. breast with ovarian cancer, colorectal with uterine or ovarian) Multiple related cancer in one person, including bilateral breast cancer Ashkenazi Jewish ancestry with any breast or ovarian cancer history. 10 or more hyperplastic polyps A known genetic mutation in the family
Other Tools and Guidelines B-RST (online tool)- Breast Cancer Genetics Referral Screening Tool https://www.breastcancergenescreen.org/provid ers.aspx Does not determine who should be offered BRCA1/2 testing but who should be referred for comprehensive genetic counseling Society of Gynecologic Oncology Clinical Practice Statement: Genetic Testing for Ovarian Cancer Women with epithelial ovarian, tubal, and peritoneal cancers should receive genetic counseling and be offered genetic testing, even in absence of family history
Post-Session Knowledge Assessment- HBOC Please select whether genetic counseling and possible genetic testing for hereditary breast ovarian cancer is indicated or not indicated for the following An adult man or woman whose father was diagnosed with breast cancer An adult man or woman who has one maternal aunt and one paternal aunt diagnosed with breast cancer, both at > 50 years of age An adult man or woman whose mother was diagnosed with breast cancer at<50 years of age An adult man or woman whose maternal aunt has a known BRCA1 or BRCA2 mutation Indicated (increased risk) Not indicated (low risk)
Post-Session Knowledge Assessment Lynch Syndrome Select whether referral for genetic counseling for Lynch syndrome (MLH1/MSH2, other mismatch repair genes) is indicated or not indicated for the following: An adult man or woman whose maternal grandmother was diagnosed with colon cancer at >50 years of age An adult man or woman whose sister colon cancer at 45 and uterine cancer at 60 An adult man or woman whose maternal aunt had colon cancer at >50 and whose paternal aunt had uterine cancer at >50 years of age An adult man or woman whose paternal grandmother has a known MLH1/MSH2 mutation Indicated (increased risk) Not indicated (low risk)
Summary All cancers are genetic but just a small percent are inherited Identifying individuals at risk for inherited cancer is important, though, because it changes medical management and can save lives Identifying patients at risk involves collecting family history information and identifying red flags. Several tools and guidelines are available to help. Providers like you are key to helping at risk individuals get access!