Cancer Genetics BMS 532 PDF

Cancer Genetics I N HE RITED CA N CE R R I S K BM S 5 3 2 M O L EC U L A R BI O LO GY A N D G E NETIC S BLO C K 4 L EC T UR E 8  Objectives 1. Describe the difference in risk of cancer development for sporadic and inherited forms of cancer and list the differences in clinical presentation...

Cancer Genetics I N HE RITED CA N CE R R I S K BM S 5 3 2 M O L EC U L A R BI O LO GY A N D G E NETIC S BLO C K 4 L EC T UR E 8  Objectives 1. Describe the difference in risk of cancer development for sporadic and inherited forms of cancer and list the differences in clinical presentation expected with inherited risk 2. Explain how Hereditary Disorders with increased cancer risk differ from Hereditary Cancers/Hereditary Cancer Syndromes 3. Diagram the Knudson Two Hit Hypothesis and demonstrate how causes increases in cancer risk and contributes to cancer development 4. List and explain the mechanisms for losing gene activity following inheritance of a pathogenic variant 5. Match the specific cancer or hereditary syndrome example with its corresponding genetic changes for the following cancers: Retinoblastoma, Hereditary Breast and Ovarian Cancer, Fanconi Anemia, Xeroderma Pigmentosa, Lynch Syndrome, and bladder cancer 6. Evaluate the consequences in terms of cancer development or progression for changes in the following types of genes: ◦ Tumor suppressor genes (Rb and BRCA1 in particular) ◦ Oncogenes (HRas in particular) 7. Identify the clinical features for hereditary Retinoblastoma, Hereditary Breast and Ovarian Cancer Syndrome, Fanconi Anemia, Xeroderma Pigmentosa and Lynch Syndrome and match the clinical presentation to the gene/pathogenic variant expected in each condition AND the associated lifetime risks of cancer development 8. Compare and contrast BRCA1 and BRCA2 mutations in Hereditary Breast and Ovarian Cancer Syndrome and explain the role of BRCA2 and other FANC mutations in Fanconi Anemia 9. List the hereditary forms of colon cancer and explain the unique features of Lynch Syndrome with emphasis on the presence of mismatch repair gene mutations role of microsatellite instability in its diagnosis 10. Compare and contrast genetic and molecular tests in cancer risk assessment and diagnosis LO1 REMINDER: The Majority of Cancer is SPORADIC LO2 Hereditary Syndrome with Cancer vs. Hereditary Cancer Mutations in genes carry wide consequences including increasing the risk for cancer Many hereditary/genetic syndromes have corresponding increases in cancer risk (sometimes quite substantial risks) ◦ Inherited mutation causes a phenotype or syndrome as the primary effect ◦ Cancer risk is elevated as a secondary consequence Hereditary Cancer or Hereditary Cancer Syndromes have cancer risk as their primary (and sometimes sole) consequence LO1 Features of Increased Cancer Risk/Cancer Predisposition Cancer predisposition = an increased risk to cancer due to inheritance of mutation Predisposition is most frequently associated with TUMOR SUPPRESSOR GENES ◦ Regulatory signals or “STOP” signals Clinical Presentation ◦ Earlier age of onset ◦ Multifocal and/or bilateral disease ◦ Increase of cancer rates (cancer “prone” families) and increase of rare cancer forms ◦ Follow Mendelian inheritance patterns with the inherited risk often being inherited in a dominant manner ◦ Inherit the mutation/pathogenic variant and your risk of developing cancer increases 5 LO3 Cancer Predisposition and the Knudson Two Hit Hypothesis Cancer development involves multiple genes and “hits” SPORADIC Limited to Both alleles of a tumor-suppressor gene fewer cell must be mutated to cause cancer = the populations Both Copies 1 = Normal Both Copies Knudson “two-hit” hypothesis and initiated are Normal 1 = Mutated are Mutated mitotically In cases where the first “hit” is an inherited mutation, cancer develops Normal Normal Tumor more readily and most likely at a younger Cells Cells Development Possible age HEREDITARY ◦ Cells are NOT more PRONE to mutation All cells (except when repair genes are altered) but rather FEWER events are needed to lead to contain the cancer and EVERY cell contains the change mutation 6 The hits keep coming: LO4 More than one way to lose activity If disease initiation or progression requires loss of both copies, all of the mechanisms through which a gene can be altered stand as potential options for the second “hit” Mechanisms include: ◦ Somatic mutation due to replication error or exogenous damage ◦ Loss of heterozygosity (see images) ◦ Chromosomal Rearrangements that cause positional effects ◦ Chromosomal rearrangements with the breakpoint within the gene ◦ Deletions ◦ Heterochromatin formation at the gene locus ◦ Excessive methylation of the promoter associated with the gene Basically, any way that you can lose gene activity may be sufficient to cause the loss of the second copy and promote disease initiation 7 LO5, LO6, LO7 Tumor Suppressor Genes Inherited Cancer Mutated Tumor Suppressor Gene Function(s) Associated Noninherited Cancers Gene(s) Retinoblastoma RB1 Cell division, DNA Many different Loss of function or Null mutations lead to replication, cell death cancers disease development Li-Fraumeni TP53 Cell division, DNA repair, Many different syndrome (brain cell death cancers Often not sufficient to cause cancer by tumors, sarcomas, themselves leukemia) Melanoma CDKN2A Cell division, cell death Many different Require additional mutations including the (INK4A) cancers Colorectal cancer APC Cell division, DNA damage, Most colorectal development of oncogenes in most sporadic (due to familial cell migration, cell cancers and inherited forms polyposis) adhesion, cell death ◦ Exceptions typically include homogeneous Colorectal cancer MLH1, MSH2, DNA mismatch repair, cell Colorectal, inherited mutations in key regulatory genes (without polyposis) MSH6 cycle regulation gastric, endometrial where the inherited mutation confers a nearly cancers 100% risk of cancer development Breast and/or BRCA1, BRCA2 Repair of double-stranded Only rare ovarian cancer DNA breaks, cell division, ovarian cancers Environmental factors also contribute cell death Kidney cancer VHL Cell division, cell death, Certain types of cell differentiation, kidney cancer response to cell stress 8 LO5, LO6, LO7 Retinoblastoma (Rb) Mutation in Rb leads to development of Retinoblastoma ◦ Childhood tumors of the retina ◦ Can be sporadic or inherited ◦ Inherited form = earlier age of onset and typically develops/affects both eyes ◦ Autosomal Dominant (RB1 at 13q14) ◦ Sporadic = only one eye (localized) ◦ ~95% of individuals who inherit a mutation in Rb will develop retinoblastoma (diagnostic marker) 9 LO5, LO6, LO7 Hereditary Breast and Ovarian Cancer (HBOC) Accounts for 60-75% of inherited cases of breast cancer BRCA1/BRCA2 mutations often observed 50-80% lifetime risk of breast cancer ◦ In families with 4 or more cases diagnosed before age 60, the chance is the higher approx. 80% ◦ Chance can be far less if only 1 one person in family history diagnosed before age 50 (importance of age of onset) Multiple breast tumor types are possible ◦ Breast: DCIS, invasive ductal, invasive lobular Multiple patterns of key molecules also possible (see FYI slides for more information) LO5, LO6, LO7 Genes Associated with Inherited Risk of Breast Cancer There are several genes associated with increased risk of Breast Cancer Ones that receive the most press due to the strong HIGH PENETRANCE association with breast cancer include BRCA1 and BRCA2 Additional genes of interest play a role in the same pathway as BRCA1 and BRCA2 while others are related to other critical activities ◦ These moderate and low penetrance genes include genes that increase risk for multiple cancer subtypes (i.e. CHEK2)  Linking pathogenic variant to function: BRCA1 and BRCA2(FANCD2) role in HR Repair CALLBACK to DNA REPAIR FYI only Breast Cancer “Typing” and Subtypes Luminal = luminal or epithelial cells Basal = basal or myoepithelial cells FYI only FYI only LO8 Mutation Consequences BRCA1 MORE FREQUENTLY BRCA2 MORE FREQUENTLY EXHIBIT: EXHIBIT: Medullary histopathology A resemblance to sporadic cancers “basal phenotype” ◦ IHC assessment shows basal keratin No specific histopathology + subtype and not typically basal High grade Not typically triple negative Lymph node positive Can be ER-/PR-/Her2- LO5, LO6, LO7 HBOC Risk Overviews WOMEN WITH HBOC MEN WITH HBOC 45-75% lifetime risk of breast cancer though Breast Cancer some numbers report as high as 80% and as ◦ BRCA1 = 10X that of general population (~1-2%) low as 10% depending on the family history ◦ BRCA2 = ~6% ◦ Accurate family history is CRITICAL Prostate OVARIAN risk ◦ BRCA1 some increased risk ◦ BRCA1 25-40% ◦ BRCA2 ~20% with significantly increased risk of ◦ BRCA2 10-20% aggressive prostate cancer Second Breast cancer (~20-40%) ***These numbers can vary depending on sources so ranges should be used LO5, LO6, LO7 Hereditary Syndrome with Cancer Risk: Fanconi Anemia Affects multiple systems ◦ Individuals may exhibit bone marrow failure, physical abnormalities (>50%), organ defects, and an increased risk of certain cancers ◦ Can show altered chromosome stability ◦ Clinical manifestations overlap with many malformation syndromes ◦ Primary radial deformities, hypoplastic thumb/thumb hypoplasia, etc… Major effects on bone marrow ◦ ~90% have impaired bone marrow function with decreases in ALL blood cells = aplastic anemia ◦ Impact on bone marrow also causes thrombocytopenia and risk of frequent infections 1 in 160,000 individuals worldwide ◦ Ashkenazi Jewish descent, Roma population of Spain, black South Africans LO5, LO6, LO7 Hereditary Syndrome with Cancer Risk: Fanconi Anemia and DNA Repair Autosomal Recessive (except FANCB which is X-linked recessive) FANC genes (at least 15 genes are known to cause this) ◦ Essential in interstrand cross-link repair ◦ Formation of FA core complex and activation of additional FANC proteins ◦ The genes are organized into complementation groups that correlate with disease and pathogenic variants Increased risk of leukemia (particularly acute myeloid leukemia) Also increased risk of squamous cell carcinoma, hepatocellular cancer, and brain tumors; women are also at increased risk of cancers of the vulva and cervix LO5, LO6, LO7 Fanconi Anemia Pathogenic Variation % of FA Attributed to Gene Pathogenic Variants in This Gene BRCA2/FANCD1 ~3% BRIP1/FANCJ ~2% FANCA 60%-70% FANCB ~2% FANCC ~14% FANCD2 ~3% FANCE ~3% FANCF ~2% FANCG ~10% FANCI ~1% LO5, LO6, LO7 Xeroderma Pigmentosum “Extreme Sensitivity to UV rays” Characteristic skin and eye manifestations ◦ 95% of individuals will develop characteristic skin changes by age 15 ◦ Xerosis, Pigmentation changes, severe sunburns (with blistering) even with mild sun exposure, etc… ◦ Cararacts, photophobia, keratitis, etc… (Ocular changes correspond with areas of the eye exposed to UV light) At risk for Basal Cell Carcinoma, Squamous cell carcinomas, and melanomas ◦ 1000 fold increased risk for cutaneous malignancy Approximately half of the affected children will develop their first cancer by age 10 10 to 20-fold increased risk of internal cancers LO5, LO6, LO7 Xeroderma Pigmentosum Genetics Autosomal Recessive AP genes including XPA and XPC Diagnosis is typically made by age 18 due to the characteristic skin and eye changes Genetic Testing: ◦ Serial single gene testing, multi-gene panel (includes DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, and XPC and other genes of interest), comprehensive genomic testing LO9 Hereditary Forms of Colon Cancer Hereditary Non-Polyposis Colon Cancer (HNPCC) ◦ Diagnostic criteria based on family history and specific rules known as the Amsterdam Criteria (see notes) Lynch Syndrome (HNPCC with Mismatch repair gene mutation) Familial Colon Cancer Syndrome X ◦ HNPCC families without an MMR gene mutation or the phenotype of Lynch (MSS, intact IHC- staining positive for mismatch repair proteins) LO5, LO6, LO7 FYI only Colon Cellular Structure Mucosa: Crypts a.k.a. Glandular Cells: secrete hormones; aid in final water and nutrient absorption Goblet Cells: produce mucus Collagen Cells a.k.a. Lamina propria: protective layer Immune Cells such as lymphocytes FYI only COLONOSCOPY and Polyp Removal FYI only LO5, LO6, LO7, LO9 Lynch Syndrome Autosomal Dominant Multiple Genes: MLH1, MSH2, MSH6, PMS2, and EPCAM Affects Mismatch Repair Multiple different lifetime cancer risks ◦ Colorectal Cancer risk = 52-82% ◦ 3-5% of all Colon cancer cases are Lynch Syndrome ◦ Mean age at diagnosis: 44-61 ◦ Additional Major Cancer Risks: Endometrial cancer risk = 20-60%, Gastric cancer risk = 6-13%; Ovarian Cancer risk = 4-12% ◦ Other types of cancer with increased risk = urinary tract, liver/bile duct, small bowel cancer, brain or CNS, pancreatic, prostate, kidney, and breast (identified within the last year) ◦ NOTE: Other numbers are available for these associated risks depending on resource used but all are substantially higher than the risks for individuals without mutations in associated genes LO7, LO9 Lynch Syndrome Given the importance of conformational testing to the diagnosis of Lynch syndrome, additional testing beyond genetic testing is typically utilized Microsatellite Instability (MSI) ◦ Tests evaluating the level of instability in repetitive sequences of DNA (indirect measure of mismatch repair function) ◦ MSI high: instability found in greater than 30% of cells ◦ MSI low: fewer than 30% ◦ MSI stable: no cells show measurable instability Baudrin LG., Deleuze JF., and How-Kit A. 2018 Dietmaier W and Hofstadter F. 2001 https://www.frontiersin.org/articles/10.3389/fonc.2018.00621/full https://www.nature.com/articles/3780358 LO6 Gain of Function and Cancer Predisposition The majority of genes analyzed for cancer predisposition have been found to be associated with loss of function mutations in tumor suppressor genes, Gain of function mutations similar to those observed in somatic cases are also important in inherited cancer development Pathogenic variants of protooncogenes have been linked to susceptibility and risk for specific cancers as it places that gene at increased risk of oncogenic activity Certain genes are known to associate with cancers of specific tissues due to their importance in the growth/regulation of that tissue/cell-type LO5 HRAS A mutation associated with bladder cancer Converts 12th glycine into valine in the HRAS protein GAIN-of-FUNCTION mutation Results in dysregulated activity for the Ras protein ◦ Constitutive activation 31 LO10 Genetic Testing For cancer risk ◦ Predictive genetic testing (inherited mutations that increase cancer risk) ◦ MOST PEOPLE DO NOT NEED THIS TYPE OF TESTING ◦ Familial risk indications Testing Cancer Cells for Genetic Changes ◦ Defining cancer subtype ◦ PROGNOSIS from genetic make-up ◦ Patterns of gene expression: gene expression profiling/molecular profiling LO10 Molecular Profiling Analysis of cancer cell behavior and gene expression PROGNOSIS AND TREATMENT ◦ Can assess likelihood of recurrence ◦ Can assess probability of metastatic growth (limited) ◦ Depending on test, can give indications of which chemotherapy would be most effective Breast Cancer tumor profiling tests ◦ OncotypeDx (only profiling test commonly used clinically in US) ◦ MammaPrint® (more common in Europe and is used for research purposes in US) LO10 Recent FDA Approved Tests In November and December of 2017, the FDA approved two tests that utilize Next Generation Sequencing for tumor profiling ◦ Foundation One CDx (F1CDx) ◦ Can identify cancer associated alterations in over 300 genes as well as two genomic signatures in ANY solid tumor ◦ Approval also allows for analysis of 15 target therapies and their potential efficacy ◦ MSK-IMPACT ◦ Can identify 468 different cancer-associated mutations or alterations In 2018, ClonoSEQ assay was approved for assessing minimal residual disease in patients with ALL or multiple myeloma ◦ Quantification of gene sequences via Next Gene Sequencing and multiplex PCR 2018 also several approvals for direct to consumer cancer testing and genetic testing occurred ◦ Advances continue to be made on a regular basis that includes testing you may have seen advertising for (i.e. Cologuard originally developed and FDA approved in 2014; now marketed directly to consumers) LO2, LO10 A Few Big Picture Takeaways… A wide range of molecular and genetic changes take place to cause disease development and progression If the change is inherited the risks of developing the disease or associated phenotype increase ◦ The specific changes can be recessive or dominant in terms of phenotypic risk Changes that occur somatically do NOT necessarily correlate with a risk to future offspring nor do they automatically imply an inherited mutation Molecular biology and genetics are intermingled in human disease and TOGETHER can provide extensive information toward therapeutic interventions Check-in Question A somatic mutation in Ras protein is identified in a tumor and is determined to be one of the initiating events for the cancer. Which of the following is most likely true about this mutation? A. The mutation is most likely a loss of function mutation B. The mutation is also a germline mutation C. The mutation is the result of a gene fusion D. The mutation is associated with a sporadic form of the cancer E. None of these are true