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what is cancer?

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A collection of disorders that share the common feature of uncontrolled cell growth.

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In order for cells to become cancerous, they much become

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resistant to signals that normally inhibit cell growth

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Neoplasm/Tumor

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mass of cells due to uncontrolled cell growth

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Tumorigenesis

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formation of tumors

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Apoptosis

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cell death

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Angiogenesis

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formation of new blood vessels

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Malignant

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a tumor that invades nearby tissues

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Metastasis

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tumor spread to distant body sites

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Benign

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tumor that does not invade tissue or metastasize

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Carcinogen

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Cancer-causing agent

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carcinogenesis

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the process of cancer development

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steps of carcinogenesis

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1. Cells become resistant to signals that normally inhibit growth. 2. Cells disable apoptosis. 3. A new blood supply is obtained through angiogenesis to nourish the tumor 4. Cancer cells override other inhibitory signals to be come malignant 5. Once malignant, the tumor may metastasize to distant body sites

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Carcinoma

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Cancer of epithelial tissue

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Sarcoma

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cancer of connective tissues

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Lymphoma

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Cancer of the lymphatic tissue

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Glioma

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Cancer of the glial cells of the central nervous system

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Leukemia

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Cancer of the hematopoietic organs

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although all cancer is genetic, mutation rates and effects can be modified by _______________.

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environmental factors - Studies have shown that certain environmental exposures increase the risk of certain cancers (i.e. cigarette smoke, HPV, asbestos) -Genetically similar populations with different environmental exposures have different cancer risks (i.e. colon cancer in Japanese (0.5%) compared to colon cancer in Japanese- Americans (5%). This is likely due to our high fat, low fiber diet.

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all cancer is a result of....

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genetic changes within the cell

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Growth Factors

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transmit signals from cell to cell (plateletderived growth factor, epidermal growth factor, steroid hormones)

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Growth Factor Receptors

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on the cell surface bind t ogrowth factors

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Signal Transduction Molecules

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activate a chain of phosphorylating reactions in the cell, targeting and altering the activity of different proteins within the cell to communicate with the cell nucleus

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Nuclear Transcription Factors in the nucleus regulate DNA transcription by...

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interpreting signals to grow, stop growing, and differentiate

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External growth factors

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proteins and steroid hormones, such as epidermal growth factor, bind to membrane-spanning growth factor receptors on the cell surface, activating signal-transduction pathways in which genes such as RAS participate.

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Components of the signal-transduction pathway in turn interact with nuclear transcription factors, such as MYC and FOS , which can bind to

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regulatory regions in DNA. mRNA, mitochondrial RNA.

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Knudson's two-hit hypothesis

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Describes how inheritance of an altered gene predisposes the gene carrier to cancer. The theory states that a cell can initiate a tumor only when it contains two damaged alleles; therefore, a person who inherits one copy of a mutant retinoblastoma gene must experience a second, somatic mutation in one or more retinoblasts in order to develop one or more retinoblastomas. 2 somatic mutations can also occur in a single retinoblast of a nonpredisposed fetus, producing sporadic retinoblastoma.

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3 classes of cancer genes

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Tumor suppressor genes: inhibit cell growth. Oncogenes: which activate cell growth DNA repair genes

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tumor suppressor genes

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Control cell division to prevent tumors - Incomplete penetrance (heterozygous cells do not form tumors - require "2nd hit") - normally block uncontrolled cell growth by participating in pathways that regulate the cell cycle, regulating transcription, or regulating cell-cell interactions.

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mutations in tumor suppressor genes typically lead to

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a loss of function, or disable the gene

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Retinoblastoma

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• pRb, the protein encoded by RB1, is active when it is unphosphorylated • When pRb is active, it binds to the E2F transcription complex, inactivating it. • Inactivation by pRb halts the cell cycle • When pRb is phosphorylated, it is inactivated and released, so that the cell cycle is reactivated. • A gene mutation in RB1 can results in permanent inactivation, so that there is no brake on the cell cycle, leading to uncontrolled cell division.

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Linkage Mapping

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using markers to try to narrow down the location of a mutation within a family

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Evaluate Chromosome Losses

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Often the normal copy of a tumor suppressor gene is lost at the 2nd hit by a deletion of the normal copy or chromosome segment that contains the gene.

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Loss of Heterozygosity

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using markers to determine in an individual, which heterozygous markers have become homozygous in the tumor DNA (one normal gene lost in the process of tumorigenesis).

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oncogenes originate from ______ which are involved in what?

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proto-oncogenes involved in regulators of normal cell growth.

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mutations in oncogenes lead to (2)

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1. an excessively active product that leads to unregulated cell growth and differentiation. 2. gain of function of the gene

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only one copy of a mutated gene is required to contribute to the process of

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tumor progression

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mutations in oncogenes are common in _____ cancers, but not typically seen in _____ cancers.

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sporadic hereditary

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HER2/NEU

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an oncogene amplified in 20-30% of invasive breast cancers • Associated with aggressive cancer • Protein product is a growth factor receptor on the surface of breast cancer cells. • The drug trastuzumab binds to this amplified gene product, downregulating it.

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Retroviruses

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RNA genome is converted to DNA, inserted into a host cell, changing the host genome, and initiating cancer

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Transfection

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material from human tumor cells transferred to non-tumor cells cause cell transformation in the recipient

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Chromosomal rearrangements

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a chromosome translocation may involve a breakpoint in a protooncogene, or lead to a fusion product that interferes with cell regulation and differentiation

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Tumor cells exhibit genomic instability (multiple mutations/ hypomethylation/ chromosome breaks/ aneuploidy) which can activate ______ or deactivate ________

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oncogenes tumor suppressor genes.

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Instability can be due to defects in proteins required for accurate cell division or DNA repair. • These defects are a result of __________

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mutations

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normal cell division ; the telomeres

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a cell can usually divide 50-70x before their telomeres are too short for the DNA polymerase to replicate the tips of the chromosomes (telomeres shorten with each division) Once the telomere is reduced to a critical length, a signal is transmitted that causes it to no longer divide

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Telomerase

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- a gene that tumor cells activate, which replaces the telomeric segments lost during cell division. - Allows uninhibited cell division and thus, accumulation of additional mutations which in turn can make the tumor cell more aggressive. - Found in ~85-90% of tumor cells

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t/f most cancers are inherited

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false. most cancers occur in people who are genetically predisposed to get that cancer (one mutant allele) but generally you don't inherit two mutant alleles- resulting in inherited cancer.

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sporadic cancers

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later onset (60s-70s) little/no family Hx single or unilateral tumors

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inherited cancers

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- Early age at onset (<50) - FHx: Multiple generations with cancer - Clustering of certain cancers (i.e. breast/ovarian)

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AD: incomplete dominance

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instead of inheriting the cancer itself, you inherit a cancer susceptibility gene

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Half of all women with hereditary risk inherited it from their _____

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father

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Ovarian cancer is an important indicator of ________, although it is not always present

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hereditary risk of breast cancer

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Age of onset of breast cancer in your family Hx is more important than...

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the number of women with the disease

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breast cancer risks based on family hx (high vs moderate vs low risk)

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High Risk--> Hereditary Cancer (i.e. HBOC): 50-85% risk Moderate Risk--> Familial Cancer (multiple relatives with breast cancer at varying ages): 15-25% risk Low Risk-->Sporadic Cancer (one or two relatives with breast cancer, usually at later ages): 10-12% risk

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Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

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Multiple cases of early onset breast cancer • Ovarian cancer • Breast and ovarian cancer in the same woman • Bilateral breast cancer • Male breast cancer • Ashkenazi Jewish heritage

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BRCA1-Associated Cancers: Risk by age 70

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Breast Cancer: 50-85% - Often early age of onset - Often triple-negative (57%) • Male Breast Cancer: 1-2% • Ovarian Cancer: 15-45% • Possible increased risk of other cancers: - Prostate

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BRCA2-Associated Cancers: Risk by age 70

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• Breast Cancer: 50-85% - Often early age of onset • Second Primary Breast Cancer: 20-60% • Ovarian Cancer: 10-20% • Male Breast Cancer: 6% • Possible increased risk of other cancers: - Pancreatic - Melanoma - Laryngeal

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Relevance of Ashkenazi Jewish descent

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• 1 in 40 (2.5%) Ashkenazi Jews (males and females) carry a BRCA1 or BRCA2 mutation • The carrier rate in non-Jewish populations is 1/400 (0.25%) • 3 mutations (2 in BRCA1 and 1 in BRCA2) account for 95% of HBOC

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Relevance of Triple-Negative Breast Cancer

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• 57% of breast tumors in BRCA1 mutation carriers were triple negative.(1) • There was a 19.5% incidence of BRCA1/2 mutations in an unselected cohort of patients with triple negative breast cancer.(2) • The 2011 National Comprehensive Cancer Network (NCCN) testing criteria recommends testing for a patient with a personal history of breast cancer, if diagnosed age <60 y with a triple negative breast cancer.

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Fanconi Anemia

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- homozygous BRCA2 mutation - Physical Abnormalities (short stature, abn skin pigmentation, malformations of the thumbs or forearms, hearing loss, devt delay) - Progressive bone marrow failure (usually presents by age 7-8) - Adult onset aplastic anemia - Myelodysplastic syndrome or AML - Solid Tumors (SCC of the head and neck, esophagus, and vulva; cervical cancer; liver)

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PALB2 (Partner And Localizer of BRCA2)

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• Breast cancer risk may be similar to BRCA2 carriers (approximately 50%) • Pancreatic cancer risk is increased • Unclear if ovarian cancer risk is increased. • Homozygous mutations cause Fanconi Anemia

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Cowden Syndrome - PTEN gene predisposes you to which 6 cancers?

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-- Breast 25-50% - Thyroid 10% (Follicular or papillary) - Endometrial 6-10% - Renal cell (Clear cell) - Colon cancer - Melanoma ?

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Li-Fraumeni Syndrome -

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• Rare. causing high lifetime risk for several cancers (Multiple cancers often seen in same individual) • 50% of affected individuals develop cancer by age 30, and 90% develop cancer by age 70.

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Li-Fraumeni syndrome is caused by a mutation in which gene?

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mutationTP53 gene and possibly the CHEK2

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5 causes of colon cancer

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Sporadic Familial Lynch Syndrome (hereditary) Familial adenomatous polyposis (FAP) Rare CRC syndromes

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Lynch Syndrome

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• Early age at CRC diagnosis (mean=45) • Tumors in proximal colon predominate • Extracolonic cancers (endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors)

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Amsterdam II criteria

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3 or more relatives with verified HNPCCassociated cancer in family • Two or more generations • One case a first-degree relative of the other two • One CRC dx <50 • FAP excluded

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Amsterdam II excludes which cancers?

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Does not include ovarian, gastric, brain, biliary tract or pancreatic cancer

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Bethesda Guidelines for clinical Dx (3)

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Colon or endometrial cancer dx 50 if patient has a first degree relative with colon or endometrial cancer at any age • Patient with more than one primary Lynch syndrome associated cancer

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which 2 genes indicate a low cancer risk

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MSH6 & PMS2

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Genetic Features of Lynch Syndrome •

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• mutations in genes belonging to DNA mismatch repair (MMR) family, which lead to microsatellite instability • MMR proteins are missing in the tumor tissue making immunohistochemical staining useful

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4 genes associated with lynch syndrome

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MSH2&6, MLH1, PMS2

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testing for lynch syndrome

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First, screen tumor for MSI; IHC - Microsatellite instability (MSI) results • 95% of HNPCC associated tumors are MSI+ vs. 15%of sporadic tumors - Immunohistochemistry (IHC) [routine at OSU for all colon and endometrial cancers] • Loss of protein indicate possibility of mutation in specific MMR genes • Second, targeted MMR gene mutation analysis

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Microsatellite Instability (MSI)

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repetitive gene sequences that repeat too much due to MMR failure

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immunohistochemistry

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Identify MMR proteins • Normally present • If protein is absent, gene is not being expressed (mutation or methylation) • Helps direct gene testing by predicting likely involved gene • If abnormal IHC (absent), MSI+

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accuracy of MSI and IHC tests

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10.7% missed by MSI - Mucin and scant tumor cells • 8.8% missed by IHC - Variability in staining

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which BRCA/CRF mutation is strongly associated with MSI+ and CpG island methylator phenotype (CIMP)?

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V600E

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MLH1 mutation in the BRCA/CRF gene

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MLH1 promoter methylation - MLH1 absent on IHC, no MMR gene mutation; 68% with V600E in BRAF

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Familial Adenomatous Polyposis (FAP)

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Estimated penetrance for adenomas >90% • Risk of extracolonic tumors

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FAP: Untreated polyposis leads to

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100% risk of cancer

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MUTYH-Associated Polyposis (MAP)

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• Autosomal recessive inheritance • Almost complete penetrance by age 60 with variable expression • 1-2% of the population are carriers • 2 common mutations (Y179C and G382D) - About 70-80% of mutations - About 4% of people with MAP will not have the 2 common mutations

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2 genes associated with familial melanoma

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CDKN2A and CDK4 Mutations in these genes lead to an increased risk of melanoma, moles, and pancreatic cancer

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CDKN2A

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(melanoma) a tumor suppressor gene - loss of this gene results in loss of p16 activity, which eliminates cell cycle regulation

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CDK4

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a proto-oncogene - mutations lead to a gain of function that down-regulates pRb, resulting in a lack of cell cycle control

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Multiple Endocrine Neoplasia is due to

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mutations in the RET proto-oncogene possible sporadic MTC had a germline RET mutation (1-7%)

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Clinical features of multiple endocrine neoplasia

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medullary thyroid carcinoma, parathyroid hyperplasia, and pheochromocytoma.

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Tx of multiple endocrine neoplasia

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Prophylactic thryoidectomy prior to 6 y/o

genetics week 9: Cancer Genetics – Flashcards

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