question

What is cancer?

answer

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

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What is required for cells to become cancerous?

answer

They must become resistant to signals that normally inhibit cell growth.

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Neoplasm/tumor

answer

Mass of cells due to uncontrolled cell growth

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Tumorigenesis

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Formation of tumors

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Angiogenesis

answer

Formation of new blood vessels

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Malignant

answer

A tumor that invades nearby tissues

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Metastasis

answer

Tumor spread to distant body sites

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Benign

answer

Tumor that does not invade tissue or metastasize

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The process of carcinogenesis (5 steps)

answer

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 become malignant 5) One malignant, the tumor may metastasize to distant body parts

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Carcinoma

answer

Cancer of epithelial tissue

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Sarcoma

answer

Cancer of connective tissue

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Lymphoma

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Cancer of lymphatic tissue

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Glioma

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Cancer of glial cells

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Leukemia

answer

Cancer of hematopoietic organs

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All cancer is ________, but mutation rates and effects can be modified through ________________ factors

answer

Genetic, environmental

question

The incidence of colon cancer among the Japanese is 0.5% but colon cancer in Japanese-Americans is 5%. Why?

answer

Different environmental exposures leads to different cancer risks in genetically similar populations. The environmental factor that likely explains this example is because Americans eat such a high fat, low fiber diet.

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Growth factors

answer

Transmit signals from cell to cell. Eg. platelet-derived growth factor, epidermal growth factor, steroid hormones

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Growth factor receptors

answer

These receptors are on the cell surface, and they bind to growth factors

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Signal transduction molecules

answer

These molecules 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

answer

These factors are in the nucleus and they regulate DNA transcription by interpreting signals to grow, stop growing, and differentiate

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The process of cellular regulation (4 steps)

answer

1) External growth factors (proteins and steroid hormones such as epidermal growth factor) bind to *membrane-spanning* growth factor receptors on the cell surface 2) This activates signal-transduction pathways in which genes such as RAS participate. 3) Components of the signal-transduction pathway in turn interact with nuclear transcription factors, such as MYC and FOS. 4) These nuclear transcription factors bind to regulatory regions in DNA.

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Knudson's two-hit hypothesis

answer

Cancer is the result of accumulated mutations to a cell's DNA.

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Two different ways to achieve the two-hit hypothesis

answer

Inherited vs. sporadic cancer

question

Two-hit hypothesis: inherited cancer

answer

1st hit: The first mutation is already present in the germline (one mutated chromosome copy in either the sperm or egg). 2nd hit: The second mutation is somatic. Tumor development.

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Two-hit hypothesis: sporadic cancer

answer

1st hit: The first hit occurs in the embryo; the first mutation is somatic, not inherited. 2nd hit: The second mutation is somatic. Tumor development.

question

3 Types of cancer genes

answer

Tumor suppressor genes Oncogenes DNA repair genes

question

Tumor suppressor genes

answer

Control cell division to *prevent* tumors. Regulates cell growth and proliferation. Some can induce apoptosis. These genes 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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How do tumor suppressor genes cause cancer?

answer

Loss of function. Mutations in these genes typically disable the gene.

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Can heterozygous mutated tumor suppressor genes cause cancer/is a 2nd hit required?

answer

No. Incomplete penetrance. Recessive.

question

Example of a tumor suppressor gene cancer?

answer

Retinoblastoma (RB1)

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How does the RB1 gene work?

answer

1) RB1 encodes the protein pRb. pRb is active when unphosphorylated and it binds to the E2F transcription complex and inactivates it, which halts the cell cycle. 2) When pRb is phosphorylated, it is inactivated and released, so the cell cycle is reactivated.

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How does a mutation in the RB1 gene cause cancer?

answer

A mutation in RB1 can result in permanent inactivation so that there is no brake on the cell cycle, leading to uncontrolled cell division.

question

Oncogenes

answer

Activate cell growth. Promotes cell growth and proliferation. Originate from proto-oncogenes which are involved in regulation of normal cell growth.

question

How do oncogenes cause cancer?

answer

Gain of function. Mutations lead to an excessively active product that leads to unregulated cell growth and differentiation.

question

Can heterozygous mutated oncogene cause cancer/is a 2nd hit required?

answer

Yes. Only a single copy of a mutated gene is required to contribute to the process of tumor progression. Dominant.

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Are oncogene cancers typically seen in sporadic or hereditary cancers?

answer

Sporadic

question

Example of an oncogene cancer?

answer

HER2/NEU; an invasive breast cancer

question

Oncogenes are amplified in what percentage of invasive breast cancers?

answer

20-30% Associated with aggressive cancer.

question

How does the drug trastuzumab downregulate oncogene invasive breast cancer?

answer

Protein product is a growth factor receptor on the surface of breast cancer cells. Trastuzumab binds to this amplified gene product, downregulating it.

question

Which is more likely to harbor a germline mutation (inherited mutation), oncogenes or tumor suppressor genes?

answer

Tumor suppressor genes

question

Tumor cells exhibit what type of genomic instability? (4 ways)

answer

Multiple mutations Hypomethylation Chromosome breaks Aneuploidy

question

What causes this genomic instability?

answer

Defects in proteins required for accurate cell division or DNA repair.

question

What causes those protein defects?

answer

Sporadic mutations, mostly

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Why is the genomic instability in the tumor cells bad?

answer

It can activate oncogenes or deactivate tumor suppressor genes.

question

How many times can a cell divide before it hits its limit?

answer

50-70 divisions (all cells)

question

Why is a cell limited as to how many times it can divide?

answer

With each division, the telomeres shorten and DNA polymerase cannot replicate the tips of the chromosomes. Once the telomere is reduced to a critical length, a signal is transmitted that causes it to no longer divide.

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How do tumor cells overcome the limit on cell division?

answer

Activating a gene called telomerase that replace the telomeric segments lost during cell division.

question

Telomerase is found in _____% of tumor cells

answer

80-90%

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What does telomerase allow the cell to do?

answer

Uninhibited cell division and accumulation of additional mutations that can make the tumor cell more aggressive.

question

What percentage of all people will be diagnosed with cancer at some point in their lives?

answer

50%

question

What percentage of deaths are due to cancer?

answer

25%

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Why are cancers increasing in incidence?

answer

Mainly as a result of the increasing age of the population over time

question

What percentage of cancers are hereditary/inherited?

answer

5-10%

question

What percentage of cancers are familial?

answer

10-15%

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What percentage of cancers are sporadic?

answer

75-85%

question

Why should practitioners be cautious with using family history to assess cancer risk?

answer

Often unrealiable. Most patients don't know the details: specific tumor sites, age of onset, even specific cancer types. Historical information needs to be verified in order to accurately assess risk.

question

Why should practitioners update family histories?

answer

With the passage of time, additional diagnoses are made; can affect likelihood of a hereditary cancer syndrome.

question

Sporadic cancer characteristics

answer

Later age of onset (60s-70s) Little to no family history of cancer Single or unilateral tumors

question

Inherited cancer characteristics

answer

Early age of onset (;50) Multiple generations with cancer Clustering of certain cancers

question

Why do autosomal dominant cancers appear to skip generations?

answer

Penetrance is often incomplete; individuals inherit the altered cancer susceptibility gene, not cancer. (Need that 2nd hit)

question

Approximate lifetime colorectal cancer risk with Lynch syndrome?

answer

70%-78%

question

HNPCC

answer

Hereditary non-polyposis colorectal cancer; a.k.a. lynch syndrome.

question

Genes involved in Lynch syndrome (4)

answer

MSH2 and MLH1, MSH6, PMS2

question

Characteristics of Lynch syndrome (3)

answer

-Early age of colorectal cancer diagnosis: mean age is 45 -Tumors predominantly in proximal colon -Extracolonic cancers are involved: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebacious skin tumors.

question

Amsterdam II criteria for diagnosing Lynch syndrome

answer

3 or more relatives with verified HNPCC-associated cancer in family, over 2 or more generations, with one case being a first degree relative of the other two, and one CRC (colorectal cancer) dx before age 50. FAP is excluded; ovarian, gastric, brain, biliary tract, and pancreatic cancer are excluded.

question

Other set of guidelines for diagnosing Lynch syndrome

answer

Bethesda

question

Easier guidelines for us to use in our clinics to diagnose Lynch syndrome

answer

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

question

Why is it getting more difficult to diagnose Lynch syndrome?

answer

Family size is getting smaller so family histories are more difficult Wider use of colonoscopies is preventing more colon cancers MSH6 and PMS2 may have lower cancer risks

question

Which two Lynch syndrome genes may have lower cancer risks?

answer

MSH6 and PMS2 may have lower cancer risks

question

Risk of getting cancer with MLH1 and MSH2 gene mutations

answer

Colon cancer, Male: 56% Colon cancer, Female: 48% Endometrial cancer: 35%

question

How much does surveillance drop risk of CRC in Lynch syndrome?

answer

From 11.9% incidence to 4.5% incidence

question

Genetic features of Lynch syndrome

answer

-Genes belong to DNA mismatch repair family (MMR) -Mutations in MMR genes lead to microsatellite instability (MSI) -MMR proteins are missing in the tumor tissue making immunohistochemical (IHC) staining useful

question

Microsatellite instability (MSI)

answer

Repetitive DNA sequences 1-4 nucleotides (microsatellites) long With MMR failure, there will be variability in repeats 95% of HNPCC tumors have MSI (compared to only 10-15% of sporadic tumors)

question

Immunohistochemistry (IHC)

answer

Identify MMR proteins If absent, gene is not being expressed (either mutation or methylated) Helps direct gene testing by predicting likely involved gene If IHC is absent, then it is MSI positive

question

Testing for Lynch syndrome

answer

1) Screen tumor for microsatellite instability (MSI); immunohistochemical (IHC). 95% of HNPCC tumors have MSI (compared to only 15% of sporadic tumors) and IHC loss of protein can help identify specific MMR genes. 2) Analyze targeted MMR genes OSU does routine IHC screening on all colon and endometrial cancers.

question

Accuracy of MSI and IHC testing

answer

10.7% missed by MSI (mucin and scant tumor cells) 8.8% missed by IHC (variability in staining)

question

Universal screening for Lynch syndrome

answer

Many hospitals do routine IHC on all or a subset of colon cancer specimens. Reported on path report; any positives reported to geneticists. OSU was one of the first hospitals to start doing this.

question

Lynch syndrome -- management

answer

Colon: Colonoscopy beginning age 20-25 every 1-2 years, or age 30 for MSH6/PMS2 carriers. Total abdominal colectomy for colon cancer or multiple adenomas/unresectable polyp. Continued surveillance for rectal cancer. Uterus: Annual TVU (transvaginal ultrasound) and endometrial aspirate starting at age 30-35. Consider TAH/BSO after childbearing.

question

Recommendations for 1st degree relatives of someone who is positive for a Lynch syndrome mutation

answer

Genetic testing; $300-400

question

Recommendations for a 1st degree relative who is negative for a Lynch syndrome mutation

answer

Can begin colonoscopies at 50 instead of 25, and only repeat every 10 years. Saves money and reduces mortality and morbidity due to unnecessary screening. Their risk for Lynch-associated cancer is the same as the general population. Their children have a 0% chance of inheriting Lynch syndrome from him.

question

Recommendations for a 1st degree relative who is positive for a Lynch syndrome mutation

answer

Colonoscopy recommended. Children have a 50% risk of being a carrier.

question

Recommendations for testing children of a parent with Lynch syndrome

answer

Testing for adult-onset cancer predisposition is NOT recommended unless it will alter management (for example, if the youngest onset in the family history was age 20, or if some symptoms affect children, then testing is recommended), due to insurance discrimination: GINA does not protect life insurance, disability insurance, or long term care.

question

5 Take Home messages about Lynch syndrome

answer

-Lynch syndrome is a relatively common cause of hereditary CRC. -Testing is cost-effective if done appropriately. -Early identification of at-risk family members can prevent cancer. -Pre-test and post-test genetic counseling are important. -Family as the patient (?)

question

FAP

answer

Familial adenomatous Polyposis

question

Estimated penetrance for adenomas with FAP

answer

90%

question

Extracolonic tumors associated with FAP

answer

Upper GI, desmoid, osteoma, thyroid, brain, others

question

Untreated polyposis leads to _____% risk of cancer

answer

100%

question

Genes associated with FAP

answer

APC, KRAS, SMAD4, TP53

question

MAP

answer

MUTYH-Associated Polyposis

question

Estimated penetrance for MAP by age 60 with variable expression

answer

Almost 100%

question

What percentage of the population are carriers for MAP?

answer

1-2%

question

2 common mutations for MAP?

answer

Y179C and G382D. These account for 70-80% of the mutations. About 4% of people who have MAP will not have these mutations.

question

What percentage of American women will be diagnosed with breast cancer within their lifetime?

answer

1 in 8

question

True or false: Breast cancer on the father's side doesn't contribute to risk

answer

False: Half of all women with hereditary risk inherited it from their father

question

True or false: Ovarian cancer is not a factor in breast cancer risk

answer

False: Ovarian cancer is an important indicator of hereditary risk, although it is not always present

question

True or false: The most important thing in a family history is the number of women with breast cancer

answer

False: Age of onset of breast cancer is more important than the number of women with the disease

question

High risk breast cancer

answer

Hereditary cancer (HBOC): 50-85% risk

question

Medium risk breast cancer

answer

Familial risk (multiple relatives with breast cancer at varying ages): 15-25% risk

question

Low risk breast cancer:

answer

Sporadic (one or two relatives with breast cancer, usually at later ages): 10-12%

question

Breast cancer genes and their contribution to breast cancer

answer

BRAC1: 20-40% BRAC2: 10-30% TP53: ;1% PTEN: ;1% Other genes: 30-70%

question

HBOC

answer

Hereditary breast cancer and ovarian cancer syndrome

question

What would you look for in the family history to be keyed into HBOC?

answer

Multiple cases of early onset breast cancer Ovarian cancer Breast and ovarian cancer in the same women Bilateral breast cancer Male breast cancer Ashkenazi Jew heritage

question

BRCA-1 associated cancers risk by age 70

answer

Breast cancer: 50-85% risk (early age of onset and triple-negative: missing 3 receptors on cells) Ovarian cancer: 15-45% Male breast cancer: 1-2% Prostate cancer: possible increased risk

question

BRCA-2 associated cancers risk by age 70

answer

Breast cancer: 50-85% risk (early age of onset) Second primary breast cancer: 20-60% (bilateral breast cancer. 2 independent tumors) Ovarian cancer: 10-20% Male breast cancer: 6% Pancreatic, melanoma, laryngeal cancers: possible increased risk

question

Breast cancer surveillance for people with HBOC

answer

BSE: breast self exam every month starting at age 18 CBE: clinical breast exam every 6-12 months at age 25 (or 5-10 years before earliest dx in family) MRI: annually starting at age 25 (or 5-10 years before earliest dx in family) Mammogram and MRI: annually starting at age 30 Consider chemoprevention: tamoxifen Consideration of prophylactic masectomies Recommend prophylactic BSO between age 35-40 (consider reproductive desires) If delaying BSO: pelvic exam and transvaginal ultrasound with color doppler imaging every 6 months beginning at age 30-35 with concurrent serum CA-125 (or 5-10 years before earliest dx in family) Consider oral contraceptive (discuss risk/benefit)

question

If your pt has a strong family hx of breast cancer, should you genetically test your pt or affected family members first?

answer

Test affected family member first, when possible (but there are always exceptions). Identifying a familial mutation allows for targeted testing of family members. Improved result interpretation.

question

Triple negative and connection to HBOC

answer

Estrogen Receptors/Progesterone receptors/Growth factor (Her-2neu) receptors negative 57% of breast tumors in BRCA1 mutation carriers were triple negative. 19.5% incidence of BRCA1/2 mutations in an unselected cohort of patients with triple negatives The 2011 National Comprehensive Cancer Network recommends genetic testing for anyone diagnosed with triple negative breast cancer before age 60

question

What is included in informed consent for genetic testing (10 things)

answer

-Syndrome, genes to be tested, associated risks -Possible results and implications (including VUS—Variants of Uncertain Significance) -Options to assess risk without testing -Implications for family members—importance of sharing information -Accuracy of testing -Cost -Psychological implications -Genetic discrimination risks -Options and limitations of results-based management -Follow up plan

question

Until 2013, what was true about genetic testing for BRCA?

answer

A company called Myriad genetics held the patent

question

Multi-gene panels

answer

Next generation sequencing--difficult to detect deletions. Panels include 6-50 + genes with some combo of: High penetrance genes associated with breast cancer (TP53, PTEN) Low penetrance genes associated with breast cancer (CHEK2, ATM) Cancer genes that are associated with other cancer syndromes (Lynch genes, thyroid genes) Other genes that are less studied and may or may not contribute to risk

question

What is the issue with multi-gene panels?

answer

Complicates informed consent process

question

If someone has only a familial risk of cancer but is negative for an inhereted HBOC gene, what are the surveillance recommendations?

answer

Still increased risk despite negative test results. Recommend increased cancer screening. -Annual mammogram +/- MRI -Consideration of chemoprevention -Consideration of risk reducing masectomies -Consideration of additional genetic testing

question

Take-home messages about family hx and cancer (5)

answer

-Family history is essential: maternal and paternal history equally important. -Obtain information about diagnoses in family including primary site and age of dx -Best if possible to initiate testing with a family member who has actually had cancer -Pre-test counseling is important -Interpret all results in context of family history (even if negative for hereditary, familial is still important--something about environment the family shared may increase cancer risk)

question

HBOC in those of Ashkenazi Jew descent

answer

1 in 40 Ashkenazi Jews (males and females) carry a BRCA1 or BRCA2 mutation 1 in 400 of non-Jewish individuals 3 mutations (2 in BRCA1 or 1 in BRCA2) cause 95% of HBOC (in Ashkenazi Jews?)

question

Relevance of a female-limited family structure to HBOC

answer

Patients with a limited family structure (less than 2 female first or second degree relatives on either the maternal or paternal side who survived past 45) may have up to a 13.7% chance of a BRCA1/2 mutation compared to a 5.2% risk in those with an adequate family structure

question

BRCA2 and Fanconi Anemia

answer

People who are homozygous for a BRCA2 mutation have a condition called Fanconi Anemia. Physical abnormalities: short stature, abnormal skin pigmentation, malformations of thumb/forearms, hearing loss, developmental delay Progressive bone marrow failure (usually presents by age 7-8) Adult onset aplastic anemia Myelodysplastic syndrome or AML Solid tumors: squamous cell carcinoma of head/neck/esophagus/vulva, cervical cancer, liver tumors

question

PALB2

answer

Partner And Localizer of BRCA2 Breast cancer risk may be similar to BRCA2 carriers (50%) Pancreatic cancer risk increased Unclear if ovarian cancer risk is increased Homozygous mutations cause Fanconi Anemia

question

PTEN—Cowden Syndrome

answer

Cancerous manifestations: Breast cancer: 25-50% Thryoid (follicular or papillary) cancer: 10%. Endometrial cancer: 6-10% Renal cell (clear cell) cancer Colon cancer Melanoma Non-cancerous manifestations: Hamartomas (skin lesions, breast, colon polyps): nearly 100% Macrocephaly (head size is greater than 97th percentile): 80% Multinodular goiter, thyroid adenomas: 56-60% Lipomas Hemangiomas (arteriovenous malformations)

question

TP53—Li-Fraumeni Syndrome

answer

Rare hereditary cancer syndrome causing high lifetime risk for cancer. Early onset breast cancer, bone/soft tissue sarcomas, brain tumors, leukemia, adrenocortical tumors, others. Multiple cancers often seen in same individual Caused by mutations in TP53 and perhaps other like CHEK2 50% of affected individuals develop cancer by age 30 and 90% develop cancer by age 70

question

CDKN2A and CDK4—Familial melanoma

answer

CDKNA2 is a tumor suppressor gene: loss of this gene results in loss of p16 activity which eliminates cell cycle regulation. CDK4 is a proto-oncogene: mutations lead to a gain of function that down-regulates pRb, resulting in a lack of cell cycle control Mutations in these genes lead to an increased risk of melanoma, moles, and pancreatic cancer

question

RET—Multiple Endocrine Neoplasia

answer

Due to mutations in the RET proto-oncogene. Clinical features can include medullary thyroid carcinoma (MTC), parathyroid hyperplasia, and pheochromocytoma. 1-7% of patients with apparently sporadic MTC had a germline RET mutation. Prophylactic thryoidectomy is recommended prior to 6 years of age.

question

When should genetic testing for cancer be considered? (4)

answer

-If significant family cancer history -If reasonable likelihood of carrying an altered cancer susceptibility gene (affected family members usually tested first) -If results will influence medical management -If patients wants information (empowerment)

question

How should genetic testing be done?

answer

In context of genetic counseling. Discuss all medical and social concerns and provide psychosocial support. It is easier and less stressful to review the implications of testing *before* obtaining results.

question

Possible results of genetic testing (4)

answer

Positive Negative 1) True Negative (a true negative result does not mean that there is no cancer risk, but rather that the risk is probably the same as the cancer risk in the general population) 2) Negative in affected individual (if strong family history, then this negative does not provide useful information--still something that is causing cancer, maybe environmental, maybe undiscovered gene mutation). VUS: Variant of Uncertain Significance, additional information is needed

question

Benefits of genetic testing (4)

answer

-Identifies high risk individuals -Identifies noncarriers in families with a known mutation -Allows early detection and prevention strategies -May relieve anxiety

question

Risks/limitations of genetic testing (4)

answer

-Does not detect *all* mutations -Continued risk of sporadic cancer (those who test neg may have false sense of assurance) -Efficacy of interventions unproven -May result in psychosocial or economic harm

question

Hereditary cancer preventative options

answer

Increased and earlier screening Consider preventative surgery Consider medications to reduce risk

question

Familial cancer preventative options

answer

Increased screening, tailored to number of diagnoses and ages of dx in family

question

Sporadic cancer preventative options

answer

Follow American Cancer Society Guidelines

question

Cancer genetic testing panels

answer

Variety of panels to choose from, depending on the combinations of cancer diagnoses identified in the family

question

Pros of cancer genetic testing panels (2)

answer

-Ordering a panel may reduce the cost of testing, if you are likely to consider ordering multiple single-gene tests -Clinical and research testing may be available, although it is important to make sure that your specific genes of interest are included in the panel you are ordering.

question

Cons of cancer genetic testing panels (2)

answer

-Some of the genes tested for in these panels are well-known with clear-cut, standard recommendations, whereas the specific cancer risks and management recommendations for other genes are yet to be clearly delineated. -Because these panels include multiple genes, and genes that have not been extensively tested, there is a higher likelihood of detecting one or more VUS

question

Things to consider when ordering panel vs single gene testing (3)

answer

-Will testing affect management for pt and/or family -Will testing be covered by insurance: Most insurers cover breast/colon panels if pt meets HBOC or lynch syndrome criteria. Some insurers will not allow reflex to a panel if BRCA 1/2 testing or Lynch testing has already been done -Timeliness of results (eg. surgical decision cases): BRCA 1/2 gene testing typically takes 2-3 weeks; panel testing can take anywhere from 3-16 weeks

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