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PROBLEM SPACE  Breast  Cancer:  What Are The Risks? PROBLEM SPACE  Breast  Cancer:  What Are The Risks?

PROBLEM SPACE Breast Cancer: What Are The Risks? - PowerPoint Presentation

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PROBLEM SPACE Breast Cancer: What Are The Risks? - PPT Presentation

Audience GenEd Biology students Linda Grisham Massachusetts Bay Community College Mark Maloney Spelman College Kim Gernert Emory University Inspired by the recent Angelina Jolie health ID: 915230

breast cancer http risk cancer breast risk http www gov genes data incidence statistics 2009 nih analysis cdc women

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Slide1

PROBLEM SPACE Breast Cancer: What Are The Risks?

Audience: GenEd Biology students

Linda Grisham, Massachusetts Bay Community CollegeMark Maloney, Spelman CollegeKim Gernert, Emory University

Slide2

Inspired by the recent Angelina Jolie health disclosures.

http://www.cnn.com/2013/05/14/showbiz/angelina-jolie-double-mastectomy

(CNN) -- Actress Angelina Jolie announced in a New York Times op-ed article on Tuesday that she underwent a preventive double mastectomy after learning that she carries a mutation of the BRCA1 gene, which sharply increases her risk of developing breast cancer and ovarian cancer.

"My doctors estimated that

I had an 87 percent risk of breast cancer and a 50 percent risk of

ovarian

cancer, although the risk is different in the case of each woman," Jolie wrote. "Once I knew that this was my reality, I decided to be proactive and to minimize the risk as much I could. I made a decision to have a preventive double mastectomy."

Videos.

Slide3

http://www.cnn.com/2013/05/14/showbiz/angelina-jolie-double-mastectomy

Angelina Jolie’s double mastectomy puts genetic testing in the spotlight. What her choice reveals about calculating risk, cost and peace of mind.

Slide4

http://www.cnn.com/2013/05/14/showbiz/angelina-jolie-double-mastectomy

STORY HIGHLIGHTS

A blood test can detect if a woman is "highly susceptible" to breast or ovarian cancer

Jolie reveals she carries a gene that increases her risk for cancer

Her mother died of ovarian cancer in 2007

Slide5

A Life at Risk for CancerMy doctors estimated that I had an 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer, although the risk is different in the case of each woman," Jolie wrote

.What does “percent risk” mean?What does this mean for you?What are your risk factors?

Slide6

OverviewAbout cancerAbout mutations

About BRCA1 gene.Genetic testingSNPs, GWAS.Background materials:

www.cancerquest.org...

Slide7

DefinitionsRisk

Relative riskIncreased risk, Decreased riskIncidenceMortality

First we will look at incidence.

Slide8

DATA

Centers for Disease Control and PreventionU.S. Cancer Statistics: An Interactive Atlas

http://apps.nccd.cdc.gov/DCPC_INCA/DCPC_INCA.aspx

United States Cancer Statistics (USCS)

View Data Online

1999–2009 Cancer Incidence and Mortality Data

This Web-based report includes the official federal statistics on cancer incidence from registries that have high-quality data and cancer mortality statistics for each year and 2005–2009 combined. It is produced by the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI), in collaboration with the North American Association of Central Cancer Registries (NAACCR).

Slide9

DATA

Centers for Disease Control and PreventionU.S. Cancer Statistics: An Interactive AtlasCancer Event: Incidence rate or Death rate.Site: Female Breast

Race / Ethnicity: Black or WhitePeriod: 1999 or 2009.U.S. State: Georgia or Maryland http://apps.nccd.cdc.gov/DCPC_INCA/DCPC_INCA.aspx

Slide10

Examine the map. Collect the data.

Repeat for Race / Ethnicity: White

Repeat for Death Rate.Repeat for second state.Collect data using the following parameters.Cancer Event: Incidence rate.Site: Female BreastRace / Ethnicity:

Black

Period: 1999 or 2009.

U.S. State:

your state.

http://apps.nccd.cdc.gov/DCPC_INCA/DCPC_INCA.aspx

You will be collecting two sets of data.

Select two states of interest for comparison

.

Type data set into Excel worksheet.

Slide11

Breast cancer

Incident

Georgia

 

year

rate

count

population

Rank

out of

 

 

 

 

 

 

 

 

 

 

 

 

 

 

White

2009

120.9

4348

3221000

21

50

Black

2009

126.1

1754

1594705

30

38

 

 

 

 

 

 

 

White

1999

127.4

36622756311745Black1999103.29851239075734       

Breast cancer

Incident

Massachusetts

rate

count

population

Rank

out of

Year

White

2009

132.8

4835

2940746

42

50

Black

2009

107.2

225

254227

6

38

White

1999

147.4

4953

2921658

38

45

Black

1999

96.6

152

216145

3

34

Slide12

Incidence RateDeath Rate

Breast Cancer, Georgia versus Massachusetts

White and Black, Year 1999 versus 2009

Slide13

Questions? Questions?Is the incidence of breast cancer the same for each group?

Has the incidence of breast cancer for your group increased or decreased between 1999 and 2009?Has the death rate changed?For each group has the incidence and death rate changed in the same direction?New questions?

Slide14

Uncertainty

 is normally an intrinsic feature of some part of nature

----- it is the same for all observers. 

Risk

 is specific to a person

--

it is 

not the same

 for all observers.  The possibility of rain tomorrow is uncertain for everyone; but the risk of getting wet is specific to

me. Taken from: http://www.solver.com/risk-analysis-tutorial

Slide15

Risk vs. Benefits?Risk is determined by two factors: How often might a

particular hazard arise?How much harm is likely to result? List small risks you take everyday? What are the benefits?

Are the risks worth the benefits?

Slide16

Risk analysis

 is the systematic study of uncertainties and risks we encounter in business, engineering, public policy, and many other areas.  

Many, but not all, risks involve choices.  By taking some action, we may deliberately expose ourselves to risk.

Slide17

http://mathbench.umd.edu/homepage/prob_stat.htm

TUTORIAL

Slide18

http

://mathbench.umd.edu/homepage/prob_stat.htm

Basic Rules of Probability

Slide19

E.Singletary

, 2003, Rating the Risk Factors for Breast Cancer

Slide20

Slide21

Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a

pooled analysis of 18 prospective cohort studies. Am J

Clin Nutr 2012;95(3):713-25. doi: 10.3945/ajcn.111.014415.http://www.ncbi.nlm.nih.gov/pubmed/22277553 Entire study has ~1 million participantsIndividual studies range from 6,000 participants to 200,000 participants

Slide22

Questions? Questions?Find one study that has a “tight” calculation of risk.Discuss how risks are calculated

Explain varianceWhy are there different studies?Evaluate.Ethics in study.What study would you design?

Slide23

OverviewRisk assessment Beyond the Human Genome Project:

Personal GenomesMicroarray analysis

Background materials:Singletary, 2003www.personalgenomes.org/Dorit, 2007Microarray animations by Davidson.

Slide24

Risk Factors

Factors such as alcohol consumption and obesity appear to have only a small to moderate effect on breast cancer risk.  Hormone replacement therapy and nulliparity have a larger but still rather moderate effect on breast cancer incidence. Age is the most reliable factor associated with increased risk of breast cancer

.Besides age, only familial history of cancer (e,g, mother or sibling having had breast cancer) together with a specific BRCA mutation correlates with a large-fold increase in risk for breast cancer.But only 5-10% of breast cancer cases are familial.

Slide25

Slide26

Slide27

Genetics of Breast and Ovarian Cancer (PDQ®)

– National Cancer ...www.cancer.gov 

Slide28

Cancer Subtypes (1)A better understanding of heterogeneity within breast cancer cells themselves is important as there are subpopulations of breast cancers:

 Breast cancers differ in terms of their specific mutations within tumor suppressor

genes such as BRCA1 (that can no longer prevent cancer) and oncogenes such as estrogen receptor and the epidermal growth factor receptor HER2 (that promote cancer cell abnormal cell division) that lead to malignant cancer

 

Slide29

What’s Missing? Increase in personal/individual genomes could provide further clues to cancer

risk: Having a larger and more varied group of individuals whose entire genome is known and whose cancer incidence can be followed would better identify gene clusters associated with cancer risk.

Slide30

A better understanding of heterogeneity within breast cancer cells themselves is important as there are subpopulations of breast cancers: Breast cancer cells differ in terms of other genes that are

upregulated and downregulated. These gene expression profiles not only define subpopulations of breast cancer cells but also provide clues to optimal therapy for the specific subtype of cancer. This could improve treatment and prognosis.

Cancer Subtypes (2)

Slide31

Microarray Analysis

Slide32

Lab Activity match the

cDNAs to the oligonucleotides in the wells (Carolina Biologicals)

Slide33

Dorit, 2007

Slide34

For confirmation of gene expression:

Multiblot Western Blots for protein expression (Kinexus)

Slide35

Questions? Questions?What factors make breast cancer risk assessment so difficult?Why might this improve in the near future?What types of genes are involved in cells becoming cancerous?

What types of genes contribute to cancer pathology?

Slide36

Breast Cancer The Angelina Effect: TIME’s New Cover Image Revealed. By Jeffrey Kluger May 15,

2013.  http://healthland.time.com/2013/05/15/the-angelina-effect-times-new-cover-image-revealed/#ixzz2WF6pF41U. CancerQuest: Cancer Biology

Introduction http://www.cancerquest.org/introduction-cancer-biology.html contains glossary Cancer Genes http://www.cancerquest.org/cancer-genes-overview.html introduces the terms: oncogenes, tumor suppressors, and microRNA.Oncogene: short video http://www.cancerquest.org/cancer-genes-overview.htmlTumor suppressor: short video http://www.cancerquest.org/introduction-tumor-suppressors.html

Micro RNA (a)

http://www.cancerquest.org/introduction-to-micrornas.html

and

(b)

http://www.cancerquest.org/mirna-and-cancer.html

How cancers begin

http://www.cancerquest.org/how-cancer-begins-introduction.htmlBibliography

Slide37

United States Cancer Statistics (USCS)1999–2009 Cancer Incidence and Mortality Data http://apps.nccd.cdc.gov/uscs/This Web-based report includes the official federal statistics on cancer incidence from registries that have high-quality data and cancer mortality statistics for each year and 2005–2009 combined. It is produced by the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI), in collaboration with the North American Association of Central Cancer Registries (NAACCR).

Graphs, Tables, Maps, State & National Statistics, gender, race/ethnicity data available. Cancer

statistics: sex, race, cancer type, incidence or mortality, state or US, etc.http://apps.nccd.cdc.gov/DCPC_INCA/DCPC_INCA.aspx  Breast cancer http://www.cdc.gov/cancer/breast/Vital Signs: Racial Disparities in Breast Cancer Severity — United States, 2005–2009http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6145a5.htm?s_cid=mm6145a5_wTop ten cancers by women. http://apps.nccd.cdc.gov/uscs/toptencancers.aspx

Caveat: Quality of US Regional Data Collected?

http://www.cdc.gov/cancer/npcr/uscs/data/00_pop_coverage.htm

Slide38

NIH: National Cancer Institute http://www.cancer.gov/cancertopics/types/breast“What You Ned to Know About” Booklet http://

www.cancer.gov/cancertopics/wyntk/breast Types, tests, stages, treatment.Finding/Understanding Cancer Statistics http://www.cancer.gov/statisticsGlossary of statistical terms http://www.cancer.gov/statistics/glossary

 Surveillance Epidemiology and End Results Incidence, mortality, survival, stage, lifetime risk, prevalence http://seer.cancer.gov/statfacts/html/breast.html  Math ResourcesMath Bench: Probability and Statistics http://mathbench.umd.edu/homepage/prob_stat.htmMath

Bench: Basic Rules of

Probablity

Module

http://mathbench.umd.edu/modules/prob-stat_probability/page01.htm

Fact

Sheet: Probabilistic Risk Assessment,

U.S.Nuclear Regulatory Commission, 2007.http://www.nrc.gov/reading-rm/doc-collections/fact-sheets/probabilistic-risk-asses.pdfRisk Analysis Tutorial http://www.solver.com/risk-analysis-tutorialWhat is risk, and why do we care about it? What are the sources of uncertainty? What is the difference between uncertainty and risk?

Slide39

CANCER RESEARCH V Rivera-Varas, Breast Cancer Genes and Inheritance (1998) http://www.ndsu.edu/pubweb/~mcclean/plsc431/students98/rivera.htm

Breast cancer is the most common cancer that affects women in the United States. There are at least two majors genes (BRCA1 and BRCA2) that when they mutate can cause breast cancer…. Since the discovery of the BRCA1 and BRCA2 in 1994 and 1995 about 80% of the women who inherit mutated forms of these genes will develop breast cancer.

E.Singletary, Rating the Risk Factors for Breast Cancer, Annals of Surgery, 2003, v.237, no. 4, 474-482. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1514477/#!po=11.9048Risk factors that have received a great deal of publicity (hormone use, alcohol consumption, obesity, nulliparity) present a relatively modest relative risk for breast cancer (<2). Factors associated with a prior history of neoplastic disease or atypical hyperplasia and factors associated with a genetic predisposition significantly affect the risk of breast cancer, with relative risks ranging from 3 (for some cases of positive family history) to 200 (for premenopausal women positive for a 

BRCA

 mutation).

 

Slide40

Zhang X, Spiegelman D

, Baglietto L, Bernstein L, 

Boggs DA, van den Brandt PA, Buring JE, Gapstur SM, 

Giles GG

Giovannucci

E

,

Goodman G, Hankinson SE, Helzlsouer

KJ

Horn-Ross PL

Inoue M

Jung S

Khudyakov

P

Larsson SC

Lof

M

McCullough ML

Miller AB

Neuhouser

ML

Palmer JR

Park Y

Robien

K

Rohan

TE

Ross JA

Schouten LJ

Shikany

JM, Tsugane S, Visvanathan K,Weiderpass E, Wolk A, Willett WC, Zhang SM, Ziegler RG, Smith-Warner SA.Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a pooled analysis of 18 prospective cohort studies. Am J Clin Nutr 2012;95(3):713-25. doi: 10.3945/ajcn.111.014415.http://www.ncbi.nlm.nih.gov/pubmed/22277553 This large collaborative analysis of data from 18 follow-up studies that included 33,380 breast cancer cases. The analysis assessed the relation of carotenoid intake from fruits and vegetables to the risk of breast cancer classified by estrogen and progesterone receptor status.  Intakes of alpha-carotene, beta carotene, and lutein/zeaxanthin were associated with a reduced incidence of estrogen receptor negative breast cancer, but not of estrogen receptor positive breast cancer. 

Slide41

Chen F, Chen GK, Millikan RC, John EM, Ambrosone CB, Bernstein L, Zheng W, Hu JJ, Ziegler RG, Deming SL, Bandera EV, Nyante S, Palmer JR,

Rebbeck TR, Ingles SA, Press MF, Rodriguez-Gil JL, Chanock SJ, Le Marchand L, Kolonel LN, Henderson BE, Stram

DO, Haiman CA. Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans. Hum Mol Genet 2011;20(22):4491-503. doi: 10.1093/hmg/ddr367.http://www.ncbi.nlm.nih.gov/pubmed/21852243

Many genetic variants may be associated with breast cancer occurrence, but the increases in risk for most variants are so small that very large studies are needed to identify them.  The BWHS (Black Woman Health Study) collaborated with eight other epidemiologic studies of African American women for this purpose; DNA samples from 3,016 cases of breast cancer and 2,745 comparison women were genotyped. This study confirmed the importance of several genetic regions for breast cancer in African American women. Further work is needed to further refine exactly which genetic variants are involved and to understand their functions.

Slide42

ANALYSIS: BREAST CANCER GENETICS “By Any Other Name” by Robert L. Dorit (2007), American Scientist v.95, p.118-120.

article suggested by Tony Weinstein.NIH: The Cancer Genome Atlas (TCGA) http://cancergenome.nih.gov/Lobular breast cancer

http://cancergenome.nih.gov/cancersselected/breastlobularDuctal breast cancer http://cancergenome.nih.gov/cancersselected/breastductalHow to Analyze DNA Microarray Data (HHMI): A Tutorial http://www.hhmi.org/biointeractive/genomics/microarray_analyzing/01.htmlWhat Are SNPs? http://ghr.nlm.nih.gov/handbook/genomicresearch/snp

includes written & audio definition of SNPs

.

Slide43

V. Rivera-Varas, Breast Cancer Genes and Inheritance, (1998) http://www.ndsu.edu/pubweb/~mcclean/plsc431/students98/rivera.htm Breast cancer is the most common cancer that affects women in the United States. There are at least two majors genes (BRCA1 and BRCA2) that when they mutate can cause breast cancer…. Since the discovery of the BRCA1 and BRCA2 in 1994 and 1995 about 80% of the women who

inherit mutated forms of these genes will develop breast cancer.

Walsh, T and King MC., Ten Genes for Inherited Breast Cancer, 2007, Cancer Cell, Feb; 11(2): 103-105http://www.ncbi.nlm.nih.gov/pubmed/17292821Inherited breast cancer is associated with germline mutations in ten different genes in pathways critical to genomic integrity. BRCA1 and BRCA2 mutations confer very high risks of breast and ovarian cancer. p53 and PTEN mutations lead to very high breast cancer risks associated with rare cancer syndromes. Mutations in CHEK2, ATM, NBS1, RAD50, BRIP1, and PALB2 are associated with doubling of breast cancer risks. In addition, biallelic mutations in BRCA2, BRIP1, and PALB2 cause

Fanconi

anemia. The convergence of these genes in a shared role reveals underlying biology of these illnesses and suggests still other breast cancer genes.

Slide44

Marjanka MK Schmidt, Alexandra J. van den Broek, Rob AEM Tollenaar, Flora E. van Leeuwen

, Laura J. Van 't Veer, Breast cancer survival of BRCA 1/2 carriers compared to non-BRCA 1/2 carriers in a large breast cancer cohort, American Association for Cancer Research, 2013; Abstract 1338.http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=f624274a-c48c-4dbb-a0d5-248d2fd6bf36&cKey=e6c1371b-e5bb-4ff4-a637-64aff16e29d5&mKey=%7B9B2D28E7-24A0-466F-A3C9-07C21F6E9BC9%7D

Breast cancer patients carrying a BRCA1 mutation had significantly worse recurrence and survival rates than patients without BRCA mutations or with aBRCA2 mutation. Data from a large Dutch study found that women with a BRCA1 mutation were 1.5 times more likely to see a breast cancer recurrence, and 1.4 times more likely to die from breast cancer at 15 years' follow-up compared with noncarriers.