PROBLEM SPACE Breast Cancer: What Are The Risks?

Audience: GenEd Biology students

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

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.

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.  

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

A Life at Risk for 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.

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

Overview

• About cancer• About mutations• About BRCA1 gene.• Genetic testing• SNPs, GWAS.

Background materials:www.cancerquest.org...

Definitions

• Risk• Relative risk• Increased risk, Decreased risk

• Incidence• Mortality

First we will look at incidence.

DATACenters 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 Online1999–2009 Cancer Incidence and Mortality DataThis 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).

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

Cancer Event: Incidence rate or Death rate.Site: Female BreastRace / Ethnicity: Black or WhitePeriod: 1999 or 2009.U.S. State: Georgia or Maryland

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

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:  BlackPeriod:  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.

Breast cancer IncidentGeorgia  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 3662 2756311 7 45

Black 1999 103.2 985 1239075 7 34

             

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

• Incidence Rate

• Death RateGA wh 1999 GA wh 2009 MA wh 1999 MA wh 2009

0

20

40

60

80

100

120

140

160

WhiteBlack

GA wh 1999 GA wh 2009 MA wh 1999 MA wh 20090

5

10

15

20

25

30

35

WhiteBlack

Breast Cancer, Georgia versus Massachusetts White and Black, Year 1999 versus 2009

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?

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

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?

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. 

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

TUTORIAL 

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

Basic Rules of Probability

E.Singletary, 2003, Rating the Risk Factors for Breast Cancer

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 participants• Individual studies range from 6,000

participants to 200,000 participants

Questions? Questions?

• Find one study that has a “tight” calculation of risk.

• Discuss how risks are calculated• Explain variance• Why are there different studies?• Evaluate.• Ethics in study.• What study would you design?

Overview

• Risk assessment • Beyond the Human 

Genome Project:• Personal Genomes• Microarray analysis

Background materials:

Singletary, 2003

www.personalgenomes.org/

Dorit, 2007

Microarray animations by Davidson.

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.

Genetics of Breast and Ovarian Cancer (PDQ®) – National Cancer ...www.cancer.gov 

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

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.

• 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)

Microarray Analysis

Lab Activity match the cDNAs to the oligonucleotides in the

wells (Carolina Biologicals)

Dorit, 2007

For confirmation of gene expression: Multiblot Western Blots for protein expression (Kinexus)

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?

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.htmlMicro RNA  (a)  http://www.cancerquest.org/introduction-to-micrornas.html   and       (b) http://www.cancerquest.org/mirna-and-cancer.htmlHow cancers begin http://www.cancerquest.org/how-cancer-begins-introduction.html

Bibliography

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.aspxCaveat: Quality of US Regional Data Collected? http://www.cdc.gov/cancer/npcr/uscs/data/00_pop_coverage.htm

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.htm

Math 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.pdf

Risk 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?

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).

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. 

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.

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/breastductal

How to Analyze DNA Microarray Data (HHMI): A Tutorial http://www.hhmi.org/biointeractive/genomics/microarray_analyzing/01.html

What Are SNPs? http://ghr.nlm.nih.gov/handbook/genomicresearch/snp  includes written & audio definition of SNPs.

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.

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.