the$effects$of$environmental$factors ... - harvard university · talk$outline$...
TRANSCRIPT
The Effects of Environmental Factors and the BRCA Gene:c Muta:on on Ovarian Cancer Risk
Andrea Lane Jennifer Osei
Nathalie Quiroz
Dr. Eric Tchetgen Tchetgen Ms. Kathy Evans
July 23, 2015
Talk Outline
● Background info & study design
● Analysis methods
● Results, conclusions, moving forward
Part 1: Background
Ovarian Cancer
● Ovarian cancer is a cancer that originates in the :ssue of the ovaries, female reproduc:ve gland that produces eggs.
● “The American Cancer Society es:mates that in 2015, about 21,290 cases of ovarian cancer will be diagnosed and 14,180 women will die of ovarian cancer in the United States”
● “The overall five-‐year survival rate for women with ovarian cancer is 45%”
Known Risk Factors
● Gene:cs o Breast Cancer Gene:c muta:ons (BRCA1 and BRCA2) o Lynch Syndrome
● Reproduc:ve History and Infer:lity o Oral Contracep:ve Use o Parity
● Family History o Ovarian Cancer o Other female reproduc:ve cancers
● Increasing Age ● Hormone Replacement Therapy ● Obesity
Known Risk Factors
● Gene:cs o Breast Cancer Gene:c muta:ons (BRCA1 and BRCA2) o Lynch Syndrome
● Reproduc:ve History and Infer:lity o Oral Contracep:ve Use o Parity
● Family History o Ovarian Cancer o Other female reproduc:ve cancers
● Increasing Age ● Hormone Replacement Therapy ● Obesity
Known Risk Factors
● Gene:cs o Breast Cancer Gene:c muta:ons (BRCA1 and BRCA2) o Lynch Syndrome
● Reproduc:ve History and Infer:lity o Oral Contracep:ve Use o Parity
● Family History o Ovarian Cancer o Other female reproduc:ve cancers
● Increasing Age ● Hormone Replacement Therapy ● Obesity
Known Risk Factors
● Gene:cs o Breast Cancer Gene:c muta:ons (BRCA1 and BRCA2) o Lynch Syndrome
● Reproduc:ve History and Infer:lity o Oral Contracep:ve Use o Parity
● Family History o Ovarian Cancer o Other female reproduc:ve cancers
● Increasing Age ● Hormone Replacement Therapy ● Obesity
Research Ques:on
Are there any significant interac:ons between the BRCA muta:on and the environmental factors: parity and oral contracep:ve use?
Research Study
● Popula:on o Women in Israel (Ashkenazi Jews) o 1994-‐1999
● Case-‐control Design o Ovarian cancer is rare
● Covariates
o Parity, Oral Contracep:ve use, BRCA muta:on, Age, Ethnicity, Family History, Gynecology History, Cancer History
Descrip:ve Sta:s:cs
Descrip:ve Sta:s:cs
Part 2: Analysis
Logis:c Regression Models
1. Isola:ng variables of interest and examining interac:on terms logit(P(Y =1)) = β0 +β1G +β2E1 +β3E2 +β4GE1 +β5GE2
α = 0.05
Logis:c Regression Models
2. Model with all variables logit(P(Y =1)) = β0 +β1G +β2E1 +β3E2 +β4C +...+β8C
3. Model with all variables and interac:on terms
Logis:c Regression Models
logit(P(Y =1)) = β0 +β1G +β2E1 +β3E2 +β4GE1 +β5GE2 +...+β10C
Problem with Interac:on
1. Sample size issue (Controls with BRCA)
2. Not the best es:mate of interac:on coefficient
eβ3 = OR(G,E |Y =1)OR(G,E |Y = 0)
logit(P(Y =1)) = β0 +β1G +β2E +β3GE
Case – Only Assump:ons
1. Ovarian cancer is a rare disease
2. The BRCA gene:c muta:on and environmental factors are independent
OR(G,E |Y = 0) ≈OR(G,E)
1),( =EGOR
1)0|,( ==YEGOR⇒
Case -‐ Only Model
Now we need to es:mate: OR(G,E |Y =1)
logit(P(G =1)) = β0 +β1E
In the case-‐only model = in the general model β3β1
Part 3: Results
Research Ques:on -‐ Revisit
Are there any significant interac:ons between the BRCA muta:on and the environmental factors: parity and oral contracep:ve use?
Results : Interac:ons
• Interac:on 1: BRCA and Oral Contracep:ve Use • Interac:on 2: BRCA and Parity
Results: With Covariates
Interac:ons Accoun:ng for Covariates (N = 832)
Conclusions
● Overall, the interac:on between BRCA and the environmental variables were not significant at the 0.05 level
● Es:mate for the interac:on between BRCA muta:on and use of oral contracep:ves is posi:ve, indica:ng increase in the risk of ovarian cancer
● Es:mate for the interac:on between BRCA muta:on and parity is nega:ve, indica:ng decrease in the risk of ovarian cancer
● Data suggests use of oral contracep:ves reduces risk of ovarian
cancer in the overall popula:on
● BRCA muta:on is the biggest indicator for ovarian cancer risk
Limita:ons
● Retrospec:ve studies o Self-‐reported data
● Case-‐control study o Cannot es:mate risk or rate, only odds ra:o
● Case-‐only analysis o limited to analysis of interac:ve coefficient
● Generalizability
Future Research
● More generalizable study popula:on
● Rela:ng environmental factors to other types of cancer
● Beier understanding of biological mechanisms
References
1. McGuire, V. (n.d.). Rela:on Of Contracep:ve And Reproduc:ve History To Ovarian Cancer Risk In Carriers And Noncarriers Of BRCA1 Gene Muta:ons. American Journal of Epidemiology, 613-‐618.
2. Modan, B., Hartge, P., Hirsh-‐Yechezkel, G., Chetrit, A., Lubin, F., Beller, U., . . . Wacholder, S. (2001). Parity, Oral Contracep:ves, and the Risk of Ovarian Cancer among Carriers and Noncarriers of a BRCA1 or BRCA2 Muta:on. New England Journal of Medicine N Engl J Med, 235-‐240.
3. Ovarian Cancer Na:onal Alliance. (n.d.). Retrieved July 5, 2015, from hip://www.ovariancancer.org/about/sta:s:cs/
Acknowledgements
• Dr. Eric Tchetgen Tchetgen • Ms. Kathy Evans • Dr. Rebecca Betensky • Ms. Tonia Smith • Ms. Heather Mane • Ms. Ellie Murray • Mr. Joshua Barback • Harvard Summer Program in Biosta:s:cs and
Computa:onal Biology