Transcript Molecular and Genetic Epidemiology

Genetic and Molecular
Epidemiology
Bio364
Special Thanks to
Emily Chen, Ph.D.
Department Of Pharmacological Sciences
Lecture
• Breast Cancer Statistics
• Breast Cancer Subtypes & Potential Risk
Factors
• Breast Cancer Susceptibility Genes
• Breast Cancer Prognosis
2011 ESTIMATED US CANCER DEATHS
* Cancer Statistics 2011, American Cancer Society
FEMALE BREAST CANCER INCIDENCE RATES*
BY RACE & ETHNICITY, US, 1975-2007
*Rates are age-adjusted to the 2000 US standard population
Data source: Surveillance, Epidemiology, and End Results (SEER) Program, 1975-2007, Division of Cancer Control and Population
Science, National Cancer Institute, 2011. Data for whites and blacks are from the SEER 9 registries. Data for other race/ethnicities are
from the SEER13 registries.
Lecture
• Breast Cancer Statistics
• Breast Cancer Subtypes & Potential Risk
Factors
• Breast Cancer Susceptibility Genes
• Breast Cancer Prognosis
PROGRESSION OF BREAST CANCER
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Histologic Subtypes By Percentage Of Cases
Infiltrating ductal carcinoma (IDC): the most commonly diagnosed breast tumor;
metastatic (lymphatics); account for 75% of breast cancers
Ductal carcinoma in situ (DCIS): most common type of non-invasive breast
cancer
Lobular carcinoma in situ (LCIS): 2.8 per 100,000 women; high incidence in
women aged 40-50 years
Infiltrating lobular carcinoma (ILC): <15% of invasive breast cancers
Medullary carcinoma: ~ 5% ; generally occurs in younger women
Mucinous (colloid) carcinom: <5% of invasive breast cancer cases
Papillary carcinoma: older women (>60 years); 1-2% of all breast cancers
Metaplastic breast cancer: <1% ; older women (>60 years); higher incidence in
African American Women
INTRINSIC SUBTYPES OF BREAST CANCER
Basal-Like (Triple
Negative, cytokeratin 5/6+
&/or EGFR+)
• Aggressive subtype
• High grade histology, and
high mitotic rate
• Risk at younger age (<40)
• More likely preenopausal
African American Women
Luminal A
(ER+ &/or PR+, HER-)
• Most common subtype
• Less aggressive
• Lower histological grade
• Good prognosis
• Hormone responsive
• Associated with increasing
age
Luminal B
(ER+ &/or PR+, HER+)
• Similar to Luminal A
• More frequently ER+/PR• Worse outcome than
Luminal A
HER2+ (ER-)
• Less common, highly
aggressive subtype
• High grade histology
• Risk at young age (<40)
greater than luminal subtypes
• African American ethnicity
maybe a risk factor
• Outcome improved with
HER2
ESTABLISHED RISK FACTORS FOR
BREAST CANCER
Table Source: American Cancer
Society. Breast Cancer Facts &
Figures 2009-2010. Atlanta.
ANATOMY OF A GENE
DNA
EXONS
INTRONS
Transcription Start site
PROMOTER
Translation start site
Stop codon
RNA
GENETIC LINKS TO BREAST CANCER
Epidemiologic studies have clearly established the role of family
history as an important risk factor for both breast and ovarian
cancer.
The search for genes associated with hereditary susceptibility to
breast cancer has been facilitated by studies of large kindreds with
multiple affected individuals, and has led to the identification of
several susceptibility genes
Penetrance of Mutations - Estimates of penetrance by age 70 years
for BRCA1 and BRCA2 mutations show a large range, from 40%
to 87% for breast cancer
FOR YOUR INFORMATION ONLY, THIS
WILL NOT BE ON THE EXAM
SUMMARY OF SIX BREAST CANCER
SUSCEPTIBILITY GENES
Pop’n carrier frequency
Risk of BC by 70 yrs (95%
CI)
BRCA1
1 in 860
65% (44-78%)
BRCA2
1 in 740
45% (31-56%)
CHEK2
1 in 90
11% (9-14%)
ATM
1 in 100
23% (13-39%)
TP53
1 in 5,000
50-60% by 45 yrs
PTEN
1 in 250,000
30-50%
Gene
From Thompson & Easton. 2004. J Mammary Gland Biol Neoplasia 9:221.
FOR YOUR INFORMATION ONLY, THIS WILL NOT BE
ON THE EXAM
BREAST CANCER METASTASIS – TISSUE TROPISM
Cell 127, November 17, 2006