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 populationData 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

Histologic Subtypes By Percentage Of Cases1. Infiltrating ductal carcinoma (IDC): the most commonly diagnosed breast tumor;

metastatic (lymphatics); account for 75% of breast cancers 2. Ductal carcinoma in situ (DCIS): most common type of

non-invasive breast cancer3. Lobular carcinoma in situ (LCIS): 2.8 per 100,000

women; high incidence in women aged 40-50 years 4. Infiltrating lobular carcinoma (ILC): <15% of

invasive breast cancers5. Medullary carcinoma: ~ 5% ; generally occurs in

younger women6. Mucinous (colloid) carcinom: <5% of invasive breast

cancer cases7. Papillary carcinoma: older women (>60 years); 1-2% of

all breast cancers8. Metaplastic breast cancer: <1% ; older women (>60

years); higher incidence in African American Women

INTRINSIC SUBTYPES OF BREAST CANCER

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

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 B(ER+ &/or PR+, HER+)• Similar to Luminal A• More frequently ER+/PR-• Worse outcome than

Luminal A

Luminal A(ER+ &/or PR+, HER-)• Most common subtype• Less aggressive• Lower histological grade• Good prognosis• Hormone responsive• Associated with increasing

age

ESTABLISHED RISK FACTORS FOR BREAST CANCER

Table Source: American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta.

ANATOMY OF A GENE

DNA

Transcription Start site

EXONSINTRONS

PROMOTER

RNA

Translation start site

Stop codon

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

GenePop’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 yrsPTEN 1 in 250,000 30-50%

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