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

ESTABLISHED RISK FACTORS FOR BREAST CANCER Table Source: American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta.

ANATOMY OF A GENE DNA RNA PROMOTER Transcription Start site EXONS INTRONS 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 Gene 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% 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