Breast Cancer

Introduction

most common malignancy in women; second leading cause of cancer mortality after lung cancer

180, 000 new cases diagnosed per year Þ lifetime risk = 1/10

most are adenocarcinomas beginning in the epithelial lining of ducts and lobules

result of many, low penetrance genes with small effects Þ complex trait

some risk factors: age; gender (female > male; 100:1); ethnicity (European > African am. > Asian); early menarche; late childbirth; genetics; estrogen therapy

Family History as a Risk for Breast Cancer

70% of breast cancers are sporadic; 20% are familial; 10% are hereditary

familial breast cancer is poorly defined - generally implies a family history containing breast cancer

risk varies with the relatedness of the proband; the age of diagnosis of the proband, number of affected family
members; number of generations affected

i.e. 2.4 for first degree relative; 1.8 for second degree relative
i.e. 4.3 for proband diagnosed at 30; 2.7 for proband diagnosed at 40

hereditary breast cancer: families with autosomal dominant form or with a mutation in a breast cancer susceptibility gene

Genetic Approach to Familial Breast Cancer

autosomal dominant pedigrees exist for breast/ovarian cancer Þ implies a genetic component

Sporadic	Inherited
older age at diagnosis	younger age at diagnosis (pre-menopause, < 45 years)
unilateral	bilateral
weak family history	strong family history
not associated with other cancers	associated with ovaian, male breast, prostate, colon cancer

caused by inherited mutation in cancer susceptibility gene

low frequency, high penetrance gene accounts for few affected families with very high relative risk

loci associated with breast cancer

BRCA1

linked to chromosome 17q; 132 mutations and many polymorphisms have been identified

accounts for 50% of hereditary breast cancer

most mutations are deletions Þ effects tumor suppressor genes

BRCA2

linked to chromosome 12q; many mutations and polymorphisms
accounts for 30% of hereditary breast cancer
risk in affected families is 50 - 85% over a lifetime for breast cancer
risk for ovarian cancer is 16 - 50%

Cancer susceptibility and the Multistage Model of Carcinogenesis

cancer is not a single event, it is a multi-stage process in which an initial mutation in a somatic cell is followed by subsequent mutations and alterations which accumulate over time and lead to cancer

Knudson’s Two Hit Hypothesis

originally based on retinoblastoma in children

cancer results from sequential cellular events where mutations occur in genes that control regulatory and growth function for the cell (i.e. p53)

the first mutation occurs in a somatic cell resulting in a pre-neoplastic cell

pre-neoplastic cells are more prone to further mutation Þ cancer

first hit may be loss of one allele of a tumor supressor, second would be loss of second allele

in hereditary cancers a pre-neoplastic condition is inherited (BRCA1)

Loss of Heterozygositiy: one allele of a regulatory product may be mutated and the individual is still okay

i.e. tumor supressor gene Þ must knock out both copies of the gene to get cancer

different tissues use different regulatory paths Þ BRCA1 mutation only affects breast tissue

Facts to Remember

180, 000 new cases of breast cancer per year - sporadic and hereditary Þ both are genetic at the cellular level

breast cancer is a complex disease which can result from:

alleles with major effects (BRCA)
combination of alleles with small effects
combination of allleles with small effects and the environment

breast cancer is genetically heterogeneous in both locus and allele (different cases have different causes)

BRCA1 and BRCA2 account for 80% of early onset, hereditary breast cancer

BRCA1 and BRCA2 are tumor supressor genes