Hereditary breast cancer: ever more pieces to the polygenic puzzle (note references to BRCA's/Lynch syndrome/risk estimates)

Introduction

Hereditary breast cancer has been formally investigated since the middle of the 19th century
[1-3]. About thirty years ago, epidemiological and genetic linkage studies of multiple-case
families have guided the identification of TP53 mutations as a cause of Li-Fraumeni
Syndrome [4-6] and of BRCA1 and BRCA2 as first genes in which mutations strongly
predispose to breast and ovarian cancer [7,8]. There are further rare syndromes which include
the occurrence of breast cancer as part of the disease spectrum, and the underlying genes have
been identified by positional cloning. Apart from Li-Fraumeni Syndrome, these include
Cowden Disease (PTEN) [9,10], Peutz-Jeghers Syndrome (LKB1/STK11) [11,12], Lynch
Syndrome  (+Muir Torre) (MSH2,MLH1) [13], Bloom’s Syndrome (BLM) [14] and Ataxia-Telangiectasia (ATM) [15]. In addition, familial lobular breast cancer has been associated with germ-line
mutations in CDH1, the gene for E-cadherin [16,17]. Although the above-mentioned
syndromes are rare, they need to be kept in mind if a breast cancer patient presents with a
more complex disorder or suspicious family history...........

Table 1 Genes with intermediate to high penetrance mutations for breast cancer