Data from <i>RASSF1A</i> Polymorphism A133S Is Associated with Early Onset Breast Cancer in <i>BRCA1/2</i> Mutation Carriers

Abstract

<div>Abstract<p>The tumor suppressor gene <i>RASSF1A</i> regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in ∼50% of breast cancers. It has been shown previously that the polymorphism A133S in <i>RASSF1A</i> reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of <i>RASSF1A</i> A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 <i>BRCA1</i> and <i>BRCA2</i> (<i>BRCA1/2</i>) mutation carriers, 395 non–<i>BRCA1/2</i> mutations carriers, and 120 untested for <i>BRCA1/2</i> mutations. Patients with breast cancer had a higher frequency of A133S than the controls [<i>P</i> = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10–2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (<i>P</i> = 0.029; OR, 1.76; 95% CI, 1.06–2.92) and patients carrying <i>BRCA1/2</i> mutations (<i>P</i> = 0.037, OR, 1.82; 95% CI, 1.04–3.18). Importantly, we found that the co-occurrence of a <i>BRCA1</i> or <i>BRCA2</i> mutation and A133S in <i>RASSF1A</i> was associated with earlier onset of breast cancer compared with those individuals with either a <i>BRCA1/2</i> mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, <i>P</i> = 0.002). Our data suggest that the presence of the <i>RASSF1A</i> A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in <i>BRCA1/2</i> mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers. [Cancer Res 2008;68(1):22–5]</p></div>