Recurrent moderate-risk mutations in Finnish breast and ovarian cancer patients

Abstract

<p>Mutations in <i>BRCA1</i> and <i>BRCA2</i> genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in <i>PALB2</i>, <i>CHEK2</i>, <i>ATM</i>, <i>FANCM</i>, <i>RAD51C</i> and <i>RAD51D</i> genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being <i>CHEK2</i> c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of <i>CHEK2</i> c.319+2T>A and c.444+1G>A in Finnish BC patients. <i>CHEK2</i> c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58–18.45], <i>p</i> = 0.007) and similarly in the familial patient group. <i>CHEK2</i> c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate‐risk gene mutations in 2,487 BC patients, 556 OC patients and 261 <i>BRCA1/2</i> carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 <i>BRCA1/2</i>‐negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate‐risk gene mutation was found in 12.5% of <i>BRCA1</i> families and 7.1% of <i>BRCA1</i> index patients, as well as in 17.0% of <i>BRCA2</i> families and 11.3% of <i>BRCA2</i> index patients, and the mutations were associated with an additional risk in the <i>BRCA1/2</i> index patients (OR = 2.63 [1.15–5.48], <i>p</i> = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.<br /></p>