Data from The <i>PALB2</i> Gene Is a Strong Candidate for Clinical Testing in <i>BRCA1</i>- and <i>BRCA2</i>-Negative Hereditary Breast Cancer

Abstract

<div>Abstract<p><b>Background:</b> Several reports indicate that inherited mutations in the <i>PALB2</i> gene predispose to breast cancer. However, there is little agreement about the clinical relevance and usefulness of mutation screening in this gene. We analyzed the prevalence and spectrum of germline mutations in <i>PALB2</i> to estimate their contribution to hereditary breast and/or ovarian cancer in the Czech Republic.</p><p><b>Methods:</b> The entire <i>PALB2</i> coding region was sequenced in 409 breast/ovarian cancer patients negative for <i>BRCA1</i> and <i>BRCA2</i> mutations. Testing for large genomic rearrangements (LGR) was performed by multiplex ligation-dependent probe amplification (MLPA) analysis.</p><p><b>Results:</b> We have identified 13 different pathogenic alterations including 10 truncating mutations and three LGRs in 16 of 409 patients (3.9%), whereas one truncating mutation was found in a group of 1,226 controls (0.08%; <i>P</i> = 2.6 × 10<sup>−9</sup>). Three novel LGRs included deletions involving exons 7–8 and 9–10, respectively, and a duplication spanning exons 9–11. Five frameshift and two nonsense mutations were novel, whereas three truncating mutations were described previously. The only recurrent mutation was the c.172_175delTTGT detected in four unrelated breast cancer individuals.</p><p><b>Conclusions:</b> Our analyses demonstrated the significant role of the <i>PALB2</i> gene in breast cancer susceptibility. The highest frequency of <i>PALB2</i> mutations (comparable with that previously reported for <i>BRCA2</i>) was found in a subgroup of patients with hereditary breast cancer (HBC) (13/235; 5.5%).</p><p><b>Impact:</b> Our results show that mutation analysis of the <i>PALB2</i> gene, including the analysis of LGRs, is primarily indicated in patients with HBC in case of their <i>BRCA1</i> and <i>BRCA2</i> negativity. <i>Cancer Epidemiol Biomarkers Prev; 22(12); 2323–32. ©2013 AACR</i>.</p></div>