The PALB2 Gene Is a Strong Candidate for Clinical Testing in BRCA1- and BRCA2-Negative Hereditary Breast Cancer

• DOI: 10.1158/1055-9965.epi-13-0745-t
• Publication Date: 2013-10-18T04:05:49Z
• Authors: Marketa Janatova; Zdenek Kleibl; Jana Stribrna; Ales Panczak; Kamila Vesela; Martina Zimovjanova; Petra Kleiblova; Pavel Dundr; Jana Soukupova; Petr Pohlreich
• Keywords: Ovarian Neoplasms; Base Sequence; Tumor Suppressor Proteins; DNA Mutational Analysis; Genes, BRCA2; Molecular Sequence Data; Genes, BRCA1; Nuclear Proteins; Breast Neoplasms; Pedigree; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Risk Factors; Case-Control Studies; Prevalence; Humans; Female; Genetic Predisposition to Disease; Fanconi Anemia Complementation Group N Protein; Gene Deletion

Abstract Background: Several reports indicate that inherited mutations in the PALB2 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 PALB2 to estimate their contribution to hereditary breast and/or ovarian cancer in the Czech Republic. Methods: The entire PALB2 coding region was sequenced in 409 breast/ovarian cancer patients negative for BRCA1 and BRCA2 mutations. Testing for large genomic rearrangements (LGR) was performed by multiplex ligation-dependent probe amplification (MLPA) analysis. Results: 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%; P = 2.6 × 10−9). 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. Conclusions: Our analyses demonstrated the significant role of the PALB2 gene in breast cancer susceptibility. The highest frequency of PALB2 mutations (comparable with that previously reported for BRCA2) was found in a subgroup of patients with hereditary breast cancer (HBC) (13/235; 5.5%). Impact: Our results show that mutation analysis of the PALB2 gene, including the analysis of LGRs, is primarily indicated in patients with HBC in case of their BRCA1 and BRCA2 negativity. Cancer Epidemiol Biomarkers Prev; 22(12); 2323–32. ©2013 AACR.