PALB2 is a well-known gene for hereditary breast cancer (BC). However, PALB2-driven BCs are less studied as compared to BRCA1/2-related malignancies, due to rarity of PALB2 deleterious alleles.
PALB2 germ-line mutation analysis was performed using blood-derived DNA.
Sequencing of the entire coding region of PALB2 gene in 190 BC patients, who had evident clinical features of hereditary disease, but lacked BRCA1/2 germ-line mutations, led to the identification of 5 PALB2 mutation carriers. In addition, we considered 4 PALB2 heterozygotes, which were identified in our earlier study [Sokolenko et al., 2015]. The mutation spectrum was represented by 7 distinct pathogenic alleles (с.1317delG, c.172-175delTTGT, c.509-510delGA, R414X (n = 2), Q921X, c.1592delT and Y1055X (n = 2)). These 7 mutations were further screened in 1126 consecutive BC cases. This analysis revealed 8 additional instances of PALB2 mutations (c.509-510delGA (n = 5), c.172-175delTTGT (n = 2), c.1592delT (n = 1)). None of the above mutations was detected in 638 elderly tumor-free controls. Among 18 patients with PALB2-related BC, only 8 women were younger than 50 years; 6 patients reported family history of BC disease and 4 suffered from bilateral BC. IHC data were available for 10 tumors: 1 case was triple-negative, 1 BC demonstrated HER2 activation coupled with negative staining for hormone receptors (HR), and the remaining 8 cases were HR+. Loss-of-heterozygosity (LOH) analysis of 8 chemonaive BCs revealed somatic deletion of the remaining PALB2 allele in 5 tumors and retention of heterozygosity in 3 cases. In addition, we analysed 2 residual BC samples obtained after neoadjuvant therapy and revealed the intact PALB2 wild-type allele in both cases.
PALB2 germ-line mutations contribute to a fraction of BC morbidity in Russia, with PALB2 c.509-510delGA allele being the most frequent pathogenic variant. Interpatient variability with regard to somatic inactivation of the wild-type PALB2 allele deserves attention, given that intratumoral PALB2 status is likely to influence the drug sensitivity of BC.
Clinical trial identification
Legal entity responsible for the study
N.N. Petrov Institute of Oncology.
Russian Science Foundation.
All authors have declared no conflicts of interest.