Frequency and molecular characteristics ofPALB2-associated cancers in Russian patients

PALB2is a high-penetrance gene for hereditary breast cancer (BC). Our study aimed to investigate the spectrum ofPALB2mutations in Russian cancer patients.PALB2sequencing revealed pathogenic variants in 3/190 (1.6%) young-onset and/or familial and/or bilateral BC cases but none in 96 ovarian cancer (OC) or 172 pancreatic cancer patients. Subsequently, seven recurrentPALB2pathogenic alleles were selected from this and previous Slavic studies and tested in an extended patient series.PALB2pathogenic variants were detected in 5/585 (0.9%) high-risk BC, 10/1508 (0.7%) consecutive BC and 5/1802 (0.3%) OC cases. Haplotyping suggested that subjects with Slavic alleles c.509-510delGA (n = 10) and c.172-175delTTGT (n = 4) as well as carriers of Finnish c.1592delT mutation (n = 4) originated from a single founder each, whilePALB2p.R414X allele (n = 4) had at least two independent founders. Somatic loss of heterozygosity (LOH) was revealed in 5/10 chemonaive BCs and in 0/2 BC samples obtained after neoadjuvant therapy. Multigene sequencing identified somaticPALB2inactivating point mutation in one out of two tumors withoutPALB2LOH but in none of four BCs withPALB2LOH. Genomic instability, as determined by NGS, was observed in four out of five tumors with biallelicPALB2inactivation but not in the BC sample with the preserved wild-typePALB2allele.PALB2germ-line mutations contribute to a small fraction of cancer cases in Russia. The majority although not allPALB2-driven BCs have somatic inactivation of the remainingPALB2allele and therefore potential sensitivity to platinum compounds and PARP inhibitors.

Automated summary

PALB2 germ-line mutations contribute to a small fraction of cancer cases in Russia. The majority although not all PALB2-driven breast cancers have somatic inactivation of the remaining PALB2 allele and therefore potential sensitivity to platinum compounds and PARP inhibitors.