A Novel Role of PALB2 in Lymphoid Tumour Development

Abstract

PALB2 is DNA damage response protein that acts in Homologous recombination Repair (HRR) pathway and promotes recruitment of principal HRR components such as BRCA1, BRCA2 and Rad51. Biallelic PALB2 inactivation is associated with the severe form of Fanconi anemia (FA-N), characterised by severe developmental abnormalities and occurrence of embryonal tumours in infancy. Given the rarity of reported patients with biallelic PALB2 inactivation, the full extent of phenotypes associated with PALB2 mutations is still unknown.Here we describe a family with two inherited PALB2 mutations where the affected individuals presented with few of the clinical features typically exhibited by FA-N patients. The patients, age 19 and 15 were lacking severe developmental abnormalities and displayed impaired growth and mild learning difficulties. Interestingly, however, both individuals developed B cell Non-Hodgkin lymphoma (NHL) at the early age of 12 and 3.5 years respectively, responded well to intensive chemotherapy and stayed in complete remission. Their cellular phenotype included a high level of spontaneous chromosomal damage suggestive of DNA repair defect, but otherwise deviated from the classic FA phenotype revealing an intermediate sensitivity to mitomycin C (MMC) by colony forming assay but an unusually high chromosomal radiosensitivity in G2.We addressed the possibility that this atypical clinical and cellular phenotype could be related to the functional properties of the mutant PALB2 protein(s) expressed from the affected alleles. Indeed, we demonstrated that the PALB2 protein (T839_K862del) produced from one of the mutant alleles carried by these patients retained both its N- and C-terminal domain required to interact with BRCA1 and BRCA2 respectively. We also showed that this mutant protein preserved some function compared with previously identifiedpatient-associated mutant PALB2 proteins and allowed low level recruitment of Rad51 foci at sites of DNA damage. We propose that the presence of this mutant protein accounts for the milder MMC hyper-sensitivity exhibited by cells from these patients and the lack of FA defining clinical characteristics.Finally, the shift in tumour spectrum from embryonal tumours towards B cell NHL observed in this family implies PALB2 as a potential suppressor of lymphoid tumourigenesis and raises the possibility that somatic mutations in this gene may contribute to the development of sporadic lymphoid tumours. DisclosuresJanic:Baxter: Other: Paid Instructor, Research Funding; Pfizer: Other: Paid Instructor, Research Funding; Bayer: Other: Paid Instructor, Research Funding; Octopharma: Research Funding; Novo Nordisk: Other: Paid Instructor, Research Funding.