Loss of PALB2 predicts poor prognosis in acute myeloid leukemia and suggests novel therapeutic strategies targeting the DNA repair pathway
Authors: Antonella Padella, Maria Chiara Fontana, Giovanni Marconi, Eugenio Fonzi, Elisabetta Petracci, Anna Ferrari, Carmen Baldazzi, Cristina Papayannidis, Andrea Ghelli Luserna Di Rorá, Nicoletta Testoni, Gastone Castellani, Torsten Haferlach, Giovanni Martinelli, Giorgia Simonetti
Journal: Blood Cancer Journal (2021)

Dear Editor,Acute myeloid leukemia (AML) patients carrying complex karyotype or aneuploidies have a very poor prognosis, with a 5-year overall survival (OS) <20% 1 .We and others have shown that these patients are characterized by high genomic instability, along with defects of DNA damage response (DDR) genes 2,3 .Partner and localizer of BRCA2 (PALB2) is a key player in the homology recombination (HR) pathway, since it functions as a scaffold for the HR complex 4 .PALB2 monoallelic germline mutations are associated with an increased risk of developing breast, pancreatic, and ovarian cancers, whereas biallelic mutations lead to Fanconi anemia 5 .Genomic lesions, including sequence mutations and copy-number alterations (CNAs) of HR and DDR genes, are rare events in sporadic cancers and no recurrent genomic alterations in these genes have been reported so far in AML.Here, we studied the genomic alterations of PALB2 in AML, including its molecular interactions and prognostic relevance.Single-nucleotide polymorphism (SNP) arrays of 119 adult AML cases and whole-exome sequencing (WES) data of 68 adult AML cases were downloaded from the NGS-PTL project repository.Mutational data from the Beat-AML study (n = 531) and acute erythroid leukemia (AEL) cohort (n = 159) were retrieved from https://www.cbioportal.org/ and https://pecan.stjude.cloud/,respectively.The GSE23452 SNP array (n = 144), the GSE14468 (n = 486), and The Cancer Genome Atlas (TCGA, n = 200) AML transcriptomic datasets were obtained from Gene Expression Omnibus collection (https://www.ncbi.nlm.nih.gov/gds) and https://cancergenome.nih.gov/,respectively.SNP array data files for the NGS-PTL cohort (n = 119) are available through the Gene Expression Omnibus public database (accession no.GSE160982).Detailed dataset information and analysis are described in the Supplemental Material section.We first looked for PALB2 sequence variations in publicly available genomic datasets (TCGA, Beat-AML, NGS-PTL, and AEL): one somatic frameshift mutation was identified in one AML patient (NM_024675:exon3: T51Qfs*2, TCGA cohort) and two missense mutations (NM_024675:exon 4:Q460R, NM_024675:exon 4:G165C) were identified in two AEL cases.We then asked whether PALB2 was affected by CNAs.PALB2 CN loss was detected in 12/233 patients (5.2%), with a minimal common deleted region of 6.6 kb at the C terminus.This region included exon 12, which encodes for the domain responsible for the interaction with the HR proteins RAD51 and BRCA2 and the DNA repair-related polymerase POLH (Fig. 1A and Supplementary Table 1).PALB2 deletion was associated with CN loss of genomic regions frequently altered in poor-prognosis AML, including chromosome 5q and 17p13 (p < 0.05 and false discovery rate <0.25; Fig. 1B and Supplementary Table 2).AML patients carrying PALB2 genomic loss were older than wild-type cases (median age of 65 years vs. 59 in the wild-type cohort, p = 0.044; Table 1) and were