Abstract 134: Mutational landscape of breast cancers from PALB2 germline mutation carriers
Authors: Piscuoglio Salvatore , Ng Charlotte KY , Wen Y Hannah , Mannermaa Arto , Peterlongo Paolo , Tondini Carlo , Janatova Marketa , Hwang Teo Soo , Ng Pei-Sze , Looi Lai-Meng , Foulkes William , Chenevix-Trench Georgia , Weigelt Britta , Southey Melissa C. , Tischkowitz Marc , Reis-Filho Jorge S. ,   PALB2 Interest Group
Published: July 2016

Abstract
Introduction: The PALB2 gene encodes the partner and localizer of BRCA2 protein, which interacts with BRCA1/2 and is involved in homologous recombination DNA repair. Germline mutations in PALB2 are associated with an increased risk of breast cancer, with a cumulative risk of 35% by age 70 in female PALB2 mutation carriers. Whether the PALB2 wild-type allele is lost in the development of PALB2 breast cancers has yet to be defined. Further, the repertoire of somatic genetic alterations in these tumors is currently unknown. In this study we sought to characterize the genomic landscape of PALB2 breast cancers and to define the differences in the repertoire of somatic genetic alterations and mutational signatures between PALB2 and BRCA1 and BRCA2 breast cancers.
Material and Methods: Representative samples from nine breast cancers from patients with known PALB2 germline mutations were microdissected. DNA samples from microdissected tumors and matched normal counterparts were subjected to whole exome sequencing on an Illumina HiSeq2000. Somatic mutations were defined using MuTect and insertions and deletions using Strelka and Varscan2. Driver mutations were defined by state-of-the-art bioinformatics methods. Mutational signatures were defined using non-negative matrix factorization. Copy number alterations (CNAs) and regions with loss of heterozygosity were determined using FACETS. The mutational frequency of breast cancers from PALB2 germline mutation carriers was compared to that of breast cancers from BRCA1 (n = 11) and BRCA2 (n = 10) germline mutation carriers from The Cancer Genome Atlas study.
Results: Three patients harbored germline frame-shift PALB2 mutations (2 S1169fs, 1 T841fs), five displayed truncating mutations (3 W1038* and 2 Q775*) and 1 harbored a missense mutation (W1140G, of uncertain significance). Somatic loss of the PALB2 wild-type allele was found in 3 cases, in 2 of which the loss was caused by CNAs and in 1 case it was caused by a somatic PALB2 Q479* mutation. A median of 65 somatic mutations (range 45-223) and a median of 1 driver mutation (range 0-3) were identified per tumor. Cancer genes mutated in PALB2 breast cancers included TP53 (n = 2), PIK3CA (n = 2), NF1 (n = 1) and NCOR1 (n = 1). Six cases displayed mutational signatures consistent with the aging process; the BRCA signature was not found in any of the cases analyzed. Breast cancers from PALB2 mutation carriers had fewer somatic TP53 mutations than BRCA1 breast cancers (2/9, 22% vs 9/11, 82%, p = 0.02). No difference in the repertoire of somatic mutations between PALB2 and BRCA2 breast cancers was observed.
Conclusion: Unlike breast cancers from BRCA1 and BRCA2 mutation carriers, the majority of breast cancers from PALB2 mutation carriers lacked somatic loss of the wild-type allele and none displayed a BRCA mutational signature. No highly recurrently mutated gene was identified, but pathogenic mutations in driver genes (TP53, PIK3CA, NF1 and NCOR1) were found.
Citation Format: Salvatore Piscuoglio, Charlotte KY Ng, Y Hannah Wen, Arto Mannermaa, Paolo Peterlongo, Carlo Tondini, Marketa Janatova, Teo Soo Hwang, Pei-Sze Ng, Lai-Meng Looi, William Foulkes, Georgia Chenevix-Trench, Britta Weigelt, Melissa C. Southey, Marc Tischkowitz, Jorge S. Reis-Filho, PALB2 Interest Group. Mutational landscape of breast cancers from PALB2 germline mutation carriers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 134.