Characterisation of PALB2 tumours through whole-exome and whole-transcriptomic analyses

Pei Sze Ng,Pathmanathan Rajadurai,Cheng Har Yip,Carlos Caldas,Muhammad Mamduh Ahmad Zabidi,Soo Hwang Teo,Antonis C Antoniou,Suet-Feung Chin,Jia Wern Pan,Alison M Dunning,Oscar M Reuda,Douglas F Easton

doi:10.1038/s41523-021-00254-4

Abstract

Rare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.

Highlights

PALB2 [Partner and Localizer of BRCA2] plays a vital role in the maintenance of genome integrity and repair of DNA doublestrand breaks via homologous recombination (HR) pathway, by localising BRCA2 to the sites of DNA damage and serving as a linker between BRCA1 and BRCA21,2
Of the 560 breast tumours with available sequencing data, subsequent genomic and transcriptomic profiling was conducted only for samples that passed quality checks [whole-exome sequencing (WES), n = 546; shallow wholegenome sequencing (sWGS), n = 533; RNA sequencing (RNA-seq), n = 527]
We found 709, 3297 and 1760 genes that were significantly differentially expressed between PALB2, BRCA1 and BRCA2 tumours compared to noncarriers

Summary

Introduction

PALB2 [Partner and Localizer of BRCA2] plays a vital role in the maintenance of genome integrity and repair of DNA doublestrand breaks via homologous recombination (HR) pathway, by localising BRCA2 to the sites of DNA damage and serving as a linker between BRCA1 and BRCA21,2. Biallelic (homozygous) germline protein-truncating variants (PTVs) in PALB2 result in Fanconi anaemia[3], whereas monoallelic (heterozygous) PTVs predispose individuals to breast, ovarian and pancreatic cancers[4,5]. Two recent studies using formalin-fixed tissues show that a significant proportion of the tumours arising in PALB2 loss of function germline carriers have a loss of the second allele and biallelic loss of PALB2 results in the acquisition of genomic characteristics consistent with deficiency in double-strand DNA break repair[6,7]. In part because of the rarity of germline carriers, there has hitherto been no reports of genomic analyses from fresh frozen tumour samples. We report the genomic and transcriptomic characteristics of fresh frozen and formalin-fixed paraffinembedded tumours with PALB2 alterations, in comparison to the tumours with BRCA1 or BRCA2 alterations and non-carriers

Methods

Results

Conclusion