Association of Palb2 variants with risk to breast cancer and molecular characterisation of PALB2 tumours / Ng Pei Sze
Purpose: Germline rare protein truncating variants (PTVs) in PALB2 are associated with an increased risk to breast cancer. At present, most of the available data on genetic predisposition to breast cancer are derived from studies in women of European descent, and it is unclear the extent to wh...
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| Format: | Thesis |
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2021
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| Online Access: | http://studentsrepo.um.edu.my/13255/ http://studentsrepo.um.edu.my/13255/4/pei_sze.pdf |
| Summary: | Purpose: Germline rare protein truncating variants (PTVs) in PALB2 are associated with
an increased risk to breast cancer. At present, most of the available data on genetic
predisposition to breast cancer are derived from studies in women of European descent,
and it is unclear the extent to which population-specific differences in genetic and lifestyle
factors may contribute to differences in lifetime risk to breast cancer in women of other
ancestries. This study sought to determine the prevalence of, mutation spectrum in and
the risk estimates associated with PALB2 in a multiethnic cohort of 7840 breast cancer
cases and 7928 healthy individuals from Malaysia and Singapore. In addition, this study
sought to describe the pathological and molecular characteristics associated with cancers
arising in carriers of PTV of PALB2. Methods: Mutation testing was performed on
genomic DNA from peripheral blood using targeted panel sequencing of 35 known or
suspected breast cancer susceptibility genes. Library preparation was conducted using the
Fluidigm Access Array or Fluidigm Juno system and the final pooled products were
sequenced on the Illumina Hiseq platform. Sanger sequencing was conducted to confirm
all variants identified in the bioinformatics analysis. For somatic mutational analyses,
DNA from fresh frozen tumour sections and matched normal DNA from peripheral blood
were subjected for whole exome sequencing (WES). For tumour gene expression
analyses, RNA from fresh frozen tumour sections were analysed using whole
transcriptomic RNA sequencing (RNA-seq). Results: The case-control analysis revealed
that germline PTV in PALB2 were rare but associated with significant increased risk of
breast cancer [OR=5.18, 95% CI 2.71 to 9.90, p<0.0001]. However, rare missense
variants in PALB2 [when analyzed as a group] were not associated with increased risk of
breast cancer. We found that tumours with PTV in PALB2 have characteristics that were
iv
similar to BRCA1 and BRCA2 tumours, having significantly more somatic alterations, and
a high proportion of mutational signature and genomic scar scores characteristic of
deficiencies in homologous recombination (HR), compared to tumours arising in patients
with no alterations. In addition, we report that unlike BRCA1 and BRCA2 tumours, PALB2
tumours did not have high prevalence of TP53 somatic alterations or an enriched immune
microenvironment. Conclusion: In this multi-ethnic cohort, which is unselected based on
age or family history, germline PTVs were identified in 0.73% of breast cancer cases and
0.14% healthy individuals. Based on the molecular profiling of PALB2 tumours, the
findings from this study suggest that breast cancer patients with PALB2 PTVs have
similar molecular characteristics to BRCA1 and BRCA2 tumours and are therefore likely
to benefit from the emerging targeted therapies for BRCA carriers such as platinum-based
chemotherapy and/or PARP inhibitors. These results confirm that PALB2 is the most
clinically significant breast cancer susceptibility gene after BRCA1 and BRCA2, thus
justifying the inclusion of PALB2 into the mainstream genetic testing to improve the
management of cancer risk for affected and unaffected carriers.
Key words: PALB2, breast cancer, germline, tumour genomics, transcriptomics |
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