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Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore

Ng PS 1 , Boonen RA 2 , Wijaya E 1 , Chong CE 1 , Sharma M 2 , Knaup S 2 Show all authors , Mariapun S 1 , Ho WK 1 , Lim J 1 , Yoon SY 1 , Mohd Taib NA 3 , See MH 3 , Li J 4 , Lim SH 5 , Tan EY 6 , Tan BK 7 , Tan SM 8 , Tan VK 9 , van Dam RM 10 , Rahmat K 11 , Yip CH 12 , Carvalho S 13 , Luccarini C 13 , Baynes C 13 , Dunning AM 13 , Antoniou A 13 , van Attikum H 2 , Easton DF 13 , Hartman M 10 , Teo SH 14

Affiliations 

  • 1 Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 2 Department of Human Genetics, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands
  • 3 University Malaya Cancer Research Institute, University of Malaya Medical Centre, Kuala Lumpur, Wilayah Persekutuan, Malaysia
  • 4 Human Genetics, Genome Institute of Singapore, Singapore
  • 5 Breast Department, KK Women's and Children's Hospital, Singapore
  • 6 Department of General Surgery, Tan Tock Seng Hospital, Singapore
  • 7 Department of Breast Surgery, Singapore General Hospital, Singapore
  • 8 Division of Breast Surgery, Changi General Hospital Department of General Surgery, Singapore
  • 9 Singhealth Duke-NUS Breast Centre, Singhealth, Singapore
  • 10 Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  • 11 Department of Biomedical Imaging, Faculty of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Wilayah Persekutuan, Malaysia
  • 12 Subang Jaya Medical Centre, Subang Jaya, Malaysia
  • 13 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and Department of Oncology, University of Cambridge, Cambridge, UK
  • 14 Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia [email protected]
J Med Genet, 2022 May;59(5):481-491.
PMID: 33811135 DOI: 10.1136/jmedgenet-2020-107471

Abstract

BACKGROUND: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.

METHODS: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.

RESULTS: PTVs in PALB2 were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in PALB2 were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in PALB2. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.

CONCLUSION: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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