Ng, Pei Sze and Boonen, Rick A. C. M. and Wijaya, Eldarina and Chong, Chan Eng and Sharma, Milan and Knaup, Sabine and Mariapun, Shivaani and Ho, Weang Kee and Lim, Joanna and Yoon, Sook-Yee and Mohd Taib, Nur Aishah and See, Mee Hoong and Li, Jingmei and Lim, Swee Ho and Tan, Ern Yu and Tan, Benita Kiat-Tee and Tan, Su-Ming and Tan, Veronique Kiat-Mien and van Dam, Rob Martinus and Rahmat, Kartini and Yip, Cheng Har and Carvalho, Sara and Luccarini, Craig and Baynes, Caroline and Dunning, Alison M. and Antoniou, Antonis and van Attikum, Haico and Easton, Douglas F. and Hartman, Mikael and Teo, Soo Hwang (2022) Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore. Journal Of Medical Genetics, 59 (5). pp. 481-491. ISSN 0022-2593, DOI https://doi.org/10.1136/jmedgenet-2020-107471.
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Funders: | Wellcome Trust (Grant No. v203477/Z/16/Z), European Union's Horizon 2020 Research and Innovation Programme (BRIDGES) (Grant No. 634935), Science and Technology Development Fund (STDF) Ministry of Higher Education & Scientific Research (MHESR) (Grant No. UM.c/Hir/MOHe/06), Science and Technology Development Fund (STDF) Ministry of Higher Education & Scientific Research (MHESR) (Grant No. UMRG RP046-15HTM), Yayasan Sime Darby, Yayasan PETRONAS, National Research Foundation, Singapore (Grant No. NRF-NRFF2017-02), NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant, Breast Cancer Prevention Programme, Asian Breast Cancer Research Fund, National Medical Research Council, Singapore, Horizon 2020 (Grant No. 634935) |
| Uncontrolled Keywords: | genetic predisposition to disease; germ-line mutation |
| Subjects: | R Medicine R Medicine > RD Surgery |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 08 Oct 2023 12:05 |
| Last Modified: | 08 Oct 2023 13:13 |
| URI: | http://eprints.um.edu.my/id/eprint/42461 |
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