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

Abstract

BackgroundRare 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.MethodsMutation 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.ResultsPTVs 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.ConclusionDespite 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.

Spectrum and characteristics of germline PALB2 pathogenic variants in 1556 early-onset breast cancer patients in China

“…In this study, the frequency of PALB2 pathogenic variants was 1.3% (3/225) among patients aged ≤ 30 years, similar to that of 1%–1.85% in previous studies involving the Chinese (Zhou et al 2020 ), Malaysian, and Singaporean populations (Ng et al 2022 ). Additionally, we observed an approximately 2-fold occurrence of PALB2 pathogenic variants in breast cancer patients aged ≤ 30 years compared to those aged 31-40 years (1.3% vs 0.68%), however, the difference was not statistically significant ( p = 0.398).…”

“…These two mutations have been reported as recurrent mutations in unselected breast cancer studies in China (c.2257C>T: 6/16501 and 4/7657, respectively; c.2167_2168del: 12/16501 and 2/7657, respectively) (Deng et al 2019;Zhou et al 2020), however, we identified these mutations only once in each case. Although the PALB2 c.509_510del and c.172_175del were identified as founder or hotspot mutations in European populations (Rogoża-Janiszewska et al 2020), and PALB2 c.2968G>T was found to be a hotspot mutation in women with breast cancer from Malaysia and Singapore, none of these were observed in our study (Ng et al 2022). This highlights the ethnic and regional disparities in the spectrum of PALB2 pathogenic variants.…”

“…PALB2 c.1056_1057del was identified in two individuals, while the other variants were identified in a single individual. The mutation frequency of c.1056_1057del was 0.13% (2/1556), which is significantly higher than previous studies in unselected breast cancer in China (1/16501, 1/7657 and 0/2769, respectively) (Deng et al 2019 ; Wu et al 2020 ; Zhou et al 2020 ) and other Asian countries (1/7840 in Malaysia and Singapore, and 0/7051 in Japan) (Momozawa et al 2018 ; Ng et al 2022 ). While PALB2 c.751C > T was reported as a hotspot mutation in previous Chinese studies (Deng et al 2019 ; Wu et al 2020 ; Zhou et al 2020 ).…”

Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients

“…Similarly, another PALB2 pathogenic variant, c.2323C>T was identified in French-Canadian women in Quebec, where the Q775X mutation occurred in about 0.5% of the women diagnosed for breast cancer [41]. An Asian study identified 0.73% and 0.14% in breast cancer and normal control cohorts, respectively, and the most common recurrent mutations were c.7G>T and c.2968G>T in the cancer cohort [19]. A higher risk of developing breast cancer was estimated in PALB2 mutation carriers, which was 9.1-fold compared to non-carriers in the UK [1].…”