Abstract 1420: Prevalence of PALB2 mutations in an unselected cohort of breast cancer patients and unaffected individuals from Malaysia and Singapore
Authors: Ng Patsy P. , Wen Wei Xiong , Wijaya Eldarina , Allen Jamie , Lim Joanna , Lau Shao Yan , Decker Brennan , Pooley Karen , Dorling Leila , Luccarini Craig , Baynes Caroline , Conroy Don , Harrington Patricia , Mariapun Shivaani , Hasan Siti Norhidayu , Lee Daphne Shin-Chin , Lee Sheau Yee , Yoon Sook Yee , Yip Cheng Har , Taib Nur Aishah , Ho Weang Kee , Hartman Mikael , Antoniou Antonis C , Dunning Alison M , Easton Douglas F , Teo Soo Hwang 
Published: August 2018

Abstract
Background: Rare variants such as protein truncating and splice-junction variants in PALB2 have been found to confer increased risk to breast cancer. However, previous studies have only investigated the prevalence of mutation carriers in individuals selected on the basis of earlier age of diagnosis or on family history of breast cancer. In this study, we sought to determine the prevalence of PALB2 in an unselected hospital-based multi-ethnic cohort of breast cancer cases and healthy women from Malaysia and Singapore.
Method: Amplicon-based targeted sequencing of the PALB2 gene which include all coding exons and splice site junctions was performed to identify germline alterations in an unselected cohort of 5021 affected and 5192 healthy individuals recruited from multiple centres. Associations between pathogenic (protein truncating) variants and breast cancer risk were evaluated using logistic regression and a Fisher's exact test.
Results: Truncating variants in PALB2 were associated with increased risk of breast cancer with an estimated OR=6.61 (95% CI 3.27 to 13.37, p&lt;0.0001). In total, there were 31 unique protein truncating variants identified in 66 individuals (57 cases [1.1%], 9 controls [0.2%]). The majority of these truncating variants were rare; of the 31 unique variants identified, 18 (58%) were found only in 1 individual. The common truncating variants in our cohort were PALB2 c.2968G&gt;T (p.Glu990Ter, rs876659036) found in 5 cases and 2 controls; PALB2 c.1037_1041delAAGAA (p.Lys346Thrfs, rs587776410) found in 4 cases and PALB2 c.1059delA (p.Lys353Asnfs, rs730881872) found in 4 cases. Of the PALB2 carriers, 24% developed ER+/HER2- disease, 14.0% developed ER+/Her2+ or ER-/Her2+ disease and 10.5% developed triple negative breast cancer.
Conclusions: We found that 1.1% of breast cancer patients and 0.2% of unaffected individuals carry a pathogenic mutation in PALB2. To the best of our knowledge, this is the first large population-based case control study that was able to estimate the breast cancer risk associated with truncating mutations in PALB2 gene in a multi-ethnic population in South East Asia.
Citation Format: Patsy P. Ng, Wei Xiong Wen, Eldarina Wijaya, Jamie Allen, Joanna Lim, Shao Yan Lau, Brennan Decker, Karen Pooley, Leila Dorling, Craig Luccarini, Caroline Baynes, Don Conroy, Patricia Harrington, Shivaani Mariapun, Siti Norhidayu Hasan, Daphne Shin-Chin Lee, Sheau Yee Lee, Sook Yee Yoon, Cheng Har Yip, Nur Aishah Taib, Weang Kee Ho, Mikael Hartman, Antonis C Antoniou, Alison M Dunning, Douglas F Easton, Soo Hwang Teo. Prevalence of PALB2 mutations in an unselected cohort of breast cancer patients and unaffected individuals from Malaysia and Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1420.