Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families

Weang-Kee Ho; Nur Tiara Hassan; Sook-Yee Yoon; Xin Yang; Joanna M C Lim; Nur Diana Binte Ishak; Peh Joo Ho; Eldarina A Wijaya; Patsy Pei-Sze Ng; Craig Luccarini; Jamie Allen; Mei-Chee Tai; Jianbang Chiang; Zewen Zhang; Mee-Hoong See; Meow-Keong Thong; Yin-Ling Woo; Alison M Dunning; Mikael Hartman; Cheng-Har Yip; Nur Aishah Mohd Taib; Douglas F Easton; Jingmei Li; Joanne Ngeow; Antonis C Antoniou; Soo-Hwang Teo

doi:10.1016/j.lanwpc.2024.101017

Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families

Lancet Reg Health West Pac. 2024 Feb 5:44:101017. doi: 10.1016/j.lanwpc.2024.101017. eCollection 2024 Mar.

Authors

Weang-Kee Ho^{1

2}, Nur Tiara Hassan², Sook-Yee Yoon², Xin Yang³, Joanna M C Lim², Nur Diana Binte Ishak⁴, Peh Joo Ho^{5

6

7}, Eldarina A Wijaya², Patsy Pei-Sze Ng², Craig Luccarini⁸, Jamie Allen⁹, Mei-Chee Tai², Jianbang Chiang⁴, Zewen Zhang⁴, Mee-Hoong See¹⁰, Meow-Keong Thong¹¹, Yin-Ling Woo¹², Alison M Dunning⁸, Mikael Hartman^{5

6

13}, Cheng-Har Yip¹⁴, Nur Aishah Mohd Taib^{10

15}, Douglas F Easton^{3

8}, Jingmei Li^{5

7}, Joanne Ngeow^{4

16}, Antonis C Antoniou³, Soo-Hwang Teo^{3

10}

Affiliations

¹ School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Jalan Broga, Semenyih, 43500, Selangor, Malaysia.
² Cancer Research Malaysia, 1 Jalan SS12/1A, Subang Jaya, 47500, Selangor, Malaysia.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, Cambridge, UK.
⁴ Cancer Genetics Service, National Cancer Centre Singapore, Singapore.
⁵ Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
⁶ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
⁷ Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A∗STAR), 60 Biopolis Street, Genome, #02-01, Singapore, 138672, Singapore.
⁸ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, 2 Worts' Causeway, CB1 8RN, Cambridge, UK.
⁹ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, UK.
¹⁰ Department of Surgery, Faculty of Medicine, University of Malaya, Jalan Universiti, Kuala Lumpur, 50630, Malaysia.
¹¹ Genetic Medicine Unit, University of Malaya Medical Center, Kuala Lumpur, Malaysia.
¹² Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹³ Department of Surgery, National University Hospital and National University Health System, Singapore, Singapore.
¹⁴ Subang Jaya Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500, Selangor, Malaysia.
¹⁵ University Malaya Cancer Research Institute, 50603, Kuala Lumpur, Malaysia.
¹⁶ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

Abstract

Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia.

Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment.

Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10^-5 for BRCA1 and 0.018 for BRCA2).

Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management.

Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).

Keywords: BRCA1; BRCA2; Breast cancer risk; Ovarian cancer risk; Penetrance.