Interplay of Mendelian and polygenic risk factors in Arab breast cancer patients

Genome Medicine

Research

Riaz Gillani¹  Yousef Al Marzooq²  Mohammed Al-Jumaan²  Areej Al Nemer²  Amein Al-Ali²  Abdullah Alsulaiman²  Afnan Almuhanna²  Chittibabu Vatte²  Fatmah Almulhim²  Sabrina Y. Camp³  Hoyin Chu³  Eliezer M. Van Allen⁴  Saud H. AlDubayan⁵  Seunghun Han⁶ 

[1] Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Department of Pediatrics, Harvard Medical School, Boston, MA, USA;Boston Children’s Hospital, Boston, MA, USA;College of Medicine, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia;Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;Center for Cancer Genomics, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA;Division of Genetics, Brigham and Women’s Hospital, Boston, MA, USA;College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia;Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;Harvard Medical School, Boston, MA, USA;

关键词: Low-pass whole genome sequencing;    Imputation;    Polygenic risk score;    Breast cancer;    Arab population;    Age of onset;    Pathogenic variants;   

DOI  :  10.1186/s13073-023-01220-4

 received in 2023-05-04, accepted in 2023-08-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundBreast cancer patients from the indigenous Arab population present much earlier than patients from Western countries and have traditionally been underrepresented in cancer genomics studies. The contribution of polygenic and Mendelian risk toward the earlier onset of breast cancer in the population remains elusive.MethodsWe performed low-pass whole genome sequencing (lpWGS) and whole-exome sequencing (WES) from 220 female breast cancer patients unselected for positive family history from the indigenous Arab population. Using publicly available resources, we imputed population-specific variants and calculated breast cancer burden-sensitive polygenic risk scores (PRS). Variant pathogenicity was also evaluated on exome variants with high coverage.ResultsVariants imputed from lpWGS showed high concordance with paired exome (median dosage correlation: 0.9459, Interquartile range: 0.9410–0.9490). After adjusting the PRS to the Arab population, we found significant associations between PRS performance in risk prediction and first-degree relative breast cancer history prediction (Spearman rho=0.43, p = 0.03), where breast cancer patients in the top PRS decile are 5.53 (95% CI 1.76–17.97, p = 0.003) times more likely also to have a first-degree relative diagnosed with breast cancer compared to those in the middle deciles. In addition, we found evidence for the genetic liability threshold model of breast cancer where among patients with a family history of breast cancer, pathogenic rare variant carriers had significantly lower PRS than non-carriers (p = 0.0205, Mann-Whitney U test) while for non-carriers every standard deviation increase in PRS corresponded to 4.52 years (95% CI 8.88–0.17, p = 0.042) earlier age of presentation.ConclusionsOverall, our study provides a framework to assess polygenic risk in an understudied population using lpWGS and identifies common variant risk as a factor independent of pathogenic variant carrier status for earlier age of onset of breast cancer among indigenous Arab breast cancer patients.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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