来自土著阿拉伯人口的乳腺癌患者比西方国家的患者早出现，并且在癌症基因组学研究中一直尚未得到充分代表。多基因和孟德尔风险对该人群乳腺癌早发性贡献的具体情况尚不清楚。我们对220名没有积极家族病史的土著阿拉伯人乳腺癌女性患者进行了低通量全基因组测序（lpWGS）和全外显子测序（WES）。使用公开可得的资源，我们补充了种群特定变异并计算了与乳腺癌负担敏感的多基因风险评分（PRS）。还要对高覆盖的外显子变异进行致病性评估。 从lpWGS补充的变异与配对外显子具有高一致性（中位数剂量相关性：0.9459，四分位范围：0.9410-0.9490）。在将PRS调整至阿拉伯人群之后，我们发现PRS在风险预测和一级亲属乳腺癌病史预测方面存在显著关联（Spearman rho=0.43，p = 0.03）。与中间百分位数相比，前百分位数PRS最高的乳腺癌患者也有5.53倍（95% CI 1.76-17.97，p = 0.003）的可能性患有一级亲属诊断出乳腺癌。此外，我们还发现乳腺癌的遗传性责任阈值模型的证据：在具有乳腺癌家族病史的患者中，致病性稀有变异携带者的PRS显著低于非携带者（p = 0.0205，曼-惠特尼U检验），而对于非携带者，PRS每增加一个标准差，患病年龄提前4.52年（95% CI 8.88-0.17，p = 0.042）。 总的来说，我们的研究提供了一种在研究不足的人群中评估多基因风险的框架，并确定了乳腺癌早发年龄的公共变异风险因素，这是与致病变异携带状况无关的因素，适用于土著阿拉伯乳腺癌患者。 ©2023. BioMed Central Ltd.（施普林格自然出版集团的一部分）。

Breast 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.We 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.Variants 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.Overall, 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.© 2023. BioMed Central Ltd., part of Springer Nature.