Nguyen T, Tallman Sam, Cho Yoonsu, Sosinsky Alona, Ambrose John, Thorn Steve, Mackintosh Maxine, Brown Matthew A, Moutsianas Loukas, Silver Matt J, Kuchenbaecker Karoline
Genomics England, London, UK.
Genomics England, London, UK; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Lancet Oncol. 2025 Jul;26(7):971-980. doi: 10.1016/S1470-2045(25)00199-8. Epub 2025 Jun 10.
Most research on genetic screening and precision oncology is based on individuals of European ancestry. We applied the National Health Service (NHS) England's cancer variant prioritisation workflow to evaluate the performance of these approaches in ethinically and ancestrally diverse populations. The second aim of the study was to assess the representativeness of the 100 000 Genomes Project cancer cohort of the population of England.
In this cross-sectional analysis, whole-genome sequencing data from patients with cancer recruited into the 100 000 Genomes Project between February 2015 to December 2018 were analysed. Clinical information, including tumour stage and grade, was gathered from the NHS England National Cancer Registration and Analysis Service. Patients with cancer types with fewer than five individuals, haematological cancers, childhood cancers, unknown primary carcinomas, patients with indeterminate sex, and patients missing somatic mutations in genes were excluded. To assess ethnicity representation in the 100 000 Genomes Project, we calculated the recruitment ratios for self-reported ethnicities for patients with cancer recruited to the 100 000 Genomes Project and patients with cancer in England. We also analysed differences in classification rates for potentially pathogenic variants to assess ancestry-related differences in germline and somatic mutations of different ancestry groups.
14 775 patients with cancer were recruited between February, 2015, and December, 2018, into the 100 000 Genomes Project. There was no evidence of under-representation of diverse ethnic groups in the 100 000 Genomes Project when compared with the national statistics. The recruitment rate ratio for breast cancer was 2·2 (95% CI 1·6-3·0) for Black versus White women in the 100 000 Genomes Project compared with 0·81 (0·79-0·83) for Black versus White women in the national data (fold-change in rate ratios 2·7; 95% CI 2·0-3·7, p<0·0001), suggesting higher representation of Black women in the 100 000 Genomes Project than expected given the ethnicity-specific incidence rates in England. Compared with national rates, the 100 000 Genomes Project also had higher recruitment rates of Black versus White men with prostate cancer (fold-change in rate ratios 3·7; 1·8-7·5, p=0·0004), Black versus White men with bladder cancer (fold change in rate ratios 6·1; 2·0-18·8, p=0·0016), and Asian versus White women with breast cancer (fold change in rate ratios 1·4; 1·2-1·7, p=0·0008). Ancestry had a significant association with the likelihood of carrying a variant classified as a potentially pathogenic (likelihood ratio test p=0·0011). Potentially pathogenic variants were identified in 23 (4·6%) of 500 South Asian (adjusted model odds ratio [OR] 1·88, 95% CI 1·21-2·93, p=0·0052) and 24 (5·3%) of 453 African ancestry patients (OR 2·24, 1·44-3·48, p=0·0003) compared with 263 (2·2%) of 11 955 in European-ancestry patients. However, we found that fewer tumour mutations in actionable genes were identified for patients of non-European ancestry compared with patients of European ancestry when adjusting for sex and cancer type (likelihood ratio test p<0·0001).
The was an excess of germline variants classified as potentially pathogenic variants in patients with non-European ancestry, which might impede the diagnostic process. Improved variant prioritisation workflows and more research in diverse groups are needed to ensure equitable implementation of genomics in cancer care.
The UK Department of Health and Social Care and the EU's Horizon 2020 Research and Innovation Programme.
大多数关于基因筛查和精准肿瘤学的研究是基于欧洲血统的个体。我们应用了英国国家医疗服务体系（NHS）英格兰的癌症变异优先级排序工作流程，以评估这些方法在种族和祖先背景多样化人群中的表现。该研究的第二个目的是评估“十万基因组计划”癌症队列对英格兰人群的代表性。
在这项横断面分析中，对2015年2月至2018年12月期间纳入“十万基因组计划”的癌症患者的全基因组测序数据进行了分析。临床信息，包括肿瘤分期和分级，从NHS英格兰国家癌症登记与分析服务中收集。癌症类型患者少于5例、血液系统癌症、儿童癌症、原发癌不明、性别不确定的患者以及基因中存在体细胞突变缺失的患者被排除。为了评估“十万基因组计划”中的种族代表性，我们计算了纳入“十万基因组计划”的癌症患者和英格兰癌症患者自我报告种族的招募比例。我们还分析了潜在致病变异分类率的差异，以评估不同祖先群体在种系和体细胞突变方面与祖先相关的差异。
2015年2月至2018年12月期间，有14775名癌症患者被纳入“十万基因组计划”。与国家统计数据相比，没有证据表明“十万基因组计划”中不同种族群体的代表性不足。在“十万基因组计划”中，黑人与白人女性乳腺癌的招募率比为2.2（95%CI 1.6 - 3.0），而国家数据中黑人与白人女性乳腺癌的招募率比为0.81（0.79 - 0.83）（招募率比的变化倍数为2.7；95%CI 2.0 - 3.7，p<0.0001），这表明在“十万基因组计划”中黑人女性的代表性高于根据英格兰特定种族发病率预期的水平。与国家发病率相比，“十万基因组计划”中黑人与白人前列腺癌男性的招募率也更高（招募率比的变化倍数为3.7；1.8 - 7.5，p = 0.0004），黑人与白人膀胱癌男性的招募率（招募率比的变化倍数为6.1；2.0 - 18.8，p = 0.0016），以及亚洲与白人乳腺癌女性的招募率（招募率比的变化倍数为1.4；1.2 - 1.7，p = 0.0008）。祖先与携带被分类为潜在致病变异的可能性有显著关联（似然比检验p = 0.0011）。在500名南亚患者中有23名（4.6%）（校正模型优势比[OR] 1.88，95%CI 1.21 - 2.93，p = 0.0052）和453名非洲血统患者中有24名（5.3%）（OR 2.24，1.44 - 3.48，p = 0.0003）被鉴定出潜在致病变异，而欧洲血统患者中11955名中有263名（2.2%）。然而，在调整性别和癌症类型后，我们发现与欧洲血统患者相比，非欧洲血统患者在可操作基因中鉴定出的肿瘤突变较少（似然比检验p<0.0001）。
在非欧洲血统患者中，被分类为潜在致病变异的种系变异过多，这可能会阻碍诊断过程。需要改进变异优先级排序工作流程，并在不同群体中进行更多研究，以确保基因组学在癌症护理中的公平实施。
英国卫生和社会保健部以及欧盟的“地平线2020”研究与创新计划。
