Chan Sock Hoai, Ni Ying, Li Shao-Tzu, Teo Jing Xian, Ishak Nur Diana Binte, Lim Weng Khong, Ngeow Joanne
Division of Medical Oncology, National Cancer Centre Singapore, Cancer Genetics Service, Singapore.
Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
JNCI Cancer Spectr. 2021 Jan 5;5(1). doi: 10.1093/jncics/pkaa117.
Fanconi anemia (FA) is a rare genetic disorder associated with hematological disorders and solid tumor predisposition. Owing to phenotypic heterogeneity, some patients remain undetected until adulthood, usually following cancer diagnoses. The uneven prevalence of FA cases with different underlying FA gene mutations worldwide suggests variable genetic distribution across populations. Here, we aim to assess the genetic spectrum of FA-associated genes across populations of varying ancestries and explore potential genotype-phenotype associations in cancer.
Carrier frequency and variant spectrum of potentially pathogenic germline variants in 17 FA genes (excluding BRCA1/FANCS, BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO) were evaluated in 3523 Singaporeans and 7 populations encompassing Asian, European, African, and admixed ancestries from the Genome Aggregation Database. Germline and somatic variants of 17 FA genes in 7 cancer cohorts from The Cancer Genome Atlas were assessed to explore genotype-phenotype associations.
Germline variants in FANCA were consistently more frequent in all populations. Similar trends in carrier frequency and variant spectrum were detected in Singaporeans and East Asians, both distinct from other ancestry groups, particularly in the lack of recurrent variants. Our exploration of The Cancer Genome Atlas dataset suggested higher germline and somatic mutation burden between FANCA and FANCC with head and neck and lung squamous cell carcinomas as well as FANCI and SLX4/FANCP with uterine cancer, but the analysis was insufficiently powered to detect any statistical significance.
Our findings highlight the diverse genetic spectrum of FA-associated genes across populations of varying ancestries, emphasizing the need to include all known FA-related genes for accurate molecular diagnosis of FA.
范可尼贫血（FA）是一种罕见的遗传性疾病，与血液系统疾病和实体瘤易感性相关。由于表型异质性，一些患者直到成年才被发现，通常是在癌症诊断之后。全球不同潜在FA基因突变的FA病例患病率不均衡，表明不同人群的基因分布存在差异。在此，我们旨在评估不同祖先人群中FA相关基因的遗传谱，并探索癌症中潜在的基因型-表型关联。
在3523名新加坡人和来自基因组聚合数据库的7个包括亚洲、欧洲、非洲及混合血统的人群中，评估了17个FA基因（不包括BRCA1/FANCS、BRCA2/FANCD1、BRIP1/FANCJ、PALB2/FANCN、RAD51C/FANCO）中潜在致病性种系变异的携带频率和变异谱。对来自癌症基因组图谱的7个癌症队列中17个FA基因的种系和体细胞变异进行了评估，以探索基因型-表型关联。
FANCA中的种系变异在所有人群中始终更为常见。在新加坡人和东亚人中检测到携带频率和变异谱的相似趋势，两者均与其他祖先群体不同，尤其是缺乏复发性变异。我们对癌症基因组图谱数据集的探索表明，FANCA和FANCC与头颈癌和肺鳞状细胞癌之间以及FANCI和SLX4/FANCP与子宫癌之间的种系和体细胞突变负担较高，但该分析的效力不足以检测到任何统计学意义。
我们的研究结果突出了不同祖先人群中FA相关基因的多样遗传谱，强调了在FA的准确分子诊断中纳入所有已知FA相关基因的必要性。
