DNA damage repair (DDR) genes play critical roles in maintaining genome stability. However, they are prone to genetic variation, of which pathogenic variation (PV) is a predisposing factor for high risk of cancer development in modern humans. Knowing the origin of DDR PV is critical for understanding the genetic basis and developing strategies against cancer risk for modern humans. So far, there is no consensus on the original sources of DDR PV in modern humans. We performed phylogenic analysis, and the results ruled out non-human species as the original source for the PV in modern humans through evolutionary conservation. We performed anthropological analyses by tracing the PV from modern humans in over 5000 ancient humans spanning the past 40,000 years. We observed a widespread distribution of DDR PV shared between modern and ancient humans. The shared DDR PV was predominantly found in modern non-Africans within the past 10,000 years rather than in modern Africans, highlighting that the arising time should be post the latest Out-of-Africa human migration. We also observed the rich distribution of Portuguese BRCA founder PV in Brazilian, highlighting that human admixture facilitated DDR PV transmission globally between ethnic human populations. The shorter arising time of DDR PV was further supported by the haplotyping results of DDR founder PV in multiple DDR genes and the predominant heterozygotic nature of DDR PV. Our comprehensive investigation reveals that DDR PV was mainly originated from the recent evolutionary history of modern humans, and highlights that the high cancer risk caused by DDR PV in modern humans is a by-product of the human evolution process.

Abnormal gene expression plays key role in cancer development. A core promoter is located around the transcriptional start site. Through interaction between core promoter sequences and transcriptional factors, core promoter controls transcriptional initiation. We hypothesized that in cancer, core promoter sequences could be mutated to interfere the interaction with transcriptional factors, resulting in altered transcriptional initiation and abnormal gene expression and cancer development. We used triple-negative breast cancer (TNBC) as a model to test our hypothesis. We collected genome-wide core promoter variants from 279 TNBC genomes. After extensive filtering of normal genomic polymorphism, we identified 19,427 recurrent somatic variants in 1,238 core promoters of 1,274 genes and 1,694 recurrent germline variants in 272 core promoters of 294 genes. Many of the affected genes were oncogenes and tumor suppressors. Analysis of RNA-seq data from the same patient cohort identified increased or decreased gene expression in 439 somatic and 85 germline variants-affected genes, and the results were validated by luciferase reporter assay. By comparing with the core promoter variation data from 610 unclassified breast cancer, we observed that core promoter variants in TNBC were highly TNBC-specific. We further identified the drugs targeting the genes with core promoter variation. Our study demonstrates that core promoter is highly mutable in cancer, and can play etiological roles in TNBC and other types of cancer through influencing transcriptional initiation.