Abstract
An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy.
Highlights
Germline mutations in both alleles of a Fanconi Anemia (FA) gene lead to FA, a rare human genetic disease, which is referred to a chromosomal abnormality syndrome [1,2,3,4,5]
We analyzed a total of 68 publicly available DNA sequence datasets for mutations occurring in the 17 FA genes and compounded a sum rate for the mutated FA pathway via c-BioPortal [17, 18]
These sum rates are scattered from 1 to 55% with a frequency in a range of 15-35% (Table 1 and Supplementary Table 1). This is the first report to comprehensively show the scale of detectable mutations in the FA pathway in nonFA human cancers, firmly supporting our prior report that the FA tumor suppressor pathway plays a crucial role in suppressing cancer development in the patients without FA [9, 10]
Summary
Germline mutations in both alleles of a Fanconi Anemia (FA) gene lead to FA, a rare human genetic disease, which is referred to a chromosomal abnormality syndrome [1,2,3,4,5]. We recently reported that the functional heterozygosity occurring in the FA signaling pathway during the course of cancer development plays a crucial role in promoting the development of human cancer in patients without FA [9, 10]. These studies, for the first time, demonstrated the tumor suppressor role of the FA signaling pathway predicated in 1971 by Dr Swift [11]. This study, for the first time, demonstrated the importance of the FA tumor suppressor pathway at the genetic level among the general population
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