Mini-reviewIdentification of novel hereditary cancer genes by whole exome sequencing
Introduction
Inherited genetic defects contribute to a significant share of familial cancer clustering and overall cancer morbidity. Earlier hereditary cancer studies were based mainly on the linkage analysis of large pedigrees, and led to the identification of a number of well-known highly-penetrant genes, e.g. BRCA1, BRCA2, MSH2, MLH1 [1], [2], [3], [4], [5]. Another strategy relies on the candidate gene analysis; it involves selection of genes with presumable cancer-related function, genetic screening of series of patients with clinical features of hereditary cancer (i.e., family history, early onset, multiple malignancies, specific disease appearance etc.) and subsequent case–control study for newly identified variants. This approach allows to reveal even those genes, which are not easily transmitted through generations due to severity of disease manifestation (e.g., TP53 [6]) or characterized by incomplete penetrance (e.g., CHEK2, NBS1 (NBN), ATM, BLM [7], [8], [9]).
All gene-seeking studies critically depend on the accessibility of DNA sequencing technologies. First discoveries of germ-line mutations were achieved by the manual DNA sequencing. Introduction of the automated DNA analysis in the mid-1990s and invention of high-resolution melting (HRM) prescreening technique in 2000s significantly improved the throughput of single-gene testing [10], [11]. The development of the next-generation sequencing, with potential applications for whole genome sequencing, apparently represents the most remarkable methodological breakthrough in the entire biomedical science since the discovery of PCR [12]. Whole exome sequencing (WES), being capable to cover almost the entire protein-coding region of the human genome, is considered to be an outstandingly powerful tool for medical genetic studies [13]. Indeed, WES already has led to the identification of causative mutations for a number of rare familial syndromes [14], [15], [16], [17]. Furthermore, WES revealed previously unknown roles for some cancer related genes. For example, PALB2 was initially discovered as a breast cancer gene; however, a whole exome study demonstrated its involvement in familial aggregation of pancreatic cancer [18]. As expected, the list of novel cancer-predisposing genes is also rapidly expanding (Table 1). Nevertheless, the impact of WES studies in resolving the issue of missing heritability for cancer patients remains somewhat lower than initially anticipated [110].
Section snippets
Breast cancer
Breast cancer (BC) is the most comprehensively investigated tumor type, and it is therefore appropriate to refer to BC as the most informative example. Pedigree-based studies led to the discovery of BRCA1 and BRCA2 two decades ago [1], [2]. These data were quickly replicated by other groups using additional sets of families [111], [112], [113], [114]. Furthermore, systematic screening for BRCA1 and BRCA2 mutations revealed that approximately 5% of total breast cancer morbidity, and about 15–25%
Other cancer types
Studies of familial cancer cases may be more efficient for those tumor types, which are characterized by moderate or rare incidence. Indeed, while the presence of multiple cases of common cancers within family, e.g. breast cancer, may occur by chance, this probability is significantly lower for many other malignancies. For example, strong familial clustering of multiple colorectal adenomas and carcinomas is relatively rare. Palles et al. [35] analyzed families with this disease, and revealed
Challenges and possible solutions
Technical limitations of whole exome sequencing are widely acknowledged. Some protein-coding regions of genome cannot be efficiently read by existing WES tools [14], [16], [17]. Furthermore, while the frequency of false-positive findings of WES can be easily analyzed by Sanger sequencing, systematic analysis of the rate of false-negatives is highly expensive and rarely performed in routine. Indeed, most of the current reasoning regarding the reliability of WES is based on the studies, which had
Conclusion
Whole exome sequencing is a powerful tool for medical genetic research. WES studies already resulted in identification of a number of genes causing rare cancer syndromes, and contributed to the understanding of genetics of common cancer types. Improvement of patients' selection and consideration of other than autosomal dominant modes of inheritance may further facilitate cancer genetic studies.
Funding
This work has been supported by the Russian Scientific Fund (Grant Number 14-25-00111).
Conflict of interest
There are no conflicts of interest in the studies reported in the paper.
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