Abstract
Recent advances in next-generation sequencing have made it possible to perform genome wide identification of somatic mutation in cancers. Most studies focus on identifying somatic mutations in the protein coding portion of the genome using whole exome sequencing (WES). Every human genome has around 4 million single nucleotide polymorphisms (SNPs). A sizeable fraction of these germline SNPs is very rare and will not be found in the databases. Thus, in order to unambiguously identify somatic mutation, it is absolutely necessary to know the germline SNPs of the patient. While a blood sample can serve as source of germline DNA from patients with solid tumours, obtaining germline DNA from patients with haematological malignancies is very difficult. Tumor cells often infiltrate the skin, and their DNA can be found in saliva and buccal swab samples. The DNA in the tips of nails stems from keratinocytes that have undergone keratinization several months ago. DNA was successfully extracted from nail clippings of 5 probands for WES. We were able to identify somatic mutations in one tumor exome by using the nail exome as germline reference. Our results demonstrate that nail DNA is a reliable source of germline DNA in the setting of hematological malignancies.
Highlights
Acute myeloid leukemia (AML) is a devastating disease with very poor survival, especially in elderly patients[1]
Bone marrow and nail DNA for this study was from a patient (P1) with a myelodysplastic syndrome (MDS) which progressed into acute myeloid leukemia who was treated at Auckland City Hospital
The nail DNA was highly fragmented with the fragments ranging in size from around 100 bp to about 2 kbp (Fig. 1A(ii-v),B), while the DNA from the bone marrow (BM) sample was running in the compression zone on the gDNA tape indicating good quality, high molecular weight DNA with fragments greater than 15 kbp (Fig. 1A(iv))
Summary
Acute myeloid leukemia (AML) is a devastating disease with very poor survival, especially in elderly patients[1]. More than 130 different fusion genes have been described so far in AML5 with 79 different fusions involving the KMT2A gene alone[6] This cytogenetic diversity in AML represents just the tip of the iceberg, i.e. only those genetic changes that can be detected by conventional cytogenetics, which has a resolution of about 5 to 10 Mbp. With the advent of next-generation sequencing (NGS) it has become possible to analyse AML genomes at single base pair resolution to identify somatic point mutations. In order to identify these tumor specific somatic variants confidently, it is essential to know the germline SNPs of the proband These can be identified by performing WES on DNA from a non-tumor tissue sample from the same proband (matched germline control). A less commonly used source for germline DNA are finger or toenails
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