Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML

Context The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. Objective Toapply whole-genome sequencing toa patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. Design, Setting, and Participant Skin (normal) and bone marrow (leukemia) DNA wereobtainedfromapatientwithearly-onset breastandovarian cancer (negative forBRCA1 andBRCA2mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping. Main Outcome Measures Structural variants, copy number alterations, singlenucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. Results Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemiaDNAas a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome. Conclusion Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.