Abstract 1302: Genetic analysis in a patient with nine primary malignant neoplasms: A rare case of Li-Fraumeni syndrome

The identification of patients with hereditary cancer predisposition syndromes has important clinical implications for early diagnosis, prevention, and treatment. We applied whole exome sequencing to identify mutations underlying a patient diagnosed with Li-Fraumeni syndrome, who had a first-degree family antecedent of breast cancer at age 42 years. Nine primary metachronous malignant neoplasms were developed in this patient within a period of 38 years, including upper lip neuroblastoma (7 years) and rhabdomyosarcoma (7 years), breast cystosarcoma phyllodes carcinoma (28 years), bronchioalveolar cell carcinoma (29 years), breast infiltrating ductal carcinoma (39 years), and thyroid papillary carcinoma (39 years), gastric adenocarcinoma (41 years), maxillary (41 years) and sternal osteosarcoma (43 years), as well as acute myeloid leukemia (45 years). Peripheral blood lymphocyte DNA from the patient was obtained. Exome capture was performed using the SureSelect Human All Exon 51Mb System, and paired-end sequencing was performed using Illumina HiSeq90 platform. A bioinformatics pipeline was used to analyze sequencing reads and call single nucleotide variants (SNVs). We used a candidate strategy to analyze mutations in the case of only a single dominantly affected individual available. Whole-exome sequencing of peripheral blood lymphocyte DNA resulted in an output of 30 GB of raw sequence. After quality control, we obtained clean reads with an average depth of coverage of 105× and 99.4% exome regions were covered at least four times. Analysis of 451,409 SNVs revealed increased genetic risk for some cancers, including genes related to hereditary cancer disposition syndromes [e.g., TP53 (p.P72R and p.R273H), BRCA1, and BRCA2], and genes associated with sporadic cancers. Pathway analysis found that, of 68 genes in p53-signaling pathway, the number of mutated genes (n=14) was significantly higher than expected (P=0.02). Of novel mutations, five nonsense mutations in four genes and 242 missense mutations in 233 genes were discovered. Whole-exome sequencing can identify known and/or novel mutations in cancer susceptibility genes and establish mutation profile in a rare case of Li-Fraumeni syndrome. Citation Format: Xiaoyuan Li, Juan Kang, Qi Pan, Wenwei Yin, Shiwen Tong, Dachun Zhao, Changting Meng, Chunmei Bai, Hong Ren, Keyue Ding. Genetic analysis in a patient with nine primary malignant neoplasms: A rare case of Li-Fraumeni syndrome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1302. doi:10.1158/1538-7445.AM2014-1302