Inherited BRCA2 mutations and tumor hemi/homozygosity of metastatic soft tissue sarcoma in up to one-third of the 55 patients with shorter survival time.

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11571 Background: Soft tissue sarcoma (STS) is well-known rare cancer with few therapeutic options. Although recent comprehensive genomic analyses of adult STS revealed few somatic mutations and many copy number variations (CNVs), the pathogenesis, prognostic markers and drug sensitivity mechanisms remain to be understood. Methods: We recruited 55 patients (50 female and 5 male, mean age 49) with a confirmed metastasis, information on familial cancer burden and detailed sarcoma pathology under written informed consent approved by IRB. Whole-exome sequencing was performed on the illumina HiSeq 2500 with the mean coverage depth of 178x in tumor and 68x in germline samples. In order to find CNVs and germline contributions in tumor, we used Strelka and Virmid analysis software filtering all mutations with allele frequencies more than 80%. CNVs and specific mutations in the BRCA2 locus identified were validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. Results: Among the somatic mutations, TP53, MED12, ATRX and RB1 are most frequently affected under mean total mutation numbers 1.26/Mb. All patients show MSS phenotype. Of the 72 genes with heritable cancer risk evaluated by Ballinger et al.(2016) in sarcoma germline, 25 have mutations with tumor bialletic loss of wild type sequence in 44/55 (80%) patients. Of these, six BRCA2 missense mutations recognized as variants of unknown significance (VUS) are most frequently found in 15/55 patients (27%, 12/37 LMS, 1/9 LPS, 1/1 MPNST, 1/1 AS) in both female and male. CNVs analysis by MLPA showed complete deletion of wild type BRCA2 locus, leading to hemizygosity of the VUS. Kaplan-Meier analysis revealed that patients with the BRCA2 mutations (N = 15) significantly reduced the 5-year survival rate as compared with patients with normal sequence or mutations in heterozygosity (N = 40) (48% vs 93%, P = 0.00272). Conclusions: Our results unveiled a different landscape of STS genomics from previous studies, indicating more germline and CNVs contributions in prognosis. Tumor loss of wild type allele and hemizygosity in BRCA2 implicates defective HRR as a potential therapeutic target in STS.

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