LAUSR

Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts. No pathogenic mutations were identified in SPRED1. A potential association between MBC and NF1 was reported in eight previous cases, but none underwent detailed genomics analysis. To identify additional candidate germline variants potentially predisposing to MBC, we conducted targeted exome sequencing of 279 established cancer-causing genes in a control blood sample, disclosing four rare SNVs. Analysis of her breast tumor showed markedly altered variant allelic fractions (VAFs) for two (50%) of them, revealing somatic loss of heterozygosity (LOH) at germline SNVs. Of these, only the VAF of the pathogenic SNV in NF1 was increased in the tumor. Tumor sequencing demonstrated five somatic mutations altering TP53, BRCA1, and other genes potentially contributing to cancer formation. Because somatic LOH at certain germline SNVs can enhance their impacts, we conclude that increased allelic imbalance of the pathogenic SNV in NF1 likely contributed to tumorigenesis. Our results highlight a need to assess predisposing genetic factors and LOH that can cause rare, aggressive diseases such as MBC in NF1.