A Comparative Study on Copy Number Variation in Subtypes of Breast Phyllodes Tumors

Breast phyllodes tumor (PT) is a biphasic tumor and constitutes about 0.3% to 1% of all breast tumors. The PT is histologically classified as benign, borderline, and malignant subtypes. Unlike epithelial breast cancers, PT is derived from breast fibroepithelial tissues, and the genomic information of PT subtypes is still limited.

The objectives were to gain a deeper understanding of genomic changes in the progression of PTs from benign and borderline to malignant.

In this study, we used an Affymetrix OncoScan Array to analyze the genome-wide copy number variations (CNVs) and nucleotide point mutations from 3 benign PTs, 3 borderline PTs, and 3 malignant PTs collected from the First Affiliated Hospital of Zhengzhou University.

DNA was extracted from formalin-fixed paraffin-embedded (FFPE) specimens using the TIANamp FFPE DNA Kit. The DNA was profiled for genome-wide CNV using the Affymetrix OncoScan Array and analyzed using the Nexus Express Chromosome Analysis Suite.

Our in silico variation analysis indicated copy number loss in Xp11.22 to q22.1 of all benign PTs (χ² = 9, P = .0027) and 22q11.23 and Xq23 in all malignant PTs (χ² = 12, P = .0005). A copy number gain was observed in 1p13.3 of all borderline PTs (χ² = 9, P = .0027) and 7p11.2 of all malignant PTs (χ² = 9, P = .0027). We also found consistent loss of heterozygosity (LOH) in 32 loci of benign PTs, 32 loci of borderline PTs, and 23 loci of malignant PTs. Among the 87 LOH, there were 15 overlapping loci across all PT subtypes. We observed missense mutations of NRAS, KRAS, IDH2, TP53, and a frameshift deletion in PTEN of sequenced PT samples, irrespective of their subtype. Interestingly, a point mutation in EGFR/EGFR-AS1 was only observed in malignant PTs.

Our data suggested that CNV at 7p11.2, 22q11.23, and Xq23 together with a point mutation in EGFR/EGFR-AS1 uniquely presented in malignant PTs may correlate with the progression of PTs.