Genomic characteristics of two breast malignant phyllodes tumors during pregnancy and lactation identified through whole-exome sequencing

Abstract

AbstractBackgroundThe genomic landscape of breast malignant phyllodes tumors (PTs) is not well defined, especially pregnancy-related malignant PTs. To clarify this topic, whole-exome next-generation sequencing (NGS) was performed on tumor samples and paired normal breast tissues from two pregnancy-related malignant PTs, followed by a functional analysis of the genetic alterations.MethodsDNA from malignant PT samples and matched normal breast tissues of both patients were subjected to molecular profiling. NGS of the whole-exome was performed in a commercial molecular pathology laboratory. Predictive tools were used to estimate genetic variation in somatic and germline genes.ResultsIn total, 29 somatic genomic alterations and 18 germline alterations were found in both patients. In Patient 1, 12 aberrations were identified in the tumor tissue, and 9 alterations were identified in matched normal breast tissue. One pathogenic variant in tumor suppressor genes (TP53) was detected in patient 1. In Patient 2, 18 and 10 variants were found in the tumor and matched normal breast tissue, respectively. In Patient 2, pathogenic alterations were identified in two tumor suppressor genes (PTENandTP53).PTENandTP53may be potential drug targets. The functional predictive tools showed that genes of unknown significance for PTs, includingFCHO1in Patient 1, andLRP12andPKMin Patient 2, were pathogenic. Several genes, includingFCHO1,LRP12andPKM, were shown for the first time to be altered in malignant PTs. A potentially pathogenic germline variant inPRF1, was detected in Patient 1.ConclusionOur study first demonstrated somatic and germline gene alterations in two malignant PTs during pregnancy and lactation. These two PTs shared major genetic events, includingTP53mutation, which commonly occurs in malignant PTs; additionally, we identified two potential genes for targeted therapy,TP53andPTEN. One germline mutation inPRF1was also detected. These results provide clues regarding tumor pathogenesis and precision therapy development.