Loss-Of-Function Mutation Of ARID1A Tumor Suppressor Gene In A Glycogen-Rich Clear Cell Mammary Carcinoma

Abstract

Abstract Introduction/Objective Glycogen-rich clear cell carcinoma (GRCC-CA) is a rare subtype of breast carcinoma accounting for 0.9 - 3% of all breast malignancies. It is characterized by more than 90% of the neoplastic cells containing glycogen-abundant clear cytoplasm. Due to the rarity of this tumor, the information about the specific genetic alterations, their prognostic significance and potential therapeutic implications are quite limited. Here we report the molecular alterations of a GRCC-CA diagnosed in a 69-year-old woman. Methods Tumor-only sequencing using a hybrid-capture next-generation sequencing (HC-NGS) assay was performed using formalin-fixed paraffin-embedded tissue. The HC-NGS panel included the coding regions of 479 cancer-related genes, select introns of 47 genes and the TERT promoter. Results The HC-NGS showed the following alterations: 1) large inversion in chromosome 1 between exon 20 of gene ARID1A (1p36.12) and intron 2 of KDM5B (1q32.1) leading to loss-of-function of ARID1A tumor suppressor gene, 2) MAP2K4 p.E376 truncating mutation with a variant allelic frequency of 87% suggestive of loss-of-heterozygosity, 3) c- MYC gene amplification (5x), 4) variant of uncertain significance in gene PTPRB (p.D1848N) and 5) deep deletions of NCKAP5, CCNT2, MAP3K19, LRP1B, and KMT2A genes. Conclusion We report for the first time a loss-of-function mutation of ARID1A gene in mammary GRCC-CA. Loss of function of ARID1A gene, as shown by molecular studies or loss of protein expression, is often seen in clear cell carcinomas with high glycogen contents from other sites (ovary and kidney), indicating similarities in the molecular mechanisms of development. In our patient, the loss of ARID1A probably enhanced the effect of the c-MYC amplification, since ARID1A is involved in the repression of c-MYC and other proliferation associated genes during differentiation. Larger molecular studies are needed to elucidate further the genetic mechanisms of mammary GRCC- CA.