Molecular characterization of mammary mucinous cystadenocarcinoma reveals recurrent TP53 and RB1 alterations with frequent PI3K–AKT pathway abnormalities

Mammary mucinous cystadenocarcinoma (MCA) is an exceedingly rare subtype of breast carcinoma with fewer than 50 cases reported worldwide and limited molecular characterization. We investigated three mammary MCA cases using integrated histopathological assessment, tumor mutation burden (TMB) analysis and targeted next‑generation sequencing of 275 cancer‑associated genes. All tumors demonstrated characteristic multiloculated cystic architecture with papillary proliferations and abundant extracellular mucin. TMB values were uniformly low, ranging from 1.461 to 4.129 mutations/Mb. Representative pivotal alterations included TP53 (truncating and missense) and RB1 (truncating) mutations in all three cases, activating PIK3CA mutations (p.Q546K, p.H419Y) and oncogenic AKT1 mutations (p.E49K, p.E17K) in two cases, whereas KRAS and TERT alterations were each identified in one case. The expanded targeted sequencing results further revealed additional pathogenic and likely pathogenic variants within TP53, PIK3CA and KRAS, particularly in case #1. Of note, the case #1 PIK3CA p.Q546K alteration was concordantly identified in our prior study. Overall, recurrent TP53 and RB1 involvement, together with frequent PI3K-AKT pathway abnormalities and low TMB, supports a distinctive molecular profile for mammary MCA by comparison to conventional mucinous breast carcinoma. These findings may assist in differential diagnosis when interpreted in conjunction with histomorphology and immunophenotype.