Abstract
Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future.
Highlights
Uterine leiomyomas (ULs) are extremely common human neoplasms that originate from the smooth muscle cells of the myometrium
Uterine smooth muscle tumor classification Based on the number of mitotic figures per 10 high power fields, severity of nuclear atypia (0–3), degree of cellularity, and presence of tumor necrosis in the hematoxylin-eosin-stained sections of the tumor specimens, the samples were classified into 65 conventional, 51 cellular (22 cellular and 29 highly cellular), and 25 mitotically active leiomyomas (11 lesions showing simultaneously increased cellularity), 18 leiomyomas with bizarre nuclei, and 51 leiomyosarcomas
Conventional leiomyomas mediator complex subunit 12 (MED12) and High mobility group AT-hook 2 (HMGA2) alterations accounted for the vast majority of conventional ULs (53/65, 81.5%) (Table 1, Fig. 1, see Additional file 5: Table S2), which is in line with previous literature [11]
Summary
Uterine leiomyomas (ULs) are extremely common human neoplasms that originate from the smooth muscle cells of the myometrium. Due to their dependency on the ovarian steroids estrogen and progesterone, ULs occur in women of reproductive age and typically regress with the onset of menopause [1]. The life time prevalence of ULs is approximately 70% among white and more than 80% among black women [2]. Despite their benign nature, ULs. Approximately 40% of leiomyomas harbor non-random cytogenetic rearrangements, of which the most common. Our recent highthroughput sequencing efforts have pointed to at least three distinct molecular subclasses among conventional ULs, each candidate subclass displaying a characteristic genetic driver aberration as well as unique global gene expression profile: MED12 mutation-positive, HMGA2overexpressing, and FH-deficient ULs [15, 16]
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