Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors

Abstract

The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.

Molecular and clinicopathologic characterization of intravenous leiomyomatosis

“…Therefore, especially in the setting of leiomyoma variants, results of genomic analysis should be interpreted carefully in correlation with the pathologic findings. That said, the majority of the tumors in our series showed simple genomic profiles (genomic index ranging from 0 to 19.3; mean 5.9), significantly different from the previously reported genomic profiles of leiomyosarcomas (with genomic index up to 180, and mean 51.8) 32 . Future studies - using other techniques (mutation and gene expression analyses) – may uncover additional genomic alterations not detectable by aCGH (mutations or balanced rearrangements) that may be responsible for the intravascular tumor location and the resulting aggressive clinical behavior in some patients.…”

“…In addition, a recent series by Croce et al . of 77 uterine smooth muscle tumors with a mean follow up of 63.6 months identified a genomic index cut off score of 10 as a predictor of recurrence and a criterion for “molecular leiomyosarcoma” 32 . Among stage 1 “molecular leiomyosarcomas” in that study, poor prognostic markers included genomic index cut-off score of 35, 5p gain, 13q loss involving RB1 and 17p gain involving MYOCD , the latter promoting smooth muscle differentiation and cell migration 73 .…”

“…Cancer related genes in the recurrent copy number aberrations were detected using the Cancer Gene Census ( https://cancer.sanger.ac.uk/cosmic/census?tier=all#cl_search ) tool 29 , including Tier 1 (documented activity in cancer with genomic alterations promoting oncogenic transformation) and tier 2 (recently emerging with strong indications of a role in cancer) genes, as well as literature search. Genomic index was calculated as A 2 /C (A=total number of alterations, C=number of involved chromosomes) 30 – 32 . Genomic index scores between IVL with aggressive clinical features and those without were compared by Mann-Whitney U Test.…”

Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes

“…D, Underexpressed genes in the low-proliferation group. studies using array CGH in uterine smooth-muscle tumors have indicated that genomic complexity is prognostic in that group of tumors (29,30). Our findings, in contrast, appear to indicate that genetic complexity is not prognostic in UUS, and thus chromosomal complexity as a prognostic marker is subtype specific.…”

Mesenchymale und gemischte Uterustumoren

“…Eine MED12-Amplifikation findet sich sowohl in Leiomyomen als auch Leiomyosarkomen. Mittels der Array-CGH ("array-based comparative genomic hybridization") konnte eine Unterscheidung benigner von malignen glattmuskulären Tumoren getroffen und damit die STUMP-Kategorie vermieden werden [8]. Es scheint, dass mittels Genexpressionsprofilen Leiomyosarkome von Stromasarkomen des Endometriums unterschieden werden können [9].…”