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. 2020 Jul 31;12(8):2126.
doi: 10.3390/cancers12082126.

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Annalisa Astolfi  1 , Margherita Nannini  2 , Valentina Indio  3 , Angela Schipani  3 , Alessandro Rizzo  4 , Anna Myriam Perrone  5 , Pierandrea De Iaco  5 , Maria Giulia Pirini  6 , Antonio De Leo  6 , Milena Urbini  7 , Paola Secchiero  1 , Maria Abbondanza Pantaleo  3   4
Affiliations

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Annalisa Astolfi et al. Cancers (Basel). .

Abstract

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either TP53, RB1, ATRX or PTEN. The most frequently mutated gene was TP53, with 61% of the patients harboring at least one mutation, followed by RB1 at 48%. PTEN alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for TP53 and RB1 mutations to occur together, while both TP53 and RB1 were mutually exclusive with respect to CDKN2A/B inactivation. Overall survival did not show significant correlation with the mutational status, even if RB1 mutation emerged as a favorable prognostic factor in the TP53-mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis.

Keywords: ATRX; PTEN; RB1; TP53; genome analysis; uLMS; uterine leiomyosarcoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Description of the cohort included in the study. (A) Distribution of the samples in the six datasets: MSK, Memorial Sloan Kettering MSK-Impact dataset; MSK/Genie, MSK samples from AACR-GENIE project; TCGA, The Cancer Genome Atlas Firehose legacy; DFCI, Dana-Farber Cancer Institute; VICC, the Vanderbilt-Ingram Cancer Center; UMich, University of Michigan metastatic solid cancer project. (B) Origin of the analyzed samples between primary and metastatic sites. (C) Distribution of the sites of metastases in the patients with metastatic disease. (D) Fraction of genome altered values in the cohort, defined as the length of segments with log2 copy number value larger than 0.2 divided by the length of all segments measured. (E) Logistic PCA of binary mutational and copy number data showing that no cluster linked to the different data source is present.
Figure 2
Figure 2
Mutational profile of uLMS. (A) Oncoprint representation of the genomic alterations in the cohort stratified by data origin and biopsy site. All alterations are shown, with indication of the OncoKB annotation. (B) Distribution of mutation type of the four most frequent genetic lesions in uLMS. (C) Association between PTEN mutations and tumor sample origin from primary tumor or metastatic site (p = 0.023).
Figure 3
Figure 3
Kaplan–Meier analysis of overall survival of RB1-mutant patients vs. RB1 wild-type among the cohort of TP53-mutant patients. (Log-rank p-value = 0.04).
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