Genomic alterations in uterine leiomyosarcomas: Potential markers for clinical diagnosis and prognosis

Abstract

Genomic alterations were analyzed in 21 uterine leiomyosarcomas (ULMSs) by comparative genomic hybridization. DNA copy number changes were detected in all 21 tumors. The most frequent losses were 13q (16/21 = 76%), 10q (13/21 = 62%), 16q (8/21 = 38%), 12p (7/21 = 33%), and 2p (9/21 = 43%). The most common gains were 17p (8/21 = 38%), Xp (7/21 = 33%), and 1q (7/21 = 33%). High-copy-number gains (ratio > 1.5) were identified in Xp, 1q, and 17p. Loss of 13q was identified in both low-grade and high-grade tumors. Inactivation of a tumor suppressor gene in 13q may be an early event in the development of leiomyosarcomas. Loss of 10q, 2p, and 12p and gains of 1q as well as 17p were frequently found in high-grade tumors and recurrent tumors. Inactivation of tumor suppressor genes and activation of oncogenes in these regions may be associated with a more aggressive behavior of ULMS. Patients with only loss of 13q and without the other alterations listed above had longer survival times. Gains of Xp, 17p, and 1q and losses of 13q, 10q, 16q, 12p, and 2p have been reported in extra-uterine leiomyosarcomas. Our findings indicate that the pathogenesis of uterine leiomyosarcomas and extra-uterine leiomyosarcomas follows the same genetic pathways.

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

“…However, we found some typical and nearly consistent DNA copy number changes, including high frequency of losses in 10q (35% of all 51 tumors), 13q (57%) and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%); aberrations that have been reported in previous CGH studies of leiomyosarcoma. 21,[23][24][25][26][27][28] The high frequency of chromosome imbalances suggests the presence of pathogenetically relevant oncogenes or tumor suppressor genes within these chromosome regions. The purpose of our study was to evaluate possible differences between chromosomal aberrations in uterine and non-uterine leiomyosarcoma.…”

“…This finding is consistent with previous results reported in leiomyosarcoma and a wide range of other malignancies. 21,23,25,27,41,44,45 The tumor suppressor gene PTEN is mapped to 10q23. 45 This chromosomal region is commensurate with the frequent loss of heterozygosity of chromosome 10 demonstrated in uterine leiomyosarcoma but not in leiomyomas.…”

“…Increased sequence copy number at 1q21.q23 has been detected frequently in several malignancies (see Knuutila et al 50 and references therein), but especially in sarcomas, including leiomyosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, and malignant fibrous histiocytoma. 21,24,26,27,34,44,[51][52][53][54][55][56] This region harbors several genes of potential significance. [56][57][58] Our study showed gains and high-level amplifications in 17p in approximately 40% of the cases.…”

“…Thus our data support previous CGH analyses, which have reported high-level amplifications in 17p in 20-30% of extra-uterine cases and, sporadically, in uterine cases. 21,23,24,26,27 One of the best known tumor suppressor genes, TP53, is located at 17p13, and p53 and p53 protein overexpression has been described in leiomyosarcoma. 42,[59][60][61][62] Gains as well as high-level amplifications at 17p11.p12 seem to be frequently involved in other sarcomas, including osteosarcoma, chondrosarcoma, and malignant fibrous histiocytoma.…”

“…Extensive genetic imbalances have been detected in nearly all cases. [20][21][22][23][24][25][26][27][28] Surgery is the main treatment modality for leiomyosarcoma irrespective of localization. Pre-or postoperative radiation therapy is used in highgrade tumors and in cases where sufficient surgical margins cannot be obtained.…”