Comprehensive Genomic Analysis of Metatstatic Uterine and Extrauterine Leiomyoscarcoma
Leiomyosarcomas (LMS) are one of the most common histologic subtypes, comprising about 25% of all
sarcomas. Clinically, they are aggressive tumors with a metastatic rate of 40-45%. Current cytotoxic
therapies, including combination chemotherapy, are less than optimal. LMS belong to the class of
sarcomas with complex genetic alterations, and a number of genetic alterations have been reported in
LMS. However, almost none of these alterations have been demonstrated to have etiologic roles in these
tumors. In working towards a goal of identifyi ng novel therapeutic targets that can be exploited in these
aggressive tumors and may potentially prolong the survival of these patients, we aim to delineate the
recurrent genetic alterations in metastatic LMS and to compare with the data from primary LMS, which
should shed light on specific genetic alterations important for metastasis. We are focusing on metastatic
LMS because metastases are the main cause of mortality in LMS and because other major cancer
genomics efforts (such as TCGA) are focused exclusively on prima1y tumors. We propose to study both
LMS of uterine origin and LMS of soft tissue origin because no systematic genomic comparisons of these
two major types ofLMS have been performed and we hypothesize that the genetic similarities and
differences between the two will provide new insights into the key biology of both. Although genetically
complex sarcomas are rather difficult to study, we aim to be successful in this study using a multipronged
genetic approach, including gene expression profiling, whole exome mutational analysis, and whole
genome copy number analyses. As describe in detail below, to make most efficient use of precious LMS
patient samples and most cost-efficient use of the funds, we will use next-generation sequencing for all
aspects of genomic profiling. Our specific aims for this project include:
Specific Aims:
Aim 1. Define genomic abnormalities in metastatic uterine and soft tissue (extra-uterine) LMS.
Aim 2. To compare the genomic alterations of metastatic LMS with existing data from primary LMS in
order to identify specific genetic alterations associated with progression and metastasis.
Aim 3. Investigate the site-specific differences between uterine and soft tissue (extra-uterine) LMS.