Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma

Hayashi, Takuma; Kawano, Miki; Ichimura, Tsuyoshi; Ito, Koichi; Ando, Hirofumi; Zharhary, Dorit; Kanai, Yae; Aburatani, Hiroyuki; Tonegawa, Susumu; Shiozawa, Tanri; Yaegashi, Nobuo; Konishi, Ikuo

doi:10.21873/anticanres.11068

Cited by 8 publications

(11 citation statements)

References 53 publications

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“…We determined that fewer mutations exist in mesenchymal tissue-derived tumors than in epithelial-derived cancers, in which the amount of mutations per sarcoma sample was less than 3; this result hence suggested that the histological origin had a significant effect on tumor mutation profiling based on TSACP assay. Besides, TSACP is a small-scale panel, the mutation frequency of 48 detected genes may underestimate the mutation abundance of PsC and mesenchymal/sarcoma mutations, which show the unique profile of cancer mutations [ 12 – 15 ].…”

Section: Resultsmentioning

confidence: 99%

Concurrent somatic mutations in driver genes were significantly correlated with lymph node metastasis and pathological types in solid tumors

Cheng

Wang²,

Han

et al. 2017

Oncotarget

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To demonstrate the mutational profiles in solid tumors, we profiled 165 solid tumor samples, including 9 cancer types and 4 sample types, by using amplicon-based next-generation sequencing panel covering 48 highly mutated tumorigenesis-related genes that were deep sequenced at an average coverage of 2000×. Both tumor and sample types had significant effect on tumor genetic mutational profiles. Concurrent driver mutations were frequently detected in solid tumor, concentrating on both modes of action driver genes (activating or loss of function). Furthermore, in non-small cell lung cancer (NSCLC), concurrent driver mutations were also significantly correlated with the lymph node metastasis status and pathological types. Higher frequency of lymph node metastasis was observed in patients with NSCLC with concurrent mutations on at least two driver genes. In addition, patients with lung adenocarcinoma were more likely to harbor concurrent driver mutations than patients with lung squamous and large cell carcinoma. Multiple mutations in the epidermal growth factor receptor gene were more frequently detected in patients with refractory NSCLC compared to untreated naive ones. Therefore, concurrent multiple driver mutations, rather than a single genetic mutation, should be investigated extensively to probe novel genetic biomarkers with clinical benefits.

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Section: Resultsmentioning

confidence: 99%

Concurrent somatic mutations in driver genes were significantly correlated with lymph node metastasis and pathological types in solid tumors

Cheng

Wang²,

Han

et al. 2017

Oncotarget

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“…However, normal physiological function of TP53 is observed in human U-LMS at high stage malignancy [19]. Together, these fi ndings indicate that while inactivation of the TP53 pathway is detected in the vast majority of human U-LMS, the mechanisms leading to disruption of the pathway vary greatly.…”

Section: Tumour Suppressor and Oncogenic Pathways Involved In Sarcomamentioning

confidence: 92%

Biological Analyses for Characterization of the Uterine Sarcoma Using Mouse Model

Hayashi¹,

Ichimura²,

Kasai³

et al. 2017

J Gynecol Res Obstet

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Uterine sarcomas are neoplastic malignancies that typically arise in tissues of a mesenchymal origin in uterine body. The identifi cation of novel molecular mechanisms leading to sarcoma formation, and the establishment of new therapies and biomarkers has been hampered by several critical factors. Uterine leiomyosarcoma (U-LMS), which is the most common sarcoma, is rarely observed in clinical settings, with fewer than 15,000 new cases being diagnosed each year in the United States. Another complicating factor is that U-LMS are extremely heterogeneous as they arise in a multitude of tissues from many different cell lineages. The scarcity of clinical samples coupled with its inherent heterogeneity creates a challenging experimental environment for clinicians and scientists. Faced with these challenges, there have been extremely limited advances in treatment options available to patients with U-LMS compared with those for patients with other malignant tumors. In order to glean insight into the pathobiology of U-LMS, scientists are now using mouse models whose genomes have been specifi cally tailored to carry gene deletions, gene amplifi cations, and point mutations commonly observed in human soft tissue sarcomas. The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis. It is the aim of many in the biological community that the use of these genetically modifi ed mouse models will serve as powerful in vivo tools to further our understanding of sarcomagenesis and potentially identify novel biomarkers and develop therapeutic strategies.

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“…Most of the immune-therapeutic focus in mesenchymal tumor types has centered on the PD-1 axis [4, 5, 10-15]. The expression of a few alternate immune-therapeutic targets, such as B7-H3, TGFB1 and TIM3, has been previously described in some mesenchymal tumor types [20, 21]. Pathological studies with anti-PD-1 and/or anti-PD-L1 antibodies have yielded inconsistent findings in mesenchymal tumors partially, because of the inclusion of heterogeneous sarcoma entities in many of the relevant studies [4-12].…”

Section: To the Editormentioning

confidence: 99%

“…Our knowledge of its functional significance in other sarcomas is limited, but its known immune-suppressive function and relatively high expression in both mesenchymal tumors and non-mesenchymal tumors suggests that it may be an important immune-suppressor in mesenchymal tumors. Overexpression of TGFB1 as the immune-suppressive cytokine has been described in mesenchymal tumors [20, 21]. Importantly, TGFB1 physiologically induces epithelial to mesenchymal transition (EMT) [24].…”

Section: To the Editormentioning

confidence: 99%