Characteristics of mismatch repair deficiency in sarcomas
Posted: Mon Sep 21, 2020 1:52 pm
Characteristics of mismatch repair deficiency in sarcomas
Abstract
Due to the efficacy of immune checkpoint inhibitor therapy in tumors with deficient mismatch repair, there has been a surge in demand for mismatch repair deficiency testing in various tumor types. Mismatch repair deficiency is not known to play a significant role in the pathogenesis of sarcomas, and the utility of testing these tumor types is not established. This study aimed to determine the frequency, pattern, and clinicopathologic correlates of mismatch repair deficiency in sarcomas. Three hundred and four sarcomas were profiled using a genomic platform that employs massively parallel sequencing to interrogate 447 cancer-associated genes. Mismatch repair status was evaluated by determining the number of small insertion/deletion events occurring in homopolymer regions per megabase of exonic sequence data across all genes. Molecular characteristics of mismatch repair-deficient sarcomas were compared to mismatch repair-deficient carcinomas (n = 70) also identified using the sequencing panel. Seven sarcomas (2.3%) were classified as mismatch repair-deficient: four unclassified sarcomas, and one each of pleomorphic rhabdomyosarcoma, epithelioid leiomyosarcoma and malignant PEComa. One patient had an established diagnosis of Lynch syndrome. In the remaining patients, the mismatch repair gene mutation was confirmed or suspected to be somatic. Mismatch repair immunohistochemistry confirmed the mismatch repair-deficiency status of all cases with alterations in the tested proteins. As expected, mismatch repair-deficient sarcomas showed a significantly elevated tumor mutation burden relative to mismatch repair-proficient sarcomas (median 16 versus 4.6, p < 0.001). However, in comparison to mismatch repair-deficient carcinomas, mismatch repair-deficient sarcomas showed a lower tumor mutation burden (median 28 versus 16, p = 0.006) and a significantly greater degree of chromosomal instability. Among mismatch repair-deficient sarcomas, PD-L1 was variably expressed on tumor-associated macrophages but not on tumor cells. Three patients received pembrolizumab: two progressed and one has stable disease with five months follow-up. Mismatch repair deficiency in histologically classifiable sarcomas is rare (1%) and is more common in unclassified sarcomas (10%). Additional study is required to determine the predictive role of mismatch repair-deficiency in sarcomas for immunotherapy.
https://www.nature.com/articles/s41379-019-0202-3
Table 1 Histologic types of sarcomas evaluated for mismatch repair deficiency
From: Characteristics of mismatch repair deficiency in sarcomas
Tumor Type Number of Cases Number (%) MMR-D
Alveolar soft part sarcoma 3 0
Angiosarcoma 11 0
Chondrosarcoma 3 0
Chordoma 1 0
Clear cell sarcoma 1 0
Well/Dedifferentiated liposarcoma 27 0
Dermatofibrosarcoma protuberans 1 0
Desmoid fibromatosis 5 0
Endometrial stromal sarcoma 6 0
Epithelioid hemangioendothelioma 2 0
Epithelioid sarcoma 1 0
Ewing sarcoma 8 0
Extraskeletal myxoid chondrosarcoma 2 0
Follicular dendritic cell sarcoma 2 0
Gastrointestinal neuroectodermal tumor 1 0
Gastrointestinal stromal tumor 62 0
Histiocytic dendritic cell sarcoma 4 0
Leiomyosarcoma:
Non-uterine 40 0
Uterine 25 1 (4%)
Malignant phyllodes tumor 1 0
Malignant peripheral nerve sheath tumor 4 0
Myxofibrosarcoma 6 0
Myxoid liposarcoma 6 0
Osteosarcoma 1 0
PEComa 10 1 (10%)
Pleomorphic liposarcoma 3 0
Pseudomyogenic hemangioendothelioma 1 0
Rhabdomyosarcoma (alveolar, pleomorphic, spindle cell) 3 (1 each) 1 (33%)
Round cell sarcoma with CIC-DUX4 fusion gene 1 0
Sclerosing epithelioid fibrosarcoma 4 0
Soft tissue myoepithelial carcinoma 2 0
Solitary fibrous tumor 4 0
Synovial sarcoma 10 0
Uterine adenosarcoma 1 0
Unclassified sarcomas 40 4 (10%)
Abstract
Due to the efficacy of immune checkpoint inhibitor therapy in tumors with deficient mismatch repair, there has been a surge in demand for mismatch repair deficiency testing in various tumor types. Mismatch repair deficiency is not known to play a significant role in the pathogenesis of sarcomas, and the utility of testing these tumor types is not established. This study aimed to determine the frequency, pattern, and clinicopathologic correlates of mismatch repair deficiency in sarcomas. Three hundred and four sarcomas were profiled using a genomic platform that employs massively parallel sequencing to interrogate 447 cancer-associated genes. Mismatch repair status was evaluated by determining the number of small insertion/deletion events occurring in homopolymer regions per megabase of exonic sequence data across all genes. Molecular characteristics of mismatch repair-deficient sarcomas were compared to mismatch repair-deficient carcinomas (n = 70) also identified using the sequencing panel. Seven sarcomas (2.3%) were classified as mismatch repair-deficient: four unclassified sarcomas, and one each of pleomorphic rhabdomyosarcoma, epithelioid leiomyosarcoma and malignant PEComa. One patient had an established diagnosis of Lynch syndrome. In the remaining patients, the mismatch repair gene mutation was confirmed or suspected to be somatic. Mismatch repair immunohistochemistry confirmed the mismatch repair-deficiency status of all cases with alterations in the tested proteins. As expected, mismatch repair-deficient sarcomas showed a significantly elevated tumor mutation burden relative to mismatch repair-proficient sarcomas (median 16 versus 4.6, p < 0.001). However, in comparison to mismatch repair-deficient carcinomas, mismatch repair-deficient sarcomas showed a lower tumor mutation burden (median 28 versus 16, p = 0.006) and a significantly greater degree of chromosomal instability. Among mismatch repair-deficient sarcomas, PD-L1 was variably expressed on tumor-associated macrophages but not on tumor cells. Three patients received pembrolizumab: two progressed and one has stable disease with five months follow-up. Mismatch repair deficiency in histologically classifiable sarcomas is rare (1%) and is more common in unclassified sarcomas (10%). Additional study is required to determine the predictive role of mismatch repair-deficiency in sarcomas for immunotherapy.
https://www.nature.com/articles/s41379-019-0202-3
Table 1 Histologic types of sarcomas evaluated for mismatch repair deficiency
From: Characteristics of mismatch repair deficiency in sarcomas
Tumor Type Number of Cases Number (%) MMR-D
Alveolar soft part sarcoma 3 0
Angiosarcoma 11 0
Chondrosarcoma 3 0
Chordoma 1 0
Clear cell sarcoma 1 0
Well/Dedifferentiated liposarcoma 27 0
Dermatofibrosarcoma protuberans 1 0
Desmoid fibromatosis 5 0
Endometrial stromal sarcoma 6 0
Epithelioid hemangioendothelioma 2 0
Epithelioid sarcoma 1 0
Ewing sarcoma 8 0
Extraskeletal myxoid chondrosarcoma 2 0
Follicular dendritic cell sarcoma 2 0
Gastrointestinal neuroectodermal tumor 1 0
Gastrointestinal stromal tumor 62 0
Histiocytic dendritic cell sarcoma 4 0
Leiomyosarcoma:
Non-uterine 40 0
Uterine 25 1 (4%)
Malignant phyllodes tumor 1 0
Malignant peripheral nerve sheath tumor 4 0
Myxofibrosarcoma 6 0
Myxoid liposarcoma 6 0
Osteosarcoma 1 0
PEComa 10 1 (10%)
Pleomorphic liposarcoma 3 0
Pseudomyogenic hemangioendothelioma 1 0
Rhabdomyosarcoma (alveolar, pleomorphic, spindle cell) 3 (1 each) 1 (33%)
Round cell sarcoma with CIC-DUX4 fusion gene 1 0
Sclerosing epithelioid fibrosarcoma 4 0
Soft tissue myoepithelial carcinoma 2 0
Solitary fibrous tumor 4 0
Synovial sarcoma 10 0
Uterine adenosarcoma 1 0
Unclassified sarcomas 40 4 (10%)