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GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.
GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.
PurposeHomologous recombination deficiency (HRD) impacts cancer treatment strategies, particularly the effectiveness of PARP inhibitors. However, the variability different HRD assays has hampered the selection of oncology patients who may benefit from these therapies. Our study aims to assess the whole genome landscape to better define HRD in a pan-cancer cohort and to contribute to harmonization of HRD detection.MethodsWe employed a whole-genome sequencing WGS HRD classifier that included genome-wide features associated with HRD to analyze 580 tumor/normal paired pan-cancer samples. The HRD results were correlated retrospectively with treatment responses and were compared with commercial HRD tests in a subset of cases.ResultsHRD phenotype was identified in 62 samples across various cancers including breast (19%), pancreaticobiliary (17%), gynecological (15%), prostate (8%), upper gastrointestinal (GI) (2%), and other cancers (1%). HRD cases were not confined toBRCA1/2mutations; 24% of HRD cases wereBRCA1/2wild-type. A diverse range of HRR pathway gene alterations involved in HRD were elucidated, including biallelic mutations inFANCF, XRCC2, andFANCC, and deleterious structural variants. Comparison with results from commercial HRD assays suggests a better performance of WGS to detect HRD, based on treatment response.ConclusionHRD is a biomarker used to determine which cancer patients would benefit from PARPi and platinum-based chemotherapy. However, a lack of harmonization of tests to determine HRD status makes it challenging to interpret their results. Our study highlights the use of comprehensive WGS analysis to predict HRD in a pan-cancer cohort, elucidates new genomic mechanisms associated with HRD, and enables an accurate identification of this phenotype, paving the way for improved outcomes in oncology care.
BackgroundEsophagogastric adenocarcinoma demands a deeper molecular understanding to advance treatment strategies and improve patient outcomes. Here, we profiled the genome and transcriptome landscape of these cancers, explored molecular characteristics that are invisible to other sequencing platforms, and analyzed their potential clinical ramification.MethodsOur study employed state-of-the-art analyses of whole genome and transcriptome sequencing on 52 matched tumor and germline samples from 47 patients, aiming to unravel new therapeutic targets and deepen our understanding of these cancers’ molecular foundations.ResultsThe analyses revealed 88 targetable oncogenic mutations and fusions in 62% of the patients, and further elucidated molecular signatures associated with mismatch repair and homologous recombination deficiency. Notably, we identifiedCDK12-type genomic instability associated withCDK12fusions, novelNTRK, NRG1, ALK,andMETfusions, and structural variants in relevant cancer genes likeRAD51B.ConclusionsOur findings demonstrate the power of integrative whole genome and transcriptome sequencing in identifying additional therapeutic targets, supporting a promising path for precision medicine in treating esophagogastric adenocarcinoma.
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