Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics

Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.

Next‐generation sequencing reveals remarkable genetic stability in primary and corresponding recurrent intestinal‐type sinonasal adenocarcinoma

“…This high percentage may be surprising, however, similar studies on other types of tumor reported remarkable genomic stability with regard to somatic mutations, genome-wide methylation patterns and chromosomal copy number abnormalities. [34][35][36][37] These studies were also similar to our present work finding no elevated genetic discordance in patients that had received adjuvant radio/ chemotherapy between the primary tumor and recurrence. Therefore, these 12 recurrent ITAC were indeed recurrences and not second primary tumors.…”

Clinically relevant molecular hallmarks of PFA ependymomas display intratumoral heterogeneity and correlate with tumor morphology

“…5k), suggesting that high cell density areas in PF-EPN-A are generally more transcriptionally active and might play a more active role in tumor propagation. dense (c, d, h, i) and cell-dense (e, f, j, k d, e, i, and j Primary tumors and their relapses differ in respect to cell density, DNA methylation and frequency of chromosome 1q gains and 6q losses CNS tumor relapses tend to acquire more aggressive biology upon relapse in many cases, one example being atypical teratoid/rhabdoid tumors, as recently described by Johann, Altendorf et al [17]. To understand possible prognostic implications of cell density in primary PF-EPN-A, we quantified the proportion of cell-dense areas in nine primary ependymomas and their corresponding relapses, which revealed a mean increase of cell-density in progressive disease (> fourfold increase of the proportion of celldense areas in the respective primary).…”

“…CNS tumor relapses tend to acquire more aggressive biology upon relapse in many cases, one example being atypical teratoid/rhabdoid tumors, as recently described by Johann, Altendorf et al [ 17 ]. To understand possible prognostic implications of cell density in primary PF-EPN-A, we quantified the proportion of cell-dense areas in nine primary ependymomas and their corresponding relapses, which revealed a mean increase of cell-density in progressive disease (> fourfold increase of the proportion of cell-dense areas in the respective primary).…”

Current Molecular and Clinical Landscape of ATRT – The Link to Future Therapies

“…Tyrosine kinase receptor genes were overexpressed in relapse in ATRT-TYR tumors, while ATRT-SHH relapse displayed higher expression of genes associated with metastases. 146 …”

“…Tyrosine kinase receptor genes were overexpressed in relapse in ATRT-TYR tumors, while ATRT-SHH relapse displayed higher expression of genes associated with metastases. 146 Paassen et al developed a series of ATRT tumoroids and performed extensive drug screening. In contrast to suggestions by Altendorf et al, tyrosine kinase inhibitors were significantly more effective in ATRT-MYC tumoroids when compared to ATRT-SHH.…”