Previous studies investigating the genomics of sporadic MMs have been limited due to single cases , or the utilization of limited genomic screening methods, without considering CNV events along with the SNV/INDELs . CNV events, in particular, are known to play a significant role in both the formation and progression of meningiomas and therefore CNVs are essential when assessing the clonal origin of a tumor [3,4,5,6,7].
With the use of comprehensive and unbiased genomic analyses, we demonstrate that sporadic MMs in the same patient can show both genomic and histologic heterogeneity. Though more commonly monoclonal in our cohort, MMs can be of both mono- and multi-clonal origin. Furthermore, we show that monoclonal formation can be observed in both NF2-loss and non-NF2 mutant tumors and those meningiomas can undergo branched evolution to display intertumoral heterogeneity in the same patient (Figs. 2c, 3c, 4c). While it has been previously reported that MMs in the same patient can be of different histological grade [1, 24, 25], we add that this also corresponds to different underlying molecular make-up. Thus, the biology and potential clinical behavior of one tumor, in a patient with MMs, cannot reliably lend insight into that of others.
Interestingly, we found that even when MMs share a monoclonal origin, they can exhibit genomic heterogeneity through branched evolution, with potential clinical implications. For instance, we showed in a patient with five NF2-loss meningiomas, one of the tumors acquired the pathogenic SMARCB1 mutation . NF2:SMARCB1 co-mutated meningiomas have been shown to have a higher proliferative index , are part of the pathway to aggressiveness and higher grade in meningiomas  and seem to benefit from greater EOR with regards to prevention of recurrence . Indeed, while this S1-T5 tumor was WHO Grade I, it did have an elevated proliferative index (Ki67 6–8%), while the four other tumors in this individual all displayed low indexes. Resection of one of the other four meningiomas, would not have allowed for this understanding.
Histological and anatomical correlations have been well established for sporadic meningioma and are useful in predicting the underlying genomic driver mutation . However, we have shown that the histological subtype, as well as the intracranial origin of each tumor in a MM patient, can vary and is not always reliable in inferring the genomic landscape of each of the multiple tumors as may be the case in solitary lesions. In another example demonstrating the branched evolution pattern of MMs (S5), we showed that while two tumors shared a chromosome X deletion, they harbored two distinct TRAF7 mutations along with two different histological subtypes. Interestingly, while the sphenoid wing tumor (S5-T1) was histologically classified as a secretory subtype, the right convexity tumor (S5-T2) was of meningothelial histology, the latter with clinical features being highly unusual for TRAF7 mutated meningiomas (Fig. 4). A similar finding was observed in patient (S4) with bilateral sphenoid wing meningiomas, in which the tumors were different grades and histologic subtypes, with the higher-grade tumor harboring additionally acquired CNV events. Thus, even in MMs with monoclonal origin, complex evolution patterns can result in genomically distinct tumors with different corresponding clinically relevant characteristics.
Interestingly, the distance between MMs does not seem to confer any useful inferences. In two cases with monoclonal origination and underlying heterogenous genomics, S2 and S4, the MMs were located at two very distant anatomical locations. Indeed, S2 had the largest intertumoral distance between the right occipital tumor and the right frontal tumor compared to the others (Fig. 3). Therefore, even in cases in which the MMs are quite distant and seemingly distinct and potentially “separate” lesions, they can still arise from the same clone. In a similar case with underlying genomic homogeneity, one tumor was located along the medial anterior skull base with the other nearby and abutting the anterior-most aspect of the left superior frontal gyrus (S3), without any obvious diseased dura in between (Additional file 3: Fig. S2). Finally, in the one case of multiclonal origin in a patient (S6), who harbored two tumors, one with a somatic TRAF7 and another with a POLR2A somatic mutation (Additional file 3: Fig. S2) we found the anatomical distance between these two genomically distinct tumors (center-distance = 48.1 mm) to be comparable to the monoclonally originating tumors (mean center-distance = 53.48 mm). These illustrations further emphasize that neither the anatomical proximity of the MMs, nor the molecular make-up and histological evaluation of a single tumor from a patient with MMs, may fully represent the biology of each tumor and may fail to reflect the scope of the overall disease and projection of its evolution. Thus, management of MMs should be based on each individual tumor’s clinical behavior (i.e. growth, symptomology).
These observations highlight the complexity of MMs and our lack of understanding of how they form, especially from a monoclonal origin. Different theories have been proposed, including potential dissemination of tumor cells along the cerebrospinal fluid or subarachnoid space [12, 14]. Additionally, it has been postulated that MMs form through dural spread, supported by the radiographic observation of “dural tails” frequently seen with these tumors. However, in all of the monoclonal MMs in our cohort, there was no concern radiographically or intraoperatively for involvement of the bridging dura, and certainly no connection between the tumors in the more distance cases. Moreover, when we analyzed a dural sample, taken from an uninvolved area centrally located to five MMs in one patient, we did not detect any genomic abnormality known to be associated with meningioma formation. Therefore, our findings suggest against dural spread being the explanation for MM formation. In the absence of a germline mutation, however, further investigation is needed to understand the pathogenesis.
MMs are relatively rare, and this is reflective in the small sample size included in this cohort. However, the use of comprehensive genomic characterization allowed for a more in-depth evaluation of the genomics of these tumors and provides novel insight into clonality. Also, we recognize the median follow-up time of the patients included was relatively short. However, the focus of this study was to provide an understanding of the inter-tumoral heterogeneity in a MM patient and how one tumor cannot reliably represent that of another highlighting clinical implications. Further studies are needed to better understand this relationship with clinical behavior, and specifically longer-term recurrence.
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