Genomic alterations of
and
in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of
and/or
(
) homozygous deletions (HD) ...on the prognosis of
(
)-mutant astrocytomas. This is highlighted by the adoption of
HD as an essential criterion for astrocytoma and
-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The
and
genes are located on the short arm of chromosome 9.
encodes for two proteins, p14 and p16, and
encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of
alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing
. While the prognostic impact of
HD is established, the role of different
alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different
alterations in
-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of
alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that
HD is an important negative prognostic marker in
-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify
deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.
Melanoma: What do all the mutations mean? Davis, Elizabeth J.; Johnson, Douglas B.; Sosman, Jeffrey A. ...
Cancer,
September 1, 2018, Volume:
124, Issue:
17
Journal Article
Peer reviewed
Open access
Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both “driver” ...and “passenger” genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen‐activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high‐frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.
Melanoma is a highly mutated malignancy, and can produce a challenging amount of genomic data for practitioners. Herein, the authors review the clinical significance of various high‐frequency mutations and their interplay with novel targeted and immune therapies.
A large noncoding RNA called ANRIL (for antisense noncoding RNA in the INK4 locus) has been identified within the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster. While the exact role of ANRIL awaited ...further elucidation, common disease genomewide association studies (GWAS) have surprisingly identified the ANRIL gene as a genetic susceptibility locus shared associated by coronary disease, intracranial aneurysm and also type 2 diabetes. Expression studies have confirmed the coregulation of p15/CDKN2B, p16/CDKN2A, p14/ARF, and ANRIL. Among the cluster, ANRIL expression showed the strongest association with the multiple phenotypes linked to the 9p21.3 region. More recent GWAS also identified ANRIL as a risk locus for gliomas and basal cell carcinomas in accordance with the princeps observation. Moreover, a mouse model has confirmed the pivotal role of ANRIL in regulation of CDKN2A/B expression through a cis-acting mechanism and its implication in proliferation and senescence. The implication of ANRIL in cellular aging has provided an attractive unifying hypothesis to explain its association with various susceptibility risk factors. ANRIL identification emphasizes the underestimated role of long noncoding RNAs. Many GWAS have identified trait-associated SNPs that felt in noncoding genomic regions. It is conceivable to anticipate that long, noncoding RNAs will map to many of these "gene deserts."--Pasmant, E., Sabbagh, A., Vidaud, M., Bièche, I. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS.
In recent years, the conditions in routine mesothelioma practice have changed dramatically. These changes include (1) the aging of patients, (2) the introduction of a combination of immune checkpoint ...inhibitors (nivolumab plus ipilimumab) that is superior to conventional chemotherapy, and (3) advances in the pathological diagnosis of cytology specimens, small biopsy tissue, and early-stage lesions. This review article outlines (i) the WHO 2021 classification, which for the first time introduced the category of "benign and preinvasive mesothelial tumors" including mesothelioma in situ, (ii) the morphological ancillary assays based on genetic alterations of mesotheliomas that enabled the diagnosis of the new disease category, and (iii) its application to cytology, followed by (iv) an overview of the genetic alterations in mesothelial tumors and mesothelioma subtypes. Given that over 80% of pleural mesotheliomas initially present with pleural effusions, the role of cytology is expected to become more important. However, there are caveats and pitfalls associated with the application of ancillary assays, and the careful management and evaluation are desirable. Furthermore, diagnosing mesothelioma is challenging for pathologists alone, so it is essential that the results of histology and ancillary assays always be assessed and interpreted together with clinical and imaging findings.
Homozygous deletion (HD) of CDKN2A/B holds important prognostic value in gliomas. This study aimed to explore the predictive potential of conventional MRI characteristics combined with dynamic ...contrast-enhanced MRI parameters in predicting CDKN2A/B HD status in gliomas.
Preoperative MRI data of 105 patients (69 without CDKN2A/B HD, and 36 with CDKN2A/B homozygous deletion) with gliomas were retrospectively collected. Conventional MRI features and dynamic contrast-enhanced-MRI qualitative parameter time-intensity curve type, quantitative parameters Ktrans, Kep, Ve, Vp, and iAUC were obtained. Logistic regression models for prediction of CDKN2A/B HD status were constructed in all types of gliomas and both subtypes of IDH-mutant and IDH-wild gliomas.
Multivariate analysis for all patients demonstrated that age (OR=1.103, p = 0.002) and Ktrans (OR=1.051, p < 0.001) independently predicted CDKN2A/B HD. In IDH-mutant subgroup, multivariate analysis results indicated that Ktrans (OR=1.098, p = 0.031) emerged as autonomous predictors of CDKN2A/B HD. In IDH-wild subgroup, age (OR=1.111, p = 0.002) and Ktrans (OR=1.032, p = 0.001) were independent predictors of CDKN2A/B HD according to the multivariate analysis. The areas under the receiver operating characteristic curve of the corresponding models were 0.90, 0.95 and 0.84, respectively.
Ktrans can serve as valuable predictive parameters for identifying CDKN2A/B HD status in all types of gliomas and both subtypes of IDH-mutant and IDH-wild gliomas. These findings provide a foundation for precise preoperative non-invasive diagnosis and personalized treatment approaches for glioma patients.
Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of cutaneous epithelium, represents 20% to 50% of skin cancers. Although the majority of cSCCs are successfully eradicated by ...surgical excision, a subset of cSCC possesses features associated with a higher likelihood of recurrence, metastasis, and death. The proper identification of these aggressive cSCCs can guide additional work-up and management. In the first article in this continuing medical education series, we discuss the incidence, recurrence rates, mortality rates, and risk factors associated with cSCC and review the staging systems used to stratify patients into high- and low-risk groups. The second article in this series reviews the treatment options for cSCC, with focused attention on the management of high-stage tumors.
Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship ...to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2A
high
) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2A
high
meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.
Purpose
Assessment of the risk of recurrence is essential to determine the therapeutic strategy of meningioma treatment. Many relapsing or aggressive meningiomas show elevated mitotic and/or Ki67 ...indices, reflecting cell cycle deregulation. As
CDKN2A
is a key tumor suppressor gene involved in cell cycle control, we investigated whether
CDKN2A
alterations may be involved in tumor recurrence.
Methods
We carried out a comparative analysis of 17 recurrent and 13 non-recurrent meningiomas.
CDKN2A
single nucleotide variations (SNVs), deletions, methylation status of the promotor, and p16 expression were investigated. Results were correlated with the recurrent or non-recurrent status and clinicopathological data.
Results
We identified a
CDKN2A
SNV (NM_000077, exon2, c.G442A, p.Ala148Thr) in five meningiomas that was significantly associated with recurrence (
p
= 0.03). This mutation, confirmed by Sanger sequencing and referenced in the COSMIC database in various cancers, has not been reported in meningioma. The presence of one of the three following
CDKN2A
alterations—p.(Ala148Thr) mutation, whole homozygous or heterozygous gene loss, or promotor methylation > 8%—was observed in 13 of the 17 relapsing meningiomas and was strongly associated with recurrence (
p
< 0.0001) and a Ki67 labeling index > 7% (
p
= 0.004).
Conclusion
We report an undescribed p.(Ala148Thr)
CDKN2A
mutation in meningioma that was only present in relapsing tumors. In our series,
CDKN2A
gene alterations were only found in recurrent meningiomas. However, our results need to be evaluated on a larger series to ensure that these
CDKN2A
alterations can be used as biomarkers of recurrence in meningioma.
According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, ...IDH-mutant (AII
IDHmut
), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII
IDHmut
), and WHO grade IV glioblastoma, IDH-mutant (GBM
IDHmut
). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII
IDHmut
and AAIII
IDHmut
have lost their significance. In contrast, GBM
IDHmut
still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was
CDKN2A/B
homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
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