Frequent homozygous deletions of the CDKN2A locus in somatic cancer tissues

Hamid, Abdulaziz; Petreaca, Beniamin; Petreaca, Ruben C.

doi:10.1016/j.mrfmmm.2019.04.002

Cited by 12 publications

(6 citation statements)

References 62 publications

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“…Current technologies have revealed huge genetic profiling whose clinical significance is mostly still uncertain. Hamid et al reported the function and tissue distribution of genes flanking the CDKN2A locus, and demonstrated that one of these genes, MTAP , which is essential for adenosine monophosphate and methionine salvage, frequently co‐deleted with CDKN2A homozygous deletion 44 . Satomi et al reported the loss of MTAP immunohistochemical staining due to MTAP homozygous deletion as a surrogate marker of CDKN2A homozygous deletion, although there were several concerns regarding the interpretation and performance of MTAP immunohistochemistry 45 .…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH‐wildtype glioblastoma

et al. 2021

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Objective Accumulating evidence from recent molecular diagnostic studies has indicated the prognostic significance of various genetic markers for patients with glioblastoma (GBM). To evaluate the impact of such genetic markers on prognosis, we retrospectively analyzed the outcomes of patients with IDH‐wildtype GBM in our institution. In addition, to assess the impact of bevacizumab (BEV) treatment, we compared overall survival (OS) between the pre‐ and post‐BEV eras. Methods We analyzed the data of 100 adult patients (over 18 years old) with IDH‐wildtype GBM from our database between February 2006 and October 2018. Genetic markers, such as MGMT methylation status, EGFR amplification, CDKN2A homozygous deletion, and clinical factors were analyzed by evaluating the patients’ OS. Results CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status (p = 0.5268), whereas among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion (median OS: 14.7 and 16.9 months, respectively, p = 0.0129). This difference was more evident in the pre‐BEV era (median OS: 10.1 and 15.6 months, respectively, p = 0.0351) but has become nonsignificant in the post‐BEV era (median OS: 16.0 and 16.9 months, respectively, p = 0.1010) due to OS improvement in patients with CDKN2A homozygous deletion. However, these findings could not be validated in The Cancer Genome Atlas cohort. Conclusions MGMT and CDKN2A status subdivided our cohort into three race‐specific groups with different prognoses. Our findings indicate that BEV approval in Japan led to OS improvement exclusively for patients with concurrent unmethylated MGMT status and CDKN2A homozygous deletion.

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Section: Discussionmentioning

confidence: 99%

Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH‐wildtype glioblastoma

et al. 2021

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“…Transcribed genomic breakpoints more often involve driver events than non-transcribed genomic breakpoints, as seen with TMPRSS2-ERG . Known exceptions that can be considered driver events include promoter and enhancer rearrangements such as known for AR and FOXP1 [ 48 ], but also tumour suppressor gene deletions [ 34 , 49 ]. The reasoning that RNA-seq is not a replacement for WGS is valid.…”

Section: Discussionmentioning

confidence: 99%

Fusion transcripts and their genomic breakpoints in polyadenylated and ribosomal RNA–minus RNA sequencing data

et al. 2021

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Background Fusion genes are typically identified by RNA sequencing (RNA-seq) without elucidating the causal genomic breakpoints. However, non–poly(A)-enriched RNA-seq contains large proportions of intronic reads that also span genomic breakpoints. Results We have developed an algorithm, Dr. Disco, that searches for fusion transcripts by taking an entire reference genome into account as search space. This includes exons but also introns, intergenic regions, and sequences that do not meet splice junction motifs. Using 1,275 RNA-seq samples, we investigated to what extent genomic breakpoints can be extracted from RNA-seq data and their implications regarding poly(A)-enriched and ribosomal RNA–minus RNA-seq data. Comparison with whole-genome sequencing data revealed that most genomic breakpoints are not, or minimally, transcribed while, in contrast, the genomic breakpoints of all 32 TMPRSS2-ERG–positive tumours were present at RNA level. We also revealed tumours in which the ERG breakpoint was located before ERG, which co-existed with additional deletions and messenger RNA that incorporated intergenic cryptic exons. In breast cancer we identified rearrangement hot spots near CCND1 and in glioma near CDK4 and MDM2 and could directly associate this with increased expression. Furthermore, in all datasets we find fusions to intergenic regions, often spanning multiple cryptic exons that potentially encode neo-antigens. Thus, fusion transcripts other than classical gene-to-gene fusions are prominently present and can be identified using RNA-seq. Conclusion By using the full potential of non–poly(A)-enriched RNA-seq data, sophisticated analysis can reliably identify expressed genomic breakpoints and their transcriptional effects.

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“…Genomic sequencing and copy number analysis have shown that pNF possess low somatic mutation rates, stable chromosomal architecture, and intact CDKN2A/B [13,14] . In contrast, aNF frequently show heterozygous or homozygous loss of the tumor suppressor genes CDKN2A/B, which are likely drivers of the transition from a pNF to an MPNST [14][15][16][17] . CDKN2A homozygous loss has been described in many cancers [18] , and in NF1, there are significant pre-clinical data that suggest this loss may be a malignant driver.…”

Section: Genomic Characterization Of Anfmentioning

confidence: 99%

Challenges in determining the malignant potential of atypical neurofibromas (aNF) using histopathologic features and the potential need for CDKN2A/2B testing: a case report

Gross,

Mahmood,

Dombi

et al. 2024

J Transl Genet Genom

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Atypical neurofibromas (aNF) are peripheral nerve sheath tumors (PNSTs) histologically defined by cytologic atypia, hypercellularity, loss of neurofibroma architecture, and/or increased mitotic activity. aNF often have a heterozygous loss of CDKN2A/B in addition to homozygous NF1 loss. On MRI, aNF frequently appear as distinct nodular lesions, grow faster than plexiform neurofibromas, and have increased avidity on fluorodeoxyglucose positron emission tomography. At least some aNF are considered to be at greater risk for transformation to highly aggressive malignant PNSTs. We have observed that some PNSTs demonstrate a discrepancy between histological, clinical, and genomic criteria, where a PNST without histologically concerning findings may have clinical and imaging features concerning aNF and CDKN2A/B loss. This case series highlights this discrepancy and suggests the inclusion of CDKN2A/B loss to define aNF, along with clinical and imaging findings, to determine the potential for malignant transformation, and to select appropriate clinical management.

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Frequent homozygous deletions of the CDKN2A locus in somatic cancer tissues

Cited by 12 publications

References 62 publications

Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH‐wildtype glioblastoma

Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH‐wildtype glioblastoma

Fusion transcripts and their genomic breakpoints in polyadenylated and ribosomal RNA–minus RNA sequencing data

Challenges in determining the malignant potential of atypical neurofibromas (aNF) using histopathologic features and the potential need for CDKN2A/2B testing: a case report

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