Summary
Delta storage pool deficiency (δ‐SPD) is a rare heterogeneous group of platelet disorders characterized by a reduction in the number or content of dense granules. δ‐SPD causes a mild to ...moderate bleeding diathesis characterized mainly by mucocutaneous bleeding. Currently, no specific treatment is available and the therapeutic approach is based on prevention of excessive bleeding. However, during the last few years, important insights into the pathophysiology of δ‐SPD have been achieved using mouse models and dense granule deficiency‐associated congenital diseases, such as Hermansky–Pudlak syndrome and Chediak–Higashi syndrome. It thus appears that δ‐SPD represents a genetically heterogeneous group of intracellular vesicle biogenesis and/or trafficking disorders. This review summarizes recent data regarding the molecular mechanisms together with clinical features of the different types of δ‐SPD. Although the molecular basis of isolated inherited δ‐SPD remains currently unknown, next‐generation sequencing strategies should enable researchers to identify the causative genes. Identification of those genes should contribute to our understanding of the pathophysiology, represent useful tools for genetic diagnosis, and eventually lead to new specific therapeutic approaches.
Background
DNA methylation‐based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly ...impacts clinical neuro‐oncology. However, current implementation using hybridisation microarrays is time consuming and costly. We recently reported on shallow nanopore whole‐genome sequencing for rapid and cost‐effective generation of genome‐wide 5‐methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows us to discriminate a wide spectrum of primary brain tumours.
Results
Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on 382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of 55 cases, we found that a minimum set of 1000 random CpG features is sufficient for high‐confidence classification by ad hoc random forests. We implemented score recalibration as a confidence measure for interpretation in a clinical context and empirically determined a platform‐specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut‐off to an independent validation series (n = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100% specificity. Cross‐lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), the median time to results was 21.1 h.
Conclusions
In conclusion, nanopore sequencing allows robust and rapid methylation‐based classification across the full spectrum of brain tumours. Platform‐specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.
In this study, we show that nanopore low‐pass whole genome sequencing allows rapid and accurate DNA methylation‐based classification of brain tumours. Using ROC analysis in a cohort of N = 382 cases, we establish a platform‐specific confidence score for implementation in clinical care assuring 100% specificity while maintaining a sensitivity of 80.4%, which is comparable to current microarray implementations.
Aims
Malignant tumours of the lacrimal apparatus are rare and frequently show a poor prognosis, with no clear therapeutic standards. Characterisation of the genetic landscape of these rare tumours is ...sparse, and therefore therapeutics generally follow those of their common salivary gland counterparts. To further clarify the pathophysiology and discover potential therapeutic targets, we investigated the genetic landscape of eight tumours of the lacrimal apparatus.
Methods and results
DNA and RNA sequencing were performed to identify genetic mutations and gene fusions. Immunohistochemistry, fluorescence
in‐situ
hybridisation and reverse transcription–polymerase chain reaction followed by Sanger sequencing were performed to confirm the identified molecular alterations. Genetic alterations were detected in six tumours. Among five adenoid cystic carcinomas (ACC), four had confirmed alterations of
MYB
or
MYBL1
genes, including a
MYB
::
NFIB
fusion, a
MYBL1
::
NFIB
fusion, a
MYB
amplification and a novel
NFIB
::
THSD7B
fusion. Mutations in genes encoding epigenetic modifiers, as well as
NOTCH1
,
FGFR2
and
ATM
mutations, were also identified in ACCs. A carcinoma ex pleomorphic adenoma showed
TP53
and
CIC
mutations and an amplification of
ERBB2
. A transitional cell carcinoma was associated with HPV16 infection. No genetic alteration was found for one adenocarcinoma, not otherwise specified.
Conclusions
Our study highlights the variety of molecular alterations associated with lacrimal system tumours and emphasises the importance of molecular testing in these tumours, which can reveal potentially targetable mutations. Our results also reinforce the hypothesis of a common physiopathology of all ACCs, regardless of their primary location.
Over the last decade, the development of next‐generation sequencing techniques has led to the molecular dismantlement of adult and pediatric sarcoma, with the identification of multiple gene fusions ...associated with specific subtypes and currently integrated into diagnostic classifications. In this report, we describe and discuss the identification of a novel EWSR1‐UBP1 gene fusion in an adult patient presenting with multi‐metastatic sarcoma. Extensive pathological, transcriptomic, and genomic characterization of this tumor in comparison with a cohort of different subtypes of pediatric and adult sarcoma revealed that this fusion represents a novel variant of spindle cell rhabdomyosarcoma with features of TFCP2‐rearranged subfamily.
Aims
The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an ...adenomatous polyposis called MUTYH‐associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.
Methods
Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.
Results
The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.
Conclusions
Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.
Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MAP. Predisposition to other tumours in MAP patients is suspected but remains unclear. We report the first case of medulloblastoma in a MAP patient. The tumour presents a somatic mutation profile close to the mutational signature associated with MUTYH deficiency (SBS36), associated with driver pathogenic variants in well‐known genes involved in medulloblastoma tumorigenesis corresponding to G:C → T:A transversions. Therefore, medulloblastoma could be a rare manifestation associated with MAP.
The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and ...offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer‐related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV‐positive tumors, while HPV‐negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV‐positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = 1.25,5.17, P value = .010; HRPIK3CA = 2.43, 95%CI = 1.3,4.56, P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV‐positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.
What's new?
To develop personalized therapies for anal squamous cell carcinoma (ASCC), researchers need to learn more about the genomics of the disease. Here, the authors examined pathogenic variants in 571 cancer‐related genes identified in surgical samples collected form patients with ASCC. They found that more than 40% of patients carried mutations known to be targetable in other cancers. In patients with HPV‐positive tumors, pathogenic variants in KMT2C and PIK3CA were associated with worse overall survival. These results support genomic profiling to identify patients for clinical trials of targeted therapies.
In breast or ovarian cancer (BC/OC) patients with evocative personal and/or family history, multigene panel sequencing is performed on blood to diagnose hereditary predispositions. Additionally, ...BRCA1/BRCA2 testing can be performed on tumor sample for therapeutic purpose. The accuracy of multigene panel tumor analysis on BC/OC to detect predisposing germline pathogenic variants (gPV) has not been precisely assessed. By comparing sequencing data from blood and fresh‐frozen tumor we show that tumor genomic instability causes pitfalls to consider when performing tumor testing to detect gPV. Even if loss of heterozygosity increases germline signal in most cases, somatic copy number variants (CNV) can mask germline CNV and collapse point gPV variant allele frequency (VAF). Moreover, VAF does not allow an accurate distinction between germline and somatic pathogenic variants.
The highly conserved RAS-mitogen activated protein kinase (MAPK) signaling pathway is involved in a wide range of cellular processes including differentiation, proliferation, and survival. Somatic ...mutations in genes encoding RAS-MAPK components frequently occur in many tumors, making the RAS-MAPK a critical pathway in human cancer. Since the pioneering study reporting that let-7 miRNA acted as tumor suppressor by repressing the RAS oncogene, growing evidence has suggested the importance of miRNAs targeting the RAS-MAPK in oncogenesis. MiRNAs alterations in human cancers may act as a rheostat of the oncogenic RAS signal that is often amplified as cancers progress. However, specific mechanisms leading to miRNAs deregulation and their functional consequences in cancer are far from being fully elucidated. In this review, we provide an experimental-validated map of RAS-MAPK oncomiRs and tumor suppressor miRNAs from transmembrane receptor to downstream ERK proteins. MiRNAs could be further considered as potential genetic biomarkers for diagnosis, prognosis, or therapeutic purpose.
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