Miika Mehine
A5040117147- Uterine Myomas and Treatments
- Cancer Genomics and Diagnostics
- Genomics and Rare Diseases
- Genetic factors in colorectal cancer
- Retinal Development and Disorders
- Lung Cancer Research Studies
- DNA Repair Mechanisms
- Photoreceptor and optogenetics research
- Retinal Diseases and Treatments
- BRCA gene mutations in cancer
- Endometriosis Research and Treatment
- Renal cell carcinoma treatment
- Neuroendocrine Tumor Research Advances
- interferon and immune responses
- RNA modifications and cancer
- Gynecological conditions and treatments
- Renal and related cancers
- PARP inhibition in cancer therapy
- CRISPR and Genetic Engineering
- Genomic variations and chromosomal abnormalities
- Molecular Biology Techniques and Applications
- Sarcoma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Endometrial and Cervical Cancer Treatments
- Neuroblastoma Research and Treatments
Memorial Sloan Kettering Cancer Center
2022-2025
Molecular Oncology (United States)
2022-2025
University of Helsinki
2014-2024
Blueprint Genetics (Finland)
2019-2024
Kettering University
2022-2024
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2023
National Institutes of Health
2023
Ambry Genetics (United States)
2023
Hospital Clínico San Carlos
2023
Broad Center
2023
Uterine leiomyomas, or fibroids, are benign tumors that affect millions of women worldwide and can cause considerable morbidity. To study the genetic basis this tumor type, we examined 18 uterine leiomyomas derived from 17 different patients by exome sequencing identified tumor-specific mutations in mediator complex subunit 12 (MED12) gene 10. Through analysis 207 additional tumors, determined MED12 is altered 70% (159 225) a total 80 patients. The Mediator 26-subunit transcriptional...
Uterine leiomyomas are benign but affect the health of millions women. A better understanding molecular mechanisms involved may provide clues to prevention and treatment these lesions.We performed whole-genome sequencing gene-expression profiling 38 uterine corresponding myometrium from 30 women.Identical variants observed in some separate tumor nodules suggested that have a common origin. Complex chromosomal rearrangements resembling chromothripsis were feature leiomyomas. These best...
Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation...
Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers1–5. However, variants of uncertain significance limit the utility test results. Thus, there is a need for functional characterization and classification all facilitate management individuals with these variants. Here we analysed possible single-nucleotide from exons 15 26 that encode DNA-binding domain hotspot pathogenic missense To enable this, used saturation...
Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many 70% of uterine leiomyomas harbour specific mutations exon 2 mediator subunit 12 (MED12). In this work, examined role MED12 other tumour types. The frequency was analysed altogether 1158 tumours direct sequencing. spectrum included mesenchymal (extrauterine leiomyomas, endometrial polyps,...
The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected tumour-only sequencing, which were based an analysis 17 152 cancers.
Abstract Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer have historically relied upon genome-wide markers, the adaptation targeted clinical sequencing panels presents an opportunity incorporate into routine diagnostic workflows. We show that global ancestral contributions and admixture continental populations can be quantitatively inferred using markers captured by MSK-IMPACT panel. In a...
Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those syndromic features. To assess whether expanded of GIST could identify hereditary cancer predisposition, we analyzed matched tumor-germline sequencing results from 103 GISTs over a 6-year period. Germline pathogenic/likely pathogenic (P/LP) variants in GIST-associated genes (SDHA, SDHB, SDHC, NF1, KIT) were identified 69% KIT/PDGFRA-wildtype GISTs, 63% whom did not have any personal or family...
Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present advanced disease and treated cytotoxic therapy. Genomic biomarkers prognostic of outcomes have been challenging to identify. Herein leveraging a cohort 2,336 spanning stages, we characterize the genomic clinical correlates in PDAC. We show that subtype wild-type tumors is associated early onset, distinct somatic germline features, significantly better overall...
Mediator regulates transcription by connecting gene-specific factors to the RNA polymerase II initiation complex. We recently discovered exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and been detected leiomyosarcomas, extrauterine leiomyomas endometrial polyps, colorectal cancers. All missense changes or in-frame insertions/deletions. Here,...
Abstract Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that typically associated with tobacco exposure and inactivation of RB1 TP53 genes. Here, we performed detailed clinicopathologic, genomic, transcriptomic profiling an atypical subset SCLC lacked co-inactivation arose in never/light smokers. We found most cases were chromothripsis—massive, localized chromosome shattering—recurrently involving 11 or 12 resulting extrachromosomal amplification CCND1 co-amplification...
<p>Chromosomal architecture of chromothripsis and amplifications. <b>A,</b> Integrated SV CNA analysis in two representative cases confirming the hallmark features suggesting formation ecDNA micronucleation as a mechanism gene amplification (see “Results”). Allele-specific CN for each genomic segment is shown on left <i>y</i>-axis. Genomic segments which greater than 5 times chromosomal baseline are indicated orange shades to highlight most significant events....
<div>Abstract<p>Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that typically associated with tobacco exposure and inactivation of <i>RB1</i> <i>TP53</i> genes. Here, we performed detailed clinicopathologic, genomic, transcriptomic profiling an atypical subset SCLC lacked co-inactivation arose in never/light smokers. We found most cases were chromothripsis—massive, localized chromosome shattering—recurrently involving 11 or 12 resulting...
<p>Cohort selection and clinicopathologic characteristics. <b>A,</b> Schematic diagram of <i>RB1</i> <i>TP53</i> inactivation (outer doughnut) smoking status (inner in a cohort 600 consecutive SCLC that underwent tNGS by MSK-IMPACT. was determined based on integrated genomic IHC data (see “Results”). <b>B,</b> Tabular (<b>C</b>) pictorial summary pathologic sample characteristics sequencing assays performed for 20 patients...
<p>Comparison of aSCLC vs. <i>RB1</i><sup>−</sup>/<i>TP53</i><sup>−</sup> nsSCLC: the dual model SCLC pathogenesis in never-smokers. <b>A,</b> Lines evidence for a histogenetic relationship between and carcinoids or their progenitors, including histologic carcinoid histotype at least one sample (see also <a href="#fig1" target="_blank">Figs. 1C</a> href="#fig5" target="_blank">5A</a>), expression lung...
<p>Chromothripsis and corresponding cancer gene amplifications losses. <b>A,</b> Representative Circos plots of SVs CNAs across the genome by WGS. Outer band shows an ideogram chromosome positions cytogenetic bands. Second depicts total CN, third minor allele CN. The inner circle as arcs connecting two relevant genomic points identified three algorithms (see “Methods”). in key genes regions chromothripsis (red, amplifications; blue, deletions) are displayed. for all cases...
<p>Supplementary Figure S1. Detailed morphologic and immunohistochemical findings: Case A01. Supplementary S2. A08. S3. A17. S4. A20. S5. Mutational signatures in atypical SCLC (aSCLC), never-smoker with RB1–/TP53– (nsSCLC) smoking-associated (sSCLC) analyzed by MSK-IMPACT. S6. Circos plots showing structural variants copy number alterations across the genome from all cases WGS. S7. Chromothripsis assessment targeted NGS (MSK-IMPACT) versus S8. RNAseq for non-recurrently amplified...
<p>Outcome and treatment responses. <b>A,</b> Kaplan–Meier analysis of the disease-specific overall survival assessed from time diagnosis. <b>B,</b> Pie chart summarizing radiologic response to platinum-based chemotherapy received in any line therapy. <b>C,</b> Swimmer plot modalities used time-on-treatment, with pathologic samples collected performed indicated. CR, complete response; PD, progressive disease; PR, partial SD, stable disease.</p>
<p>Multisample analysis from all temporally or spatially distinct samples obtained for each patient. <b>A,</b> Conservation of chromothripsis and corresponding amplifications across with available data individual patients. ^ indicates lower purity compared the other sample same patient (Supplementary Table S5); CN values in such may be falsely low. * detected by WGS only, but not tNGS. N/A, available: without NGS IHC. Sample numbering is chronologic S3)....
<p>Mutation and CNA landscape of aSCLC. <b>A,</b> Mutations CNAs in aSCLC comparison to the control groups sSCLC (<i>n</i> = 206) pulmonary carcinoids 157) analyzed by MSK-IMPACT. OncoPrint summarizing assays performed overall genomic features: MSI vs. MSS, TMB, signature (full analysis shown Supplementary Fig. S5). Case A09 lacked a matched normal DNA sample was therefore excluded from MSI, analysis. Displayed alterations include selected recurrently altered...
Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations FH mutually exclusive determine the contribution on HLRCC patients' myomagenesis. exons 1 2 mutation screening 2SC immunohistochemistry indicative for deficiency performed a comprehensive series (122 specimens) sporadic (66 tumours....