Journals Cold Spring Harbor Molecular C...

Cold Spring Harbor Molecular Case Studies
Lisa Welter, Liya Xu, Dillon McKinley, Angel E Dago, Rishvanth K Prabakar, Sara Restrepo-Vassalli, Kevin Xu, Mariam Rodriguez-Lee, Anand Kolatkar, Rafael Nevarez, Carmen Ruiz, Jorge Nieva, Peter Kuhn, James B Hicks
Currently, clinical characterization of metastatic breast cancer is based on tissue samples taken at time of diagnosis. However, tissue biopsies are invasive and tumors are continuously evolving, which indicates the need for minimal invasive longitudinal assessment of the tumor. Blood-based liquid biopsies provide minimal invasive means for serial sampling over the course of treatment and the opportunity to adjust therapies based on molecular markers. Here, we aim to identify cellular changes that occur in breast cancer over the lifespan of an affected patient through single-cell proteomic and genomic analysis of longitudinally sampled solid and liquid biopsies...
November 17, 2020: Cold Spring Harbor Molecular Case Studies
Francis P Lach, Sonia Singh, Kimberly A Rickman, Penelope D Ruiz, Raymond J Noonan, Kenneth B Hymes, Mark D DeLacure, Jennifer A Kennedy, Settara C Chandrasekharappa, Agata Smogorzewska
Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand crosslinks. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels, and point and splicing variants. Genotype-phenotype associations in FA are complex and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear...
November 10, 2020: Cold Spring Harbor Molecular Case Studies
Timothy Tidwell, Malia Deshotel, Janice Palumbos, Chris Miller, Pinar Bayrak-Toydemir, John C Carey
The archain 1 (ARCN1) gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in ARCN1 have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5- year-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the ARCN1-related syndrome caused by a novel de novo intronic variant...
November 5, 2020: Cold Spring Harbor Molecular Case Studies
Dong-Anh Khuong-Quang, Lauren M Brown, Marie Wong, Chelsea Mayoh, Alexandra Sexton-Oates, Amit Kumar, Mark Pinese, Sumanth Nagabushan, Loretta Lau, Louise E Ludlow, Andrew J Gifford, Michael Rodriguez, Jayesh Desai, Stephen B Fox, Michelle Haber, David S Ziegler, Jordan R Hansford, Glenn M Marshall, Mark J Cowley, Paul G Ekert
The identification of rearrangements driving expression of Neurotrophic Receptor Tyrosine Kinase (NTRK) family kinases in tumours has become critically important due to the availability of effective, specific inhibitor drugs. Whole genome sequencing (WGS) combined with RNA Sequencing (RNAseq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L-NTRK fusions identified in two paediatric central nervous system cancers and an extracranial solid tumour using WGS and RNAseq. These fusions arose either through a simple balanced rearrangement, or in the context of a complex chromoplexy event...
November 3, 2020: Cold Spring Harbor Molecular Case Studies
Lane T Savage, Stacie D Adams, Kiely N James, Shimul Chowdhury, Surender Rajasekaran, Jeremy W Prokop, Caleb P Bupp
Rapid whole genome sequencing (rWGS) allows for a diagnosis to be made quickly and impact medical management, particularly in critically ill children. Variants identified by this approach are often not identified using other testing methodologies, such as carrier screening or gene sequencing panels, targeted panels, or chromosomal microarrays. However, rWGS can identify variants of uncertain significance (VUS), which challenges clinicians in the rapid return of information to families. Here we present a case of the metabolic condition D-bifunctional protein deficiency in a neonate with epilepsy and hypotonia born to consanguineous parents...
October 28, 2020: Cold Spring Harbor Molecular Case Studies
Bing Xu, Anu Amallraja, Padmapriya Swaminathan, Rachel Elsey, Christel Davis, Stephanie Theel, Sarah Viet, Jason Petersen, Amy Krie, Gareth Davies, Casey B Williams, Erik Ehli, Tobias Meissner
Metastatic breast cancer is one of the leading causes of cancer related death in women. Limited studies have been done on the genomic evolution between primary and metastatic breast cancer. We reconstructed the genomic evolution through the sixteen year history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long term exposure to hormonal therapy. Genomic and transcriptome profiling was performed on primary breast tumor (2002), initial recurrence (2012) and liver metastasis (2015) samples...
October 2, 2020: Cold Spring Harbor Molecular Case Studies
Tammarah Sklarz, Stephanie N Hurwitz, Natasha L Stanley, Jane Juusola, Adam Bagg, Daria V Babushok
Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation...
September 24, 2020: Cold Spring Harbor Molecular Case Studies
Nobuyuki Takahashi, Vinodh N Rajapakse, Lorinc Pongor, Suresh Kumar, Camille Tlemsani, Rebecca Erwin-Cohen, Howard A Young, Stephen Hewitt, Jun S Wei, Javed Khan, Alejandro V Villarino, Jane B Trepel, Anish Thomas
Mismatch repair-deficient (dMMR) cancers generate a substantial number of immunogenic neoantigens, rendering them sensitive to immunotherapy. Yet, there is considerable variability in responses, and roughly one-half of dMMR cancers are refractory to immunotherapy. Here we study a patient with dMMR lung cancer refractory to immunotherapy. The tumor exhibited typical dMMR molecular features, including exceptionally high frameshift insertions and deletions (indels). Despite the treatment inducing abundant intratumoral T-cell infiltrates, it failed to elicit tumor regression, pointing to the T cells lacking cytotoxic activity...
October 2020: Cold Spring Harbor Molecular Case Studies
Lara Kamal, Sarah B Pierce, Christina Canavati, Amal Abu Rayyan, Tamara Jaraysa, Orit Lobel, Suhair Lolas, Barbara M Norquist, Grace Rabie, Fouad Zahdeh, Ephrat Levy-Lahad, Mary-Claire King, Moien N Kanaan
Fanconi anemia is a genetically and phenotypically heterogeneous disorder characterized by congenital anomalies, bone marrow failure, cancer, and sensitivity of chromosomes to DNA cross-linking agents. One of the 22 genes responsible for Fanconi anemia is BRIP1 , in which biallelic truncating mutations lead to Fanconi anemia group J and monoallelic truncating mutations predispose to certain cancers. However, of the more than 1000 reported missense mutations in BRIP1 , very few have been functionally characterized...
October 2020: Cold Spring Harbor Molecular Case Studies
Ajay Gupta, Jennifer A Belsky, Kathleen M Schieffer, Kristen Leraas, Elizabeth Varga, Sean D McGrath, Selene C Koo, Vincent Magrini, Richard K Wilson, Peter White, Elaine R Mardis, Kris R Jatana, Catherine E Cottrell, Bhuvana A Setty
Infantile fibrosarcoma (IFS) is nearly universally driven by gene fusions involving the NTRK family. ETV6-NTRK3 fusions account for ∼85% of alterations; the remainder are attributed to NTRK-variant fusions. Rarely, other genomic aberrations have been described in association with tumors identified as IFS or IFS-like. We describe the utility of genomic characterization of an IFS-like tumor. We also describe the successful treatment combination of VAC (vincristine, actinomycin, cyclophosphamide) with tyrosine kinase inhibitor (TKI) maintenance in this entity...
October 2020: Cold Spring Harbor Molecular Case Studies
Erica Sanford, Marilyn C Jones, Matthew Brigger, Monia Hammer, Lucia Giudugli, Stephen F Kingsmore, David Dimmock, Matthew N Bainbridge
Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c...
October 2020: Cold Spring Harbor Molecular Case Studies
Alessia Pancaldi, Lei Peng, Daniel S Rhee, Emily Dunn, Jessica A Forcucci, Deborah Belchis, Christine A Pratilas
We report a case of a DICER1 -associated EWSR1 -rearranged malignant primitive neuroectodermal tumor (PNET) arising in a patient with DICER1 tumor predisposition syndrome. A 16-yr-old female with a history of multinodular goiter presented with a widely metastatic abdominal small round blue cell tumor with neuroectodermal differentiation. EWSR1 gene rearrangement was identified in the tumor by fluorescence in situ hybridization (FISH). Genetic analysis revealed biallelic pathogenic DICER1 variation. The patient was treated with an aggressive course of chemotherapy, surgery, and radiation with complete pathologic response...
October 2020: Cold Spring Harbor Molecular Case Studies
George Zanazzi, Benjamin L Liechty, Danielle Pendrick, Olga Krasnozhen-Ratush, Matija Snuderl, Jeffrey C Allen, James H Garvin, Mahesh M Mansukhani, Kevin A Roth, Susan J Hsiao
We report a case of a slow-growing, diffuse, infiltrating glioma in the right brainstem of a 9-yr-old boy. The tumor was negative by immunohistochemical staining for histone H3 K27M, BRAF V600E, and IDH1 R132H mutations. Fluorescence in situ hybridization did not reveal a BRAF duplication. Genomic profiling of the tumor, by DNA methylation array and cancer whole-exome and transcriptome sequencing, was performed. This analysis showed copy-number alterations, including gains of several chromosomes. In addition, a novel fusion involving the first 17 exons of FGFR2 fused to exon 2 of VPS35 was identified...
October 2020: Cold Spring Harbor Molecular Case Studies
Monica H Wojcik, Pankaj B Agrawal
Congenital anomalies, or structural birth defects, are common in the population, with 2-3% of infants estimated to have at least one major congenital malformation and countless others with minor malformations of lesser cosmetic or medical importance. As congenital malformations are major drivers of morbidity and mortality, representing the leading cause of infant mortality in the United States, there is substantial interest in understanding the underlying etiologies - particularly if modifiable causes may be identified or pre- or postnatal treatments can be offered...
August 21, 2020: Cold Spring Harbor Molecular Case Studies
Elena Busch, Simon Kreutzfeldt, Abbas Agaimy, Gunhild Mechtersheimer, Peter Horak, Benedikt Brors, Barbara Hutter, Martina Fröhlich, Sebastian Uhrig, Philipp Mayer, Evelin Schröck, Albrecht Stenzinger, Hanno Glimm, Dirk Jäger, Christoph Springfeld, Stefan Fröhling, Stefanie Zschäbitz
Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAF V600E -mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors...
August 2020: Cold Spring Harbor Molecular Case Studies
Erica Sanford, Terence Wong, Katarzyna A Ellsworth, Elizabeth Ingulli, Stephen F Kingsmore
Relatively little is known about phenotypic variability in nonsyndromic nephropathy associated with the gene encoding the WT1 transcription factor. We report a 12-mo-old female who presented with vomiting, diarrhea, and fatigue in the setting of renal failure and malignant hypertension. Trio ultra-rapid whole-genome sequencing identified a novel, likely pathogenic, de novo missense variant (c.485T > A, p.Val162Asp) in WT1 in 46 h, consistent with a diagnosis of nephrotic syndrome type 4 (NPHS4; OMIM 256370)...
August 2020: Cold Spring Harbor Molecular Case Studies
Ashley N Anderson, Danielle McClanahan, James Jacobs, Sophia Jeng, Myles Vigoda, Aurora S Blucher, Christina Zheng, Yeon Jung Yoo, Carolyn Hale, Xiaoming Ouyang, Daniel Clayburgh, Peter Andersen, Jeffrey W Tyner, Anna Bar, Olivia M Lucero, Justin J Leitenberger, Shannon K McWeeney, Molly Kulesz-Martin
Although cutaneous squamous cell carcinoma (cSCC) is treatable in the majority of cases, deadly invasive and metastatic cases do occur. To date there are neither reliable predictive biomarkers of disease progression nor FDA-approved targeted therapies as standard of care. To address these issues, we screened patient-derived primary cultured cells from invasive/metastatic cSCC with 107 small-molecule inhibitors. In-house bioinformatics tools were used to cross-analyze drug responses and DNA mutations in tumors detected by whole-exome sequencing (WES)...
August 2020: Cold Spring Harbor Molecular Case Studies
Josue A Flores Daboub, Johanes Fred Grimmer, Alice Frigerio, Whitney Wooderchak-Donahue, Ryan Arnold, Jeff Szymanski, Nicola Longo, Pinar Bayrak-Toydemir
Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic "second hit" inactivating changes in RASA1 are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity...
August 2020: Cold Spring Harbor Molecular Case Studies
Erica L Macke, Joel A Morales-Rosado, Aditi Gupta, Christopher T Schmitz, Teresa Kruisselbrink, Brendan Lanpher, Eric W Klee
Pathogenic variants in the XPC complex subunit, DNA damage recognition, and repair factor ( XPC ) are the cause of xeroderma pigmentosum, group C (MIM: 278720). Xeroderma pigmentosum is an inherited condition characterized by hypersensitivity to ultraviolet (UV) irradiation and increased risk of skin cancer due to a defect in nucleotide excision repair (NER). Here we describe an individual with a novel missense variant and deletion of exons 14-15 in XPC presenting with a history of recurrent melanomas. The proband is a 39-yr-old female evaluated through the Mayo Clinic Department of Clinical Genomics...
August 2020: Cold Spring Harbor Molecular Case Studies
Daniel Gamu, William T Gibson
Within histone H3, lysine 27 (H3K27) is one of the residues that functions as a molecular switch, by virtue of being subject to mutually exclusive post-translational modifications that have reciprocal effects on gene expression. Whereas acetylation of H3K27 is associated with transcriptional activation, methylation at this residue causes transcriptional silencing; these two modifications are mutually exclusive. Establishment of these epigenetic marks is important in defining cellular identity and for maintaining normal cell function, as evidenced by rare genetic disorders of epigenetic writers involved in H3K27 post-translational modification...
August 2020: Cold Spring Harbor Molecular Case Studies
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