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Tag Archives: Molecular Pathology Selected Abstracts

Molecular pathology selected abstracts

February 2024—Precision cancer medicine relies heavily on understanding the genomic landscape of tumors. Prior comparisons between African and European ancestry, though based on limited data, have indicated distinct differences in the landscape of cancer driver alterations between these populations. Whether these discrepancies are mediated by genetic variants or environmental influences is still unclear. Accurately characterizing ancestry-associated genomic alterations is essential to not only improving genomic diagnostic testing but also to developing targeted therapies, biomarkers, and personalized cancer care for diverse populations. The authors conducted a study that leveraged two large genomic cohorts to investigate the relationship between genomic alterations and African ancestry in six common cancers: prostate, pancreas, ovary, nonsmall cell lung cancer (NSCLC), colorectal, and breast.

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Molecular pathology selected abstracts

December 2023—Immune checkpoint blockade therapy has dramatically altered treatment options for a variety of cancers. A high tumor mutation burden (TMB) is considered one of the strongest predictors of immune checkpoint blockade response. DNA mismatch repair deficiency (MMRd) is associated with a high TMB, and many tumors associated with MMRd have shown excellent response to immunotherapy. However, most MMRd tumors do not show durable response to treatment with immune checkpoint blockade (ICB). Intratumor heterogeneity may further mediate response to ICB therapy.

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Molecular pathology selected abstracts

November 2023—Dilated cardiomyopathy is characterized by dilation and weakening of one or both ventricles combined with impaired contractility. Although several external etiologies are associated with dilated cardiomyopathy (DCM), a familial form (comprising about half the known cases of DCM) has symptoms that tend to arise in mid-adulthood. Despite the genetic nature of the familial form, little is known about the genetic profile of the disease. Black patients have an increased familial risk of DCM and often have a worse prognosis. The authors conducted a study in which they used genomic ancestry to compare the rare variant genetic architecture of DCM within a diverse patient population.

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Molecular pathology selected abstracts

October 2023—Ovarian cancer is the eighth most common cancer in women. There are several histological types of ovarian neoplasms, and all rank among the deadliest gynecological cancers. However, those with homologous recombination deficiency (HRD) may benefit from a recently discovered category of drugs, called poly ADP-ribose polymerase inhibitors (PARPi). The homologous recombination repair pathway, which is responsible for repairing double-strand DNA damage, involves several genes, including BRCA1, BRCA2, and ATM. People with germline or somatic deleterious alterations of these genes are at higher risk of certain malignancies, such as ovarian, breast, prostate, and pancreatic cancers.

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Molecular pathology selected abstracts

September 2023—Neurodegenerative diseases are a broad group of disorders characterized by progressive loss of nerve cells in the central or peripheral nervous system. These diseases are often chronic and incurable, with symptoms ranging from cognitive decline to motor or sensory dysfunction. There are many types of neurodegenerative diseases, with various underlying etiologies. One group of diseases, the synucleinopathies, are associated with the misfolding and aggregation of the protein α-synuclein. This group includes disease entities such as Parkinson disease, dementia with Lewy bodies, and multiple-system atrophy.

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Molecular pathology selected abstracts

Augstus 2023—Atypical hemolytic uremic syndrome is a rare, potentially life-threatening thrombotic microangiopathy. The disorder causes tiny blood clots to form in blood vessels and results in organ damage. Clinical findings in atypical hemolytic uremic syndrome (aHUS) include hemolytic anemia, low platelet count, and acute kidney failure. In many cases, HUS is caused by Shiga toxin-producing E. coli, other infections, or certain medications, or it can result from other health conditions. The label “atypical” is used to delineate hemolytic uremic syndrome that is not due to any of these common causes.

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Molecular pathology selected abstracts

July 2023—Non-muscle-invasive bladder cancer accounts for the majority of bladder tumors and is typically treated with transurethral resection of the bladder tumor followed by adjuvant intravesical Bacillus Calmette-Guérin instillations. However, the long-term effectiveness of Bacillus Calmette-Guérin (BCG) is limited, and patients with recurrent or progressive disease have lower survival rates. Understanding the genetic makeup of tumors and identifying molecular subtypes associated with BCG response could provide valuable insights that aid in developing personalized treatments. The authors conducted a study in which they performed whole-transcriptome sequencing of non-muscle-invasive bladder cancers (NMIBCs) from 132 patients who had never received BCG treatment and 44 patients whose cancer recurred after BCG treatment. Based on these patients’ results, the authors identified three unique molecular subtypes among the tumors—BRS1, 2, and 3. Patients with BRS3 showed increased epithelial-to-mesenchymal transition pathway activity and their tumors were enriched for mutations associated with the extracellular matrix when compared with the other two subtypes.

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Molecular pathology selected abstracts

June 2023—Endometriosis is defined by the presence of endometrial-like tissue outside of the uterus and can cause debilitating pelvic pain and often infertility. It has also been associated with a range of reproductive, metabolic, inflammatory, and chronic pain conditions. While it is fairly common, affecting five to 10 percent of women of reproductive age, treatment options are limited, and the precise causes of endometriosis, as well as its relationship with other conditions that cause chronic pain, remain unclear. Studies estimate that endometriosis has a heritability of approximately 50 percent. Nine genomewide association studies (GWAS) of endometriosis involving women of European and East Asian ancestry were reported prior to this study.  

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Molecular pathology selected abstracts

May 2023—One in four children worldwide have unregistered births according to 2019 data from UNICEF. While efforts are underway to mitigate this staggering statistic by prioritizing documentation of birth, millions of people still cannot prove their date of birth. Age-assessment methods, most commonly used in forensics, have relied on bone radiography. However, more recently, chronologic age-prediction models have been developed based on knowledge of how epigenetics change with age. Epigenetics is the modification of gene expression without changing the underlying genetic code.

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Molecular pathology selected abstracts

April 2023—Clonal hematopoiesis of indeterminate potential refers to the clonal expansion of hematopoietic stem cells that harbor a somatic mutation in people who do not exhibit hematological symptoms. This phenomenon is common in the elderly and associated with an increased risk of hematological malignancies, cardiovascular disease, infection, and all-cause mortality. Several somatic alterations are frequently detected in clonal hematopoiesis of indeterminate potential (CHIP), but the medical community’s understanding of the underlying genetic predisposition to CHIP is limited. The authors conducted a large-scale exome-sequencing study involving more than 600,000 people to characterize CHIP status and discover rare somatic variants and possible predisposing germline alterations. The prevalence of CHIP was 15 percent by 75 years of age, and the affected individuals were more likely to be heavy smokers, in agreement with previous studies.  

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Molecular pathology selected abstracts

March 2023—The Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists published a formalized somatic variant classification system in 2017. The tiered system stratifies variants based on clinical importance, taking into account how variants affect cancer diagnosis, prognosis, or treatment strategies. Somatic variants with strong clinical significance, including those that are associated with FDA-approved therapies or included in professional guidelines, are tier one; variants with potential clinical significance are tier two; variants of unknown significance are tier three; and benign variants are tier four. The authors, members of the AMP Variant Interpretation Across Testing Laboratories Working Group, assessed how laboratories are using the AMP/ASCO/CAP guidelines and whether there is good concordance among laboratories in applying the guidelines to variant interpretation. A somatic variant interpretation challenge was sent to participating laboratories.  

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Molecular pathology selected abstracts

February 2023—Systemic lupus erythematosus is an autoimmune disease that affects multiple organ systems and is most prevalent in women of Asian, Hispanic, and African ancestries. People with the heterogeneous disease experience major organ damage, which primarily affects the kidneys, skin, heart, and joints. Transcriptomic studies of systemic lupus erythematosus (SLE) have implicated increased type 1 interferon signaling, dysregulated lymphocyte activation, and failure of apoptotic clearance as hallmarks of the disease. Many genes are near the approximately 100 loci associated with SLE. Despite the use of flow cytometry and transcriptome profiling to characterize the role of circulating immune cells in SLE, there is not a complete census of circulating immune cells in the disease, and characterizing the genetic associations has been challenging.

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Molecular pathology selected abstracts

January 2023—An international group of scientists and clinicians identified the molecular cause of a rare neurodevelopmental syndrome affecting children worldwide. This discovery was made possible through such publicly available online databases as MyGene2, GeneMatcher, and Matchmaker Exchange, which match genotypic profiles with phenotypic profiles of rare diseases.

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Molecular pathology selected abstracts

November 2022—Spontaneous coronary artery dissection is an uncommon cause of acute heart attack. It is not associated with high cholesterol or atherosclerosis but, instead, occurs when a small tear or separation in the wall of the coronary artery leads to blood entering a false lumen, occluding blood flow and impairing oxygenation of the heart muscle.

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Molecular pathology selected abstracts

September 2022—The widespread availability of next-generation sequencing-based somatic mutation analysis of solid tumors has led to the routine identification of patients eligible for FDA-approved targeted therapies, including immunotherapies. However, validated targeted therapies are available for only a small number of mutations, thereby preventing many patients from realizing the benefits of these life-extending modalities. With a focus on reducing the gap in eligibility for targeted therapy, the authors conducted a large-scale retrospective analysis of interactions between mutations, drug responses, and long-term cancer survival outcomes. They performed the analysis using the nationwide U.S.-based Flatiron Health–Foundation Medicine clinicogenomic database. The authors analyzed data on more than 40,000 patients from approximately 280 cancer clinics.

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Molecular pathology selected abstracts

July 2022—Although offspring share similar DNA, their physical and behavioral differences are multifactorial. One of those factors is epigenetics, the chemical and structural modifications of DNA by proteins and enzymes. Whereas the DNA sequence is relatively stable, epigenetic modifications are dynamic, as they are critical to controlling gene expression in response to cellular development and environment. Reproductive cells, or gametes, carry half the normal set of chromosomal DNA. Advances in molecular technologies demonstrate that this DNA is epigenetically modified to influence traits of future offspring, referred to as transgenerational epigenetic inheritance.

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Molecular pathology selected abstracts

May 2022—The most common cause of death related to gynecological malignancies is epithelial ovarian cancer. One of the biggest challenges to treating this disease is the lack of reliable biomarkers for identifying its underlying precancerous and early stages. The study of epigenetic changes in epithelial cells shows some promise for detecting early ovarian cancer. In previous studies, DNA methylation performed on blood samples demonstrated important epigenetic changes associated with ovarian cancer but did not yield realistic screening parameters due to the heterogeneity of blood samples. To identify ovarian cancer risk earlier, the authors conducted a molecular epigenetic analysis of cervical epithelial cells derived from the Mullerian duct and collected using the ThinPrep system to establish a methylation model index called the Women’s Risk Identification for Ovarian Cancer [WID-OC] index.

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Molecular pathology selected abstracts

July 2021—The accurate diagnosis of malignant pleural mesothelioma is important because of its association with asbestos inhalation and because it is an aggressive tumor with poor outcome despite multimodal treatment. Unfortunately, however, diagnosing malignant pleural mesothelioma is not straightforward. Initial diagnosis often occurs on small biopsies, and the disease has morphologic overlap not only with other neoplasms that affect the lungs and pleura, such as solitary fibrous tumor or synovial sarcoma, but also with reactive conditions, such as reactive mesothelial hyperplasia or sclerosing fibrous pleuritis. While immunohistochemical markers can provide ancillary information, many of them are nonspecific and can lead to diagnostic dilemmas. Sequencing of cancer genes can help in some situations but cannot provide a definitive diagnosis.

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Molecular pathology selected abstracts

June 2021—In myeloid malignancies, identification of genetic abnormalities informs diagnostic classification, aids risk stratification, and often predicts response to clinical therapy. Multiple methodologies generally are necessary to detect these abnormalities given the diversity of genetic occurrences, which can range from single-nucleotide variants to chromosomal translocations.

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Molecular pathology selected abstracts

May 2021—Autoinflammatory and rheumatologic disorders in adults often present with overlapping clinical features and are challenging to treat. A genotype-first approach has been helpful to guide proper clinical management in other analogous disease settings. The authors conducted a study in which they analyzed the exome/genome sequencing data of peripheral blood cells from two large cohorts: 1,477 people who had undiagnosed recurrent fevers or systemic inflammation, or both, and 1,083 people affected by atypical, unclassified disorders who were identified through the National Institutes of Health Undiagnosed Diseases Program. Recurrent novel missense mutations affecting the methionine-41 codon of the X-linked gene UBA1, which codes for a major E1 enzyme that initiates ubiquitylation, were identified in three men. These UBA1 mutations were confirmed as somatic because they were not found in the matched fibroblasts of the affected individuals and their family members.

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Molecular pathology selected abstracts

March 2021—High tumor mutational burden in certain cancers has become an established biomarker for predicting a response to immune checkpoint inhibitor therapy and longer overall survival after such treatment. The immune checkpoint inhibitor (ICI) pembrolizumab, for example, has recently been approved by the FDA for patients whose solid tumors, regardless of histology, have a high tumor mutational burden (TMB), defined as 10 or more mutations per megabase. TMB, assessed by next-generation sequencing, varies considerably among cancers and can range from 0.01 to more than 1,000 somatic mutations per megabase of sequenced genome. The presumed mechanism for the enhanced responsiveness to immunotherapy associated with high TMB is the creation, by somatic mutation, of potentially immunogenic neoantigens that facilitate an enhanced antitumor immune response. Given this presumed mechanism, the authors addressed whether high TMB levels, which are associated with better cancer outcomes in patients treated with immune checkpoint inhibitors, might also lead to better outcomes for patients treated with other anti-cancer therapies.

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Molecular pathology selected abstracts

February 2021—Beta-thalassemia and sickle cell disease are common hereditary conditions that can have life-threatening complications. Both diseases are caused by genetic alterations affecting the beta subunit of hemoglobin. Mutations that reduce or prevent the synthesis of the beta-globin protein cause beta-thalassemia, a disease characterized by inadequate red blood cell production and, therefore, anemia. In contrast, sickle cell anemia results from a specific point mutation in the beta-globin gene that causes the resulting protein to polymerize. These protein polymers form rigid fibers that affect the stability of the red blood cell and cause its characteristic sickling deformity. Destruction of the aberrant red blood cells leads to anemia, and the sickled cells can also cause painful vaso-occlusive episodes and tissue damage.

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Molecular pathology selected abstracts

January 2021—Circular RNAs are a novel class of recently discovered RNA with emerging roles in gene regulation, homeostasis, and disease. They are generated by ligation of the distal ends to form a circular product and originate from parental-coding genes and noncoding regions of the genome. Circular RNAs (circRNAs) are widespread in the plant and animal kingdoms and conserved in multiple species. Recent literature suggests that they inhibit micro RNA (mi­RNA), an important class of RNAs that regulates gene expression by binding to messenger RNAs (mRNA). Therefore, the post-transcriptional regulation of gene expression by RNAs has expanded to include a circRNA–mi­RNA–mRNA regulatory network.

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Molecular pathology selected abstracts

December 2020—Next-generation sequencing-based mutation testing of various cancer types is clinically indicated and widely used to diagnose disease, inform potential therapeutic targets, prognosticate disease course, and monitor responses to targeted and nontargeted therapies. The genetic variants discovered by tumor-based next-generation sequencing (NGS) can be somatically acquired by the neoplastic cells or a fixed inherited component of the patient’s germline genome. Distinguishing the germline versus somatic status of tumor NGS-defined variants is of significant clinical importance not only for patient care but possibly for patients’ families. Because many cancers have a substantial inherited component, the discovery of a pathogenic germline mutation by tumor-based NGS may have substantial familial implications. For example, being aware of a cancer risk allele, such as BRCA1, can lead to the use of highly effective interventions to prevent or treat the related cancer in family members. Consensus guidelines recommend germline genetic testing only for those cancer patients who have a clinical presentation or family history suggestive of hereditary disease.

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Molecular pathology selected abstracts

November 2020—Sporadic vascular malformations are congenital malformations of arteries, veins, capillaries, or lymphatic vessels, or a combination of these, and are associated with significant morbidity. The majority of them are caused by postzygotic somatic pathogenic variants in oncogenes in the PI3K-MTOR and RAS-MAPK pathways, including within PIK3CA, TEK, MAP2K1, BRAF, and KRAS. Investigators have assessed whether therapeutic agents targeting these pathways should be used to augment or replace traditional surgical management. But because these somatic variants are restricted to cells within the tissue of vascular malformations (VM), it is necessary to conduct genetic testing on the surgically resected tissue to qualify patients for trials of targeted therapies. Approximately 10 percent of cell-free DNA (cfDNA) originates from endothelial cells.

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Molecular pathology selected abstracts

October 2020—An increase in the number of copies of a gene, or amplification, is regarded as the most common gain-of-function alteration across various cancer types. The authors developed a bioinformatics tool (Amplicon Architect) to identify extrachromosomal oncogene (ecDNA) amplification from whole genome sequencing (WGS) data based on three characteristic features: circularity of ecDNA, absence of a centromere, and high levels of amplification. The tool was validated in 44 cancer-derived cell lines known to have ecDNA. A combination of centromeric and noncentromeric FISH probes was used to identify extrachromosomal DNA, and the tool was able to classify 83 percent of these signals as representing circular ecDNA amplicons. Interestingly, some of these cases revealed the presence of concurrent extrachromosomal and intrachromosomal signals, suggesting that some ecDNA had reintegrated into the genome.

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Molecular pathology selected abstracts

September 2020—Whole genome methylation profiling is used to subclassify neuroepithelial tumors and soft tissue sarcomas. Extending its use to much more common cancers, such as prostate cancer, has the potential to benefit a large number of patients. Metastatic castration-resistant prostate cancer (mCRPC) is the incurable and lethal form of prostate cancer and consists of different subgroups with variable morphologies and genomic alterations. The emergence of distinct subtypes of mCRPC likely represents adaption of the cancer cells to treatment and the microenvironment. The authors conducted a study that integrated methylation profiling with genomic sequencing and RNA transcriptome analysis in 100 mCRPC tumors, yielding a comprehensive molecular profile of these metastatic tumors.

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Molecular pathology selected abstracts

August 2020—Patients and families suspected of having Mendelian diseases, syndromes thought to be caused by a single mutated gene, often undergo comprehensive next-generation sequencing to determine the underlying pathogenic variant. Whole exome sequencing, in which the coding regions of all genes are analyzed, is usually the preferred testing method. However, this identifies the diagnostic pathogenic variant in only 25 to 52 percent of cases. Whole genome sequencing appears to confer only marginal benefit over whole exome sequencing, presumably because the pathogenic variants likely are not missed by whole exome sequencing but may be misinterpreted as nondiagnostic. Among the variants that are difficult to interpret are those that affect RNA by directly influencing transcription, or altering normal splicing, or by mediating their effects through chromatin.

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Molecular pathology selected abstracts

July 2020—Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a rare but well-known full-body inflammatory skin condition that leads to life-threatening complications if untreated. The authors conducted a case study that involved a 44-year-old male who developed DiHS/DRESS after taking the combined antibiotic trimethoprim-sulfamethoxazole. Following standard treatment for this condition, the patient was started on high-dose prednisone, which provided no benefit. Subsequent tapering of prednisone advanced the disease to a toxic epidermal necrolysis-like condition. The patient was then given etanercept and high-dose intravenous immunoglobulin, without benefit. Next, the patient received cyclosporine, which resulted in some improvement but led to uncontrollable renal hypertension.

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Molecular Pathology Selected Abstracts

June 2020—The COVID-19 pandemic has focused the world’s attention on using sensitive high-throughput molecular diagnostic testing for the SARS-CoV-2 virus as a public health tool for “flattening the curve” of the infection. Although initial shortages of specialized polymerase chain reaction (PCR) testing reagents that plagued the early weeks of the pandemic have slowly improved (as of CAP TODAY press time), an obstacle to universal testing continues to be the first-step bottleneck of collecting respiratory tract samples for virus-specific reverse transcriptase-PCR (RT-PCR) testing. The traditional gold standard sample for COVID-19 testing has been a nasopharyngeal (NP) swab. However, nationwide shortages of NP swabs, personal protective equipment (PPE), and viral transport media have intermittently delayed the testing process. In an attempt to alleviate these critical sample-collection issues and promote more widespread testing, the medical community and other entities have been investigating alternative sample-collection procedures.

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Molecular Pathology Selected Abstracts

May 2020—Each year a growing number of novel viruses are discovered in the wild animal kingdom with the use of next-generation sequencing technology. However, the current method of functionally assessing the zoonotic potential—that is, the potential to be transmitted to humans—of novel viruses involves synthesis of viral genomes (tens of thousands of bases) and reverse genetic engineering to produce a recombinant virus. This is expensive and time-consuming, and it is not practical due to the scale of new viral strains being discovered. To overcome this hurdle, Letko, et al., developed a rapid and cost-effective method that could functionally assess a number of related viruses for zoonotic potential. The essential component of viral cross-species transmission is cell entry, which is a multi-step process involving attachment of the virus to the host cell surface, receptor engagement, processing of host proteases, and downstream membrane fusion.

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Molecular Pathology Selected Abstracts

April 2020—Prior to the recent novel coronavirus outbreak, the vast majority of coronaviruses that were known to be pathogenic in humans caused mild symptoms, with the exception of two strains. These included SARS (severe acute respiratory syndrome coronavirus [SARS-CoV]) and MERS (Middle East respiratory syndrome coronavirus [MERS-CoV]). SARS was documented as having emerged in the Guangdong province in southern China in 2002 and having caused at least 774 reported fatalities worldwide, while MERS, which was first detected in Saudi Arabia in 2012, was responsible for at least 858 fatalities worldwide.

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Molecular Pathology Selected Abstracts

March 2020—Microsatellite instability status in solid tumors is a critical biomarker for predicting tumor response to an immune checkpoint inhibitor drug. The immune system is more likely to attack those tumors that have a high degree of microsatellite instability, a consequence of the genomic instability that also leads to generation of the neoantigens the immune system is designed to recognize.

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Molecular Pathology Selected Abstracts

Overall survival rates for lung cancer patients receiving osimertinib

Guidelines recommend testing patients with advanced or metastatic nonsmall cell lung cancer (NSCLC) for epidermal growth factor receptor (EGFR) alterations because targeted treatment with a tyrosine kinase inhibitor (TKI) is available for patients with EGFR exon 19 deletions or L858R point mutations. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that selectively inhibits EGFR-TKI–sensitizing and EGFR p.Thr790Met-resistance mutations.

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Molecular pathology selected abstracts

Virtual staining of tissue slides to conserve precious diagnostic samples
January 2020—Precise classification of neoplasms improves risk stratification and the ability to apply targeted treatment options, enhancing patient care. These granular diagnostic classifications increasingly rely on molecular findings that go beyond what the microscope shows the pathologist.

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Molecular pathology selected abstracts

Personalized oligonucleotide therapy for treatment of a rare genetic disease December 2019—A variety of molecular diagnostic laboratory tools are available to diagnose diseases caused by mutations in the human genome. However, few treatments are available to correct the underlying pathophysiology driven by these mutations. This is due, in part, to pharmaceutical companies’ inability to justify, from a business perspective, the expense and time necessary to develop and obtain FDA approval for novel therapies that benefit only a small number of patients.

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Molecular pathology selected abstracts

Tumor microbiome diversity 
and composition: influence on pancreatic cancer outcomes November 2019—Pancreatic adenocarcinoma has a dismal prognosis, with a high incidence of relapse and a median overall survival of 24 to 30 months. Only nine percent of patients are alive five years after surgery. Genome-wide mutational landscape studies to decipher the factors that contribute to long-term survival have been futile. Recent studies in patients with melanoma and lung cancer have shown that the gut microbiota can mediate tumor responses to chemotherapy and immunotherapy, influencing overall outcome.

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Molecular pathology selected abstracts

Circulating tumor DNA as a clinical test in resected pancreatic cancer
October 2019—Pancreatic ductal adenocarcinomas are associated with high rates of mortality due, in part, to a lack of effective screening strategies and advanced disease at diagnosis. Residual occult disease is thought to contribute to disease recurrence in up to 80 percent of patients treated surgically for localized disease. These findings highlight the critical need for biomarkers for detecting disease early and monitoring tumor dynamics. Current strategies involve a combination of serum markers (carbohydrate antigen [CA] 19–9) and imaging modalities, both of which have limitations, particularly for detecting early disease recurrence postoperatively.

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Molecular pathology selected abstracts

September 2019—The pathologist’s ability to interpret the complex spatial organization within and between cells and intercellular matrices is the basic underlying principle of morphologic pathology. Even in the genomic era, molecular genetic information is not clinically useful without tissue context. Modern spatial capturing methods, either by low-fidelity light microscopy or high-fidelity electron microscopy, cannot concomitantly interrogate a nucleic acid sequence.

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Molecular pathology selected abstracts

July 2018—The use of liquid biopsies to non-invasively detect and monitor cancer is rapidly expanding. In these assays, fragments of cell-free DNA (cfDNA), which are released when cells undergo necrosis or apoptosis, are isolated from the patient’s plasma and sequenced. Because cfDNA can originate from cancer cells and normal cells, the variant allele frequency of cancer-specific somatic mutations can often be very low.

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Molecular pathology selected abstracts

June 2019—Link between immunogenic neoantigens derived from gene fusions and T-cell responses. Immunotherapy is quickly emerging as an important therapeutic strategy for hematologic and solid tumors. In 
principle, immune cells recognize unique non-self antigens expressed by cancer cells and this serves as the initial step in eliminating such cells. Among the metrics used to assess the likelihood of response to immunotherapy is the presence of a high level of somatic mutations, referred to as tumor mutation burden (TMB). This serves as a surrogate for extrapolating the level of neoantigens ex-
pressed by cancer cells.

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Molecular pathology selected abstracts

April 2019—Variants in NUDT15: association with thiopurine–induced myelosuppression: The thiopurines mercaptopurine, thioguanine, and azathioprine are purine antimetabolites widely used as anticancer and immunosuppressive agents. Commonly prescribed in patients with inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, they are valuable steroid-sparing treatment options.

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Molecular pathology selected abstracts

March 2019—Using circulating cell-free fetal DNA to test for monogenic disorders: Screening for fetal chromosomal abnormalities can be performed by noninvasive methods in which fetal cell-free DNA (cfDNA) circulating in the maternal blood is isolated and analyzed. However, the standard of care for screening for monogenic diseases remains population-based carrier screening—testing the parents for their carrier status of deleterious genes.

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Molecular pathology selected abstracts

Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; James Solomon, MD, PhD, resident, Department of Pathology, UCSD; Richard Wong, MD, PhD, molecular pathology fellow, Department of Pathology, UCSD; and Sounak Gupta, MBBS, PhD, molecular pathology fellow, Memorial Sloan Kettering Cancer Center, New York. Development of brain circuits ...

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Molecular pathology selected abstracts

December 2018—Profiling of chromatin-accessibility landscape of primary cancers: The chromatin-accessibility profiles generated in this study by The Cancer Genome Atlas represent the largest pan-cancer effort to characterize the regulatory landscape of human cancers. The study primarily used an assay for transposase-accessible chromatin using sequencing (ATAC-seq).

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Molecular pathology selected abstracts

November 2018—Common genetic variants contribute to risk of rare severe neurodevelopmental disorders: The traditional paradigm broadly classifies genetic diseases into rare disorders caused by a single gene variant and common disorders caused by complex interplay among multiple genes. However, recent research has shown that penetrance and disease phenotype, even in disorders thought to be monogenic, are affected by common genetic variation.

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Molecular pathology selected abstracts

Cell-free DNA tumor mutational burden predicts efficacy of immune checkpoint inhibitors October 2018—Immune checkpoint inhibitors have emerged as a potent class of therapy for a variety of malignancies. The biologic rationale for these drugs is that somatic mutations, not necessarily in cancer driver genes, may accumulate in tumor cells, resulting in amino acid changes that create neoantigens (epitopes not present in normal cells during maturation of the immune system).

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Molecular pathology selected abstracts

Ability of genetic alterations to predict development of acute myeloid leukemia
September 2018—Acute myeloid leukemia affects more than 60,000 people in the United States every year and has a mortality rate of more than 90 percent. It is the most common form of acute leukemia and is caused by unchecked growth of immature precursor cells in the bone marrow. These immature cells, or blasts, are myeloid precursors that often develop into dysfunctional, cancerous white blood cells that fill the bone marrow and spread into the blood.

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Molecular Pathology Abstracts

Prevalence of clonal hematopoiesis mutations in tumor-only clinical genomic profiling of solid tumors
August 2018—Challenges to implementing next-generation sequencing-based comprehensive molecular profiling of solid tumors include reliably separating germline variants from somatic variants. This is an important consideration, particularly when a “tumor-only” profiling approach is used.

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Molecular pathology selected abstracts

July 2018—Correlation between tumor mutation burden and efficacy of combination immunotherapy in nonsmall cell lung cancer: Checkpoint inhibitor therapy has dramatically improved outcomes in many cancer types, with treatments including antibodies against cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death receptor-1 (PD-1), and its ligand (PD-L1).

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Molecular Pathology Abstracts, 5/18

May 2018—DNA methylation-based testing to classify central nervous system tumors: Despite being the mainstay of pathology tissue diagnostics, microscope-based histological review has limitations. Among them is that pathologists may have differing opinions about a case. This interobserver variability may result in over- or undertreatment of the patient and lack of agreement about which diagnosis is correct.

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Molecular Pathology Abstracts

April 2018—Effect of inherited TP53 mutations on children with B-cell ALL: TP53 has been referred to as the “guardian of the genome” because it plays a central role in regulation of the cell cycle, DNA repair, and apoptosis, and because somatic mutations in TP53 are frequently identified in many tumor types.

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Molecular Pathology Abstracts, 3/18

March 2018—Nonendoscopic detection of Barrett’s esophagus using DNA methylation biomarkers: Esophageal adenocarcinoma is an aggressive disease, with a less than 20 percent five-year survival rate, and its incidence is rapidly increasing. Early detection of esophageal adenocarcinoma or its precursor lesion, Barrett’s esophagus, would enable more effective treatment strategies and a greater chance of cure.

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Molecular Pathology Abstracts, 2/18

February 2018—Gene expression and risk of leukemic transformation in myelodysplasia: The myelodysplastic syndromes represent a group of clonal hematopoietic disorders with varying prognoses, with survival ranging from a few months to more than 10 years. Multiple laboratory measurements have been used in attempts to provide reliable prognostic assessments, including bone marrow blast counts, severity of peripheral cytopenia, cytogenetic findings, and, most recently, gene-mutation profiling.

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Molecular Pathology Abstracts, 1/18

January 2018—Importance of interstitial genes that exist between gene fusion partners in prostate cancer: Prostate cancer is one of the most common cancers affecting men, yet understanding of the disease’s development and progression is limited. One of the most effective ways to stratify treatment and outcomes is based on pathology review of prostate biopsies, though the application of molecular testing to these samples is increasing.

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Molecular Pathology Abstracts, 12/17

December 2017—Refining subgroups of pediatric gliomas using molecular markers: Pediatric high-grade and diffuse intrinsic pontine gliomas are a rare and heterogeneous group of tumors that show diverse histology, location, and prognosis. Although little was known regarding the development of these tumors, recent genomic studies have begun to elucidate their biological underpinnings. The authors conducted a study to further understanding of such gliomas by breaking them into subgroups.

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Molecular Pathology Abstracts, 10/17

Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, associate professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory ...

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Molecular Pathology Abstracts, 9/17

September 2017—Ability of cell-free circulating tumor DNA to reflect genomic changes in cancer deposits: Analysis of cell-free circulating tumor DNA is an emerging precision medicine technology that may be used to assess molecular alterations in cancer-derived DNA present in the blood, as well as to monitor cancer genomic changes over time and assess genomic changes and resistance following cancer therapy.

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Molecular Pathology Abstracts, 8/17

August 2017—Mismatch repair-deficient tumors and immune checkpoint inhibitors: Immune checkpoint inhibitors have yielded highly effective therapeutic responses in a subset of tumors by eliciting an endogenous adaptive immune response. The determinants that define this subset of tumors are still unclear, but several markers, including PD-L1 expression and mutational burden, have been evaluated in various tumor types.

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Molecular Pathology Abstracts, 7/17

July 2017—Immune checkpoint inhibition therapy, such as blockage of PD-1/PD-L1 interaction, has proven effective in many types of cancers. The mechanism underlying this therapy is postulated to involve “disinhibition” of tumor-infiltrating lymphocytes that respond to neoantigens expressed by tumor cells. In theory, the larger the number of neoantigens expressed, the greater the immune response resulting from disinhibition.

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Molecular Pathology Abstracts, 6/17

June 2017—Whole genome single-cell copy number profiling on FFPE tissue samples Single-cell genomic methods take the concept of analyzing intratumor genetic heterogeneity to its logical conclusion. Traditionally, however, single-cell methods can only be used to analyze fresh or rapidly frozen tissue because formalin fixation and paraffin embedding degrades tumor DNA and cross-links proteins.

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Molecular Pathology Abstracts, 4/17

April 2017—Molecular profiling in MDS to predict clinical outcomes after transplantation: In recent years, several insights have been gleaned regarding the role of molecular markers for prognosis in myeloproliferative disease. This study expanded the use of molecular markers for prognosis in myelodysplastic syndrome (MDS) to predicting clinical outcomes after allogeneic hematopoietic stem-cell transplants.

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Molecular Pathology Abstracts, 3/17

March 2017—Effects of ovarian cancer cells manipulating mesothelial cells that line the peritoneal cavity: spread within the peritoneal cavity, resulting in cell implantation and metastasis at many secondary sites. The peritoneal cavity and associated organs are lined by a single layer of mesothelial cells that it has been suggested not only provides a physical barrier to prevent implantation and invasion but also plays a more complex interactive role in regulating cancer spread.

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Molecular Pathology Selected Abstracts, 2/17

February 2017—Concordance between liquid biopsy and patient-matched tumor molecular testing: The use of sequence analyses of extended panels of genes to identify therapeutic targets in cancer is becoming commonplace. These assays typically rely on the availability of tissue biopsies as a source of genomic material, which can become a limitation in situations where insufficient tissue is available or an invasive procedure to collect tissue is impractical. A potential solution to this dilemma is the use of a blood-based, or liquid biopsy, approach, in which a peripheral blood sample is used as a source of tumor-derived genomic material, either in the form of cell-free DNA (cfDNA) or via circulating tumor cells (ctcDNA).

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Molecular Pathology Selected Abstracts, 12/16

December 2016—ANXA1 as a predictive biomarker for resistance to trastuzumab in breast cancer: Treatment with the HER2-targeting antibody trastuzumab (Herceptin) is a key component of therapy for women with HER2-positive breast cancer. However, a subset of women with advanced disease shows initial or acquired resistance to therapy, although the mechanisms that control this resistance are largely unknown. Some studies have suggested that activation of the PI3K/mTOR signaling pathway may be responsible for trastuzumab resistance.

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Molecular Pathology Selected Abstracts, 11/16

November 2016—Misclassification of genetic variants associated with hypertrophic cardiomyopathy: Hypertrophic cardiomyopathy has a variable clinical presentation and may lead to sudden cardiac death. In many cases, it is associated with pathogenic genetic variants, enabling screening of relatives and, possibly, the ability to individualize treatment strategies through lifestyle modification or invasive procedures.

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Molecular Pathology Selected Abstracts, 9/16

September 2016—Mutations causing acquired resistance to PD-1 blockade in melanoma: Immunotherapy in metastatic cancer has achieved durable responses in a wide variety of cancer types. Antibodies that block programmed cell death protein-1 (PD-1) are particularly effective in metastatic melanoma, but a recent study showed that approximately 25 percent of patients that achieved a durable response ultimately had disease progression at a median follow-up of 21 months.

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Molecular Pathology Selected Abstracts, 8/16

August 2016—Germline mutations in men with metastatic prostate cancer: Prostate cancer displays great diversity in clinical behavior, ranging from essentially silent, organ-confined disease to rapid and aggressive metastatic spread. The authors know of no clear-cut screening method that can reliably identify those patients whose tumors are likely to behave aggressively and, therefore, may benefit from a more active treatment strategy. Prostate cancer has also been shown to have a significant component of heritability.

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Molecular Pathology Selected Abstracts, 7/16

July 2016—Using single nucleotide polymorphism arrays in acute lymphoblastic leukemia: In patients with acute lymphoblastic leukemia/lymphoma, the identification of chromosomal abnormalities at the time of diagnosis is important for risk classification. The current standard of care includes karyotype and FISH analysis to identify recurrent cytogenetic abnormalities.

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Molecular Pathology Selected Abstracts, 3/16

March 2016—Enhancing tumor selectivity of a picornavirus virotherapy: Oncolytic viruses that selectively target tumor cells are a promising cancer therapy and are thought to work not only via direct lysis and destruction of tumor cells but also through recruitment and activation of the host’s anti-tumor immune response. While there are a number of naturally occurring viruses that preferentially replicate in cancer cells and have otherwise limited effects in human tissue, the real therapeutic promise lies in genetically engineered viruses.

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Molecular Pathology Selected Abstracts, 1/16

January 2016—Genomic sequencing of tumors can be used clinically to identify acquired somatic mutations in cancer-related genes. In an era of personalized medicine, tumor-specific mutational status can be used to acquire prognostic information and guide molecular targeted therapies. However, many patients also have germline variants in these genes, which not only can make it difficult to identify the tumor-specific somatic mutations, but may also affect the biological mechanism of tumorigenesis.

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Molecular Pathology Selected Abstracts, 11/15

November 2015—Off-label use of molecularly targeted therapy: Advances in technology allow for genetic and molecular profiling of tumors, findings that are useful for guiding molecularly targeted therapy. Molecularly targeted agents are usually tested and developed on groups of tumors based on histologic type and primary location, but many genetic abnormalities overlap across tumor types.

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Molecular Pathology Selected Abstracts, 10/15

October 2015—Mutation clearance after induction therapy in acute myeloid leukemia: After initial induction chemotherapy for acute myeloid leukemia, approximately 20 percent of patients fail to achieve complete remission, and approximately 50 percent experience relapse within one year. Therefore, it would be clinically useful to identify patients at higher risk of induction therapy failure or relapse.

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Molecular Pathology Selected Abstracts, 9/15

September 2015—Molecular profile of diffuse lower-grade gliomas: Diffuse low- and intermediate-grade gliomas include World Health Organization grade II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. These lower-grade gliomas usually arise in the cerebral hemispheres of adults, and they are highly infiltrative and, therefore, cannot be completely resected.

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Molecular Pathology Selected Abstracts, 8/15

August 2015—Studying clonal dynamics in response to cancer therapy using barcoding: The emergence of resistance to targeted cancer therapeutics is a significant problem clinically and is generally believed to result from genetic alterations in tumor cells. Whether resistance exists within a subpopulation of a tumor prior to treatment or develops de novo during treatment is a fundamental question that may significantly impact therapy.

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Molecular Pathology Selected Abstracts, 5/15

May 2015—Clinical and molecular effects of order of acquired mutations in myeloproliferative neoplasms: Cancers arise and evolve from the accumulation of somatic mutations. With the addition of each mutation, tumor subclones are selected for biologic attributes that increase growth and proliferation potential. However, the authors hypothesized that it may not only be the presence of the mutations that affects these attributes but also the order in which the mutations arise, since their interactions and resulting environment likely play a key role in the development of subsequent genetic events and the tumor’s neoplastic behavior.

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Molecular Pathology Selected Abstracts, 4/15

April 2015—Interpreting pathogenic variants in TTN for dilated cardiomyopathy: In this era of expanding gene panels and whole-exome and whole-genome sequencing for rare disease molecular diagnostics, it remains a challenge to filter numerous resulting variants from these sequencing assays, assign functional consequences of a variant in the resulting protein, and then determine potential pathogenicity.

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Molecular Pathology Selected Abstracts, 1/15

January 2015—Age-related mutations linked to clonal hematopoietic expansion and malignancies: A common practice in molecular profiling of tumors is to subtract mutations detected in DNA derived from blood (representing germline or inherited polymorphisms) from mutations detected in DNA derived from the paired tumor to assess the tumor’s somatic molecular profile.

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Molecular Pathology Selected Abstracts, 12/14

December 2014—Overcoming limitations in the sequencing of whole viral genomes: The identification and analysis of pathogenic viruses, especially the Ebola virus, has recently received significant attention. The sequencing of newly identified viral genomes has presented historical challenges as existing technology fails to capture the 3’ and 5’ terminal ends of the viral genome.

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Molecular Pathology Selected Abstracts, 11/14

November 2014—Whole exome sequencing of Merkel cell carcinoma demonstrates conserved retinoblastoma pathway dysregulation: Merkel cell carcinoma is a rare aggressive neuroendocrine malignancy of the skin that is associated with infection by Merkel cell polyomavirus. Viral integration into the human genome and subsequent expression of the large T antigen is thought to cause cell cycle dysregulation via binding and inactivation of the retinoblastoma tumor suppressor protein and is a key step in the development of Merkel cell carcinoma.

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Molecular Pathology Selected Abstracts, 10/14

October 2014—A gene panel to examine mosaic somatic mutations in cerebral malformations: Somatic mutations are widely recognized in cancer, often affecting prognosis and determining candidacy for use of molecular targeted treatments. These somatic mutations may lead to a mosaic population of cells. Recent advances in technology involving deep next-generation sequencing have allowed for detection and quantification of these mosaic variants.

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Molecular Pathology Selected Abstracts, 8/14

August 2014—The dystrophin gene is the largest known human gene, comprising 2.2 Mb of the genome and 79 coding exons: Through the use of multiple tissue-specific promoters and alternative splicing of RNA, several isoforms of the protein dystrophin are encoded by the dystrophin (DMD) gene. The primary 427-kDA dystrophin isoform (Dp427) is found in the cytoplasm of skeletal and cardiac muscle cells, where it is involved in physically linking the cytoskeleton to protein structures outside the cell and, therefore, strengthens and protects muscle fibers during contraction and relaxation.

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