Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lymphocytes with 5-year overall survival rates of only ϳ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogenesis of PTCL, with a resulting paucity of molecular targets for therapy. We developed bioinformatic tools to identify chromosomal rearrangements using genomewide,

Bioinformatics pipelines are an integral component of next-generation sequencing (NGS). Processing raw sequence data to detect genomic alterations has significant impact on disease management and patient care. Because of the lack of published guidance, there is currently a high degree of variability in how members of the global molecular genetics and pathology community establish and validate bioinformatics pipelines. Improperly developed, validated, and/or monitored pipelines may generate inaccurate results that may have negative consequences for patient care. To address this unmet need, the Association of Molecular Pathology, with organizational representation from the College of American Pathologists and the American Medical Informatics Association, has developed a set of 17 best practice consensus recommendations for the validation of clinical NGS bioinformatics pipelines. Recommendations include practical guidance for laboratories regarding NGS bioinformatics pipeline design, development, and operation, with additional emphasis on the role of a properly trained and qualified molecular professional to achieve optimal NGS testing quality.

Key Points DUSP22-rearranged ALCLs belong to a distinct subset of ALCLs lacking activated STAT3. DUSP22-rearranged ALCLs have a unique molecular signature characterized by DNA hypomethylation and an immunogenic phenotype.

• The NF-kB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells.• A positive feedback loop involving CD30, NF-kB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-kB inhibitors.Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kB (NF-kB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. (Blood. 2015; 125(20):3118-3127) Introduction Peripheral T-cell lymphomas (PTCLs) are aggressive non-Hodgkin lymphomas (NHLs) characterized by poor overall survival rates. [1][2][3] Most patients are treated with anthracycline-based chemotherapy regimens originally designed for B-cell lymphomas. Five-year overall survival rates vary somewhat by subtype but average ;35%. The possibility of individualized targeted therapy holds promise, but advances have been hindered by the fact that few therapeutic targets have been identified and validated in PTCLs. Our group's approach to this challenge has been to characterize the genetics of PTCLs to identify novel biomarkers and therapeutic targets. We have focused particularly on chromosomal translocations, which have played a major role in identifying diagnostic, prognostic, and theranostic biomarkers in hematologic neoplasms in general (eg, BCR-ABL) and PTCLs specifically (ALK rearrangements). 4,5 We previously discovered a recurrent translocation in PTCL, t(6;14)(p25.3;q11.2), that juxtaposes the interferon regulatory factor-4 (IRF4) and T-cell receptor-a (TRA) genes and is associated with increased IRF4 expression. 6 Because TRA translocation partners typically function as oncogenes in T-cell malignancies, we postulated that IRF4 plays an oncogenic role in PTCLs.7 IRF4 is a tightly regulated transcription factor involved in growth and differentiation of normal T and B lymp...

BACKGROUND: Up to 80% of thyroid nodules with an indeterminate diagnosis on fine‐needle aspiration (FNA) (eg, “suspicious for follicular neoplasm”) prove to be benign at the time of surgical resection. Ancillary tests in current use are limited in their ability to improve the preoperative detection of malignant follicular thyroid nodules. Studies using paraffin‐embedded tissue have indicated that high mobility group AT‐hook 2 (HMGA2) overexpression is present in a high percentage of malignant thyroid neoplasms but not in benign thyroid neoplasms. In the current study, the ability of HMGA2 overexpression analysis to preoperatively distinguish benign from malignant thyroid nodules by reverse transcriptase–polymerase chain reaction (RT‐PCR) on suspicious cytologic smears was evaluated. METHODS: Patients who underwent thyroid FNA and subsequent thyroid resection from 2001 through 2007 were identified. A subset of these patients who had a cytologic diagnosis of “suspicious” underwent HMGA2 expression analysis. HMGA2 expression was detected on cells scraped from cytologic smears with 1‐step, real‐time quantitative RT–PCR. RESULTS: Of the 125 cases identified, RNA extraction and HMGA2 analysis were successful in 115 cases. With an HMGA2 overexpression change of 5.9‐fold or greater compared with a thyroid tumor cell line as a positive cutoff, the test was found to have the following overall performance for detecting malignant nodules: sensitivity of 71%, specificity of 97%, positive predictive value of 94%, and negative predictive value of 84%. HMGA2 overexpression was found to have low sensitivity for detecting Hurthle cell carcinoma (33%). CONCLUSIONS: HMGA2 mRNA expression analysis can be performed on cytologic smears and demonstrates a high specificity and positive predictive value and relatively high sensitivity and negative predictive value for detecting malignancy in “suspicious” thyroid aspirate specimens. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.

Background: Cardiac myxomas are benign tumors that commonly arise within the left atria. Familial cardiac myxomas are a part of Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome caused by germline mutations in PRKAR1A. Seven percent of cardiac myxomas are associated with CNC. To date, the genetic basis of isolated cardiac myxomas (ICM), however, has not been fully elucidated. Methods: We investigated the genetic profile of ICM using whole exome sequencing (WES). Suspected mutations were confirmed using targeted sanger sequencing. To further examine the presence of PRKAR1A mutations in ICM, we performed targeted sequencing in an additional 61 ICM specimens. Results: 87.5% (7/8) of ICM harbored mutations in PRKAR1A. Three of the 8 ICM harbored biallelic somatic mutations of PRKAR1A, including c.607_610del:p. Leu203fs (pathogenic) + c.C896G:p.Ser299X (pathogenic), c.952delT:p.Leu318fs (pathogenic) + c.769-2 A>G (pathogenic) and c.178-1 G>C (pathogenic) + c. 550+1 G>C (pathogenic). Four of 8 tumors harbored monoallelic PRKAR1A mutations, including c.523_524insG:p.Tyr175_Val176delinsX (pathogenic), c.C920A:p.Ser307X (pathogenic), c.30delG:p.Glu10fs (pathogenic) and c.C289T:p.Arg97X (pathogenic). No identical variants were observed across the 8 ICM samples. Interestingly, none of these variants have been previously described in familial cardiac myxomas. In order to confirm our findings, directed sequencing of 61 ICM specimens was subsequently performed. Sixty-four percent (39/61) of ICMs tumors contained inactivating PRKAR1A mutations. Conclusion: Our findings suggest that loss-of-function mutations of PRKAR1A may play a vital role in the formation of isolated cardiac myxomas.

Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods and resources from epidemiology, pathology, biostatistics, bioinformatics and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: 1) the development of new statistical methods to address etiologic heterogeneity; 2) the enhancement of causal inference; 3) the identification of previously unknown exposure-subtype disease associations; and 4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields.

Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition.