Gene Summary

Gene:AKR1B10; aldo-keto reductase family 1 member B10
Aliases: HIS, HSI, ARL1, ARL-1, ALDRLn, AKR1B11, AKR1B12
Summary:This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member can efficiently reduce aliphatic and aromatic aldehydes, and it is less active on hexoses. It is highly expressed in adrenal gland, small intestine, and colon, and may play an important role in liver carcinogenesis. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:aldo-keto reductase family 1 member B10
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AKR1B10 (cancer-related)

Kutahyalioglu M, Nguyen HT, Kwatampora L, et al.
Genetic profiling as a clinical tool in advanced parathyroid carcinoma.
J Cancer Res Clin Oncol. 2019; 145(8):1977-1986 [PubMed] Related Publications
CONTEXT: Parathyroid carcinoma (PC) is a rare endocrine malignancy with no approved systemic therapies for unresectable locally invasive or distant metastatic disease. Understanding the molecular changes in advanced PC can provide better understanding of this disease and potentially help directing targeted therapy.
OBJECTIVE: To evaluate tumor-specific genetic changes using next-generation sequencing (NGS) panels.
DESIGN: All patients with advanced PC were tested for hot-spot panels using NGS panels including a 50-gene panel, a 409-gene panel if the standard 50-gene panel (Ion Torrent, Life Technology) was negative or a FoundationOne panel.
SETTING: The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
PATIENTS OR OTHER PARTICIPANTS: 11 patients with advanced PC were selected to undergo molecular testing.
MAIN OUTCOME MEASURE(S): Genetic profiles of advanced PC.
RESULTS: Among the 11 patients, 4 patients had the 50-gene panel only, 6 had 409-gene panel after a negative 50-gene panel and 1 had FoundationOne. One patient who had 50-gene panel only also had his metastatic site (esophagus) of his tumor tested with FoundationOne. The most common mutations identified were in the PI3 K (PIK3CA, TSC1 and ATM) (4/11 patients) and TP53 (3/11) pathways. Genes not previously reported to be mutated in PC included: SDHA, TERT promoter and DICER1. Actionable mutations were found in 54% (6/11) of the patients.
CONCLUSIONS: Mutational profiling using NGS panels in advanced PC has yielded important potentially targetable genetic alterations. Larger studies are needed to identify commonly mutated genes in advanced PC patients. Development of novel therapies targeting these cellular pathways should be considered.

Ye J, Luo D, Yu J, Zhu S
Transcriptome analysis identifies key regulators and networks in Acute myeloid leukemia.
Hematology. 2019; 24(1):487-491 [PubMed] Related Publications
OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied.
METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets.
RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network.
CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.

De Falco V, Natalicchio MI, Napolitano S, et al.
A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant.
Medicine (Baltimore). 2019; 98(21):e15759 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. About 5% of the population is deficient in DPD enzyme activity. The most well studied DPYD variant is the IVS14+1G>A, also known as DPYD *2A. In this report, we present a case of a patient with a double heterozygote DPYD variant (DPYD activity score: 0,5 according to Clinical Pharmacogenetics Implementation Consortium) who experienced a severe fluoropyrimidine-related toxicity resolved without any consequence.
PATIENT CONCERNS: A 46-years-old Caucasian man with diagnosis of left colon adenocarcinoma underwent left hemicolectomy on July 2017: pT3 G3 N1c M0. According to the disease stage, he started an adjuvant therapy with XELOX using capecitabine at 50% of total dose, because of his DPYD IVS14+1G>A variant, detected before the treatment.
DIAGNOSIS: After few days, despite of this dose reduction, he experienced life-threatening adverse events such as mucositis G3, diarrhea G3, neutropenia G4, thrombocytopenia G4, and hyperbilirubinemia G3 according to Common Terminology Criteria for Adverse Events v 5.0.
INTERVENTIONS: As first, we set up an intensive rehydration therapy, antibiotic and antifungal prophylaxis, Granulocyte-Colony Stimulating Factors, and supportive blood transfusions. Additional genetic tests revealed a double heterozygote variant of DPYD gene (DPYD IVS14+1G>A and 2846A>T) which is a very rare situation and only 3 cases are described in literature, all of them concluded with patient's death.
OUTCOMES: After 3 weeks of intensive therapy, the patient was fully recovered. Furthermore, all the whole-body CT scans performed since discharge from the hospital until now, have confirmed no evidence of disease.
CONCLUSIONS: Recent studies demonstrated that screening strategy for the most common DPYD variants allowed for avoiding toxicities and saving money. This report underlines the importance of genotyping DPYD before treatment and emphasizes the role of genotype-guided dose individualization.

Lu G, Qiao L, Li D, et al.
Concurrent lymphoma and hemophilia B in a pediatric patient: A case report.
Medicine (Baltimore). 2019; 98(19):e15474 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Lymphoma is the third most common cancer among children in the United States and Europe. Hemophilia is a congenital bleeding disorder characterized by deficiency of coagulation factor VIII or IX. Hemophilia B is a consequence of factor IX deficiency and has an incidence of 1 in 20,000 male births. A concurrence of these 2 uncommon diseases is rare except in patients infected with the human immunodeficiency virus (HIV). We report a case of a patient with both Burkitt lymphoma and hemophilia B; this is only such report in China since 1987.
PATIENT CONCERNS: A 3-year-old boy was admitted to our hospital because of melena and jaundice for several days. His older brother had died due to hemophilia B and ventricular septal defect. The patient had not experienced any previous episodes of severe bleeding. Gradual abdominal distention was observed after admission; the patient's superficial lymph nodes were not enlarged. Results of blood routine and bone marrow examinations showed no abnormalities. He was diagnosed with sclerosing cholangitis, abdominal infection, and hepatitis. However, after treatment of reducing enzyme activity and eliminating jaundice, the patient's condition deteriorated. Hydrops abdominis was detected on abdominal ultrasonography. Tumor cells were found by pathological examination of peritoneal effusion. Both a c-myc gene translocation and a c-myc-IgH gene fusion were detected.
DIAGNOSIS: Burkitt lymphoma and hemophilia B.
INTERVENTIONS: The patient was transferred to the Pediatric Hematology Department of our hospital and treated with a modified B-NHL-BFM-95 protocol. During chemotherapy, platelet changes were monitored regularly and blood products were infused timely.
OUTCOMES: The patient died of infection and bleeding after chemotherapy.
CONCLUSION: Concurrent hemophilia and lymphoma are rare, especially in children. When encountering a patient with unexplained obstructive jaundice and massive ascites, the possibility of a tumor should be considered. Early diagnosis and adequate treatment of such tumor may improve prognosis.

Guo L, Wen Z, Su X, et al.
Indolent T-cell lymphoproliferative disease with synchronous diffuse large B-cell lymphoma: A case report.
Medicine (Baltimore). 2019; 98(17):e15323 [PubMed] Related Publications
RATIONALE: Indolent T-cell lymphoproliferative disease (T-LPD) of gastrointestinal tract is a rare recently described disease that seldom progresses. We report a case of T-LPD with synchronous diffuse large B-cell lymphoma (DLBCL) that cause aggravation of disease.
PATIENT CONCERNS: A 46-year-old Chinese male presented with intermittent paraumbilical colic pain, bloating, and occasional diarrhea for 10 years. His condition aggravated with partial bowel obstruction recently. The patient was diagnosed as T-LPD initially based on histological result and T-cell receptor-gamma clonal gene rearrangement test. The patient was followed without chemotherapy. His condition stabilized for 1 year and then deteriorated with small intestine perforation.
DIAGNOSIS: The patient was diagnosed as indolent T-LPD and DLBCL finally.
INTERVENTIONS: The patient had surgery for intestine perforation and received chemotherapy for DLBCL and T-LPD afterward.
OUTCOMES: At 6 months follow-up, the patient continued to have resolution of his symptoms.
LESSONS: Early detection of high-grade transformation of T-LPD or the coexistence of aggressive lymphoma is essential for the patient. DLBCL may coexist in the indolent course of T-LPD. The diagnosis of T-LPD should be made cautiously in case with progressing symptoms such as intestinal obstruction.

Han W, Ye Y
A repository of microbial marker genes related to human health and diseases for host phenotype prediction using microbiome data.
Pac Symp Biocomput. 2019; 24:236-247 [PubMed] Free Access to Full Article Related Publications
The microbiome research is going through an evolutionary transition from focusing on the characterization of reference microbiomes associated with different environments/hosts to the translational applications, including using microbiome for disease diagnosis, improving the effcacy of cancer treatments, and prevention of diseases (e.g., using probiotics). Microbial markers have been identified from microbiome data derived from cohorts of patients with different diseases, treatment responsiveness, etc, and often predictors based on these markers were built for predicting host phenotype given a microbiome dataset (e.g., to predict if a person has type 2 diabetes given his or her microbiome data). Unfortunately, these microbial markers and predictors are often not published so are not reusable by others. In this paper, we report the curation of a repository of microbial marker genes and predictors built from these markers for microbiome-based prediction of host phenotype, and a computational pipeline called Mi2P (from Microbiome to Phenotype) for using the repository. As an initial effort, we focus on microbial marker genes related to two diseases, type 2 diabetes and liver cirrhosis, and immunotherapy efficacy for two types of cancer, non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC). We characterized the marker genes from metagenomic data using our recently developed subtractive assembly approach. We showed that predictors built from these microbial marker genes can provide fast and reasonably accurate prediction of host phenotype given microbiome data. As understanding and making use of microbiome data (our second genome) is becoming vital as we move forward in this age of precision health and precision medicine, we believe that such a repository will be useful for enabling translational applications of microbiome data.

Guo X, Cui J, Zhao Y, et al.
The therapeutic value of cerebrospinal fluid ctDNA detection by next-generation sequencing for meningeal carcinomatosis: a case report.
BMC Neurol. 2019; 19(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It is usually very complicated to treat meningeal carcinomatosis, and it is important to treat it as soon as possible.
CASE PRESENTATION: The 19-Del mutation was found in the exon for the epidermal growth factor receptor gene in the pleural effusion of a patient on March 11th, 2015. He took 250 mg of oral gefitinib once a day for 11 months beginning in December of 2015. On the 3rd of November 2016, he arrived at the hospital and presented with dizziness, headache and transient blurred vision. At this time, he began to take 4 mg of oral zoledronic acid once a month to prevent bone metastases. The result of a cytology exam of the cerebrospinal fluid showed that the man had meningeal carcinomatosis. The 19-Del mutation and the 20-T790 M mutation in the exon of the epidermal growth factor receptor gene was found by the next generation sequencing of the CSF. Then, he discontinued taking gefitinib and began to take 90-100 mg of oral AZD9291 once a day in November 2016. After adjusting the medication dose based on the NGS, his headache was noticeably reduced, and his condition gradually stabilized.
CONCLUSIONS: Cerebrospinal fluid ctDNA detection by next generation sequencing may become a suitable biomarker to monitor clinical treatment response in meningeal carcinomatosis.

Hajirawala L, Barton JS
Diagnosis and Management of Lynch Syndrome.
Dis Colon Rectum. 2019; 62(4):403-405 [PubMed] Related Publications
CASE SUMMARY: A 56-year-old man with a history of hypertension and hyperlipidemia was referred by gastroenterology for bleeding per rectum. Because of a family history of colon cancer, he had several prior colonoscopies, most recently 3 years ago, without evidence of pathology. His mother was diagnosed with colon cancer in her mid-40s. His current colonoscopy demonstrated a 2.4 × 1.5 cm cecal adenocarcinoma. Staging workup revealed no evidence of metastatic disease. Because of the patient's family history, the specimen was further evaluated and found to have high microsatellite instability (MSI-H). The patient was referred to a genetic counselor and found to have a germline pathogenic variant in MSH6 on gene panel testing. The patient did not have a family history of any extracolonic malignancies.The patient underwent an uncomplicated laparoscopic total abdominal colectomy with ileorectal anastomosis, which revealed a T2N0Mx adenocarcinoma with abundant peritumoral lymphocytes. He was discharged on postoperative day 2, and recuperated appropriately from surgery. Follow-up surveillance proctoscopy showed no evidence of disease. His sole offspring, a 25-year-old man, was negative for a pathogenic variant in MSH6 and had no polyps on colonoscopy. His siblings did demonstrate a pathogenic variant in MSH6 and are currently opting for annual surveillance colonoscopy.

Pradhan AK, Bhoopathi P, Talukdar S, et al.
MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF.
Proc Natl Acad Sci U S A. 2019; 116(12):5687-5692 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Melanoma differentiation-associated gene-7/interleukin-24 (

Varmus H
Of oncogenes and open science: an interview with Harold Varmus.
Dis Model Mech. 2019; 12(3) [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Harold Varmus has made pioneering contributions to our understanding of cancer as a genetic disease. The discovery of the cellular origin of retroviral oncogenes earned him and his long-term collaborator, Michael Bishop, the Lasker Prize for Basic Medical Sciences in 1982 and the Nobel Prize in Physiology and Medicine in 1989. Throughout his career, Varmus has held several leadership roles that shaped science policy in the US and worldwide, and he has been an outspoken advocate for open science. In this interview, he talks (among other things) about the factors that shaped his early career choices, the thrill of scientific discovery, and the importance of including diverse populations in genomic studies of cancer and other diseases.

Borzooee F, Larijani M
Pichia pastoris as a host for production and isolation of mutagenic AID/APOBEC enzymes involved in cancer and immunity.
N Biotechnol. 2019; 51:67-79 [PubMed] Related Publications
AID/APOBEC3 enzymes are cytidine deaminases that mutate antibody and retroviral genes and also mediate extensive tumor genome mutagenesis. The study of purified AID/APOBEC3 proteins is challenged by difficulties with their expression and purification arising from genotoxicity in expression hosts, extensive non-specific protein-protein/DNA/RNA interactions and haphazard oligomerization. To date, expression hosts for purification of AID/APOBEC3 enzymes include bacteria, insect and mammalian cells. Here the establishment and optimization of a yeast expression/secretion system for AID/APOBEC3s are reported, followed by comparison with the same enzymes expressed in bacterial and mammalian hosts. AID and APOBEC3G were expressed successfully in Pichia pastoris, each either with an N-terminal GST tag, C-terminal V5-His tag or as untagged native form. It was verified that the yeast-expressed enzymes exhibit identical biochemical properties to those reported using bacterial and mammalian expression, indicating high fidelity of protein folding. It was demonstrated that the system can be adapted for secretion of the enzymes into the media which was used directly in various enzyme assays. The system is also amenable to elimination of bulky fusion tags, providing native untagged enzymes. Thus, P. pastoris is an advantageous expression factory for AID/APOBEC3 enzymes, considering the cost, time, efficiency and quality of the obtained enzymes. The first report is also provided here of a functionally active, untagged, secreted AID, which may become a useful research reagent. A comprehensive comparison is made of the effect of fusion tags and expression hosts on the biochemical actions of AID and APOBEC3G.

Wang YM, Mo JQ, Kuo DJ, Wong V
BMJ Case Rep. 2019; 12(2) [PubMed] Related Publications
We describe an unusual case of pre-B lymphoblastic leukaemia presenting with a unilateral maxillary sinus mass in which biopsies of the primary mass and the bone marrow demonstrated conflicting immunophenotyping results. The extramedullary mass was consistent with a precursor B-cell malignancy, while the bone marrow was initially reported as a possible mature B-cell malignancy. The treatments for the two are fundamentally different, which necessitated a delay in the initiation of his chemotherapy until a clear diagnosis was made. Mixed lineage leukaemia gene rearrangement was confirmed by fluorescence in situ hybridisation in both the primary mass and bone marrow, which unified the diagnosis as pre-B acute lymphoblastic leukaemia given the common cytogenetic feature.

Ocak S, Kebudi R, Cebeci Z, et al.
Neuroblastoma of the Iris in Children.
J Pediatr Ophthalmol Strabismus. 2019; 56:e12-e16 [PubMed] Related Publications
Neuroblastoma of the iris is an extremely rare clinical entity. An otherwise healthy 2-month-old male infant presented to the oncology clinic with a nodular whitish iris lesion in his right eye. The excisional tumor biopsy was consistent with a pathological diagnosis of neuroblastoma with differentiation and negative MYCN gene mutation. Further systemic evaluation revealed a right adrenal mass with no metastatic lesion. The biopsy of the adrenal lesion was also consistent with neuroblastoma. After four courses of chemotherapy, the adrenal mass was completely resected. The patient underwent two additional courses of postoperative chemotherapy and continued retinoic acid treatment. The patient is under regular follow-up with no evidence of recurrence 36 months after the initial diagnosis. This is the first case report to present a histopathological verification of neuroblastoma of the iris. The authors suggest that neonates and infants who are diagnosed as having neuroblastoma undergo an ophthalmologic examination after the initial diagnosis to investigate the true incidence of small iris lesions in neuroblastoma that may have been unrecognized. Neuroblastoma should be included in the differential diagnosis of amelanotic iris lesions in infants and young children. [J Pediatr Ophthalmol Strabismus. 2019;56:e12-e16.].

Chou CK, Huang HW, Yang CF, et al.
Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes.
Environ Toxicol. 2019; 34(4):401-414 [PubMed] Related Publications
Di(2-ethylhexyl)phthalate (DEHP) has been considered as an estrogen receptor alpha (ERα) agonist due to its ability to interact with ERα and promote the cell proliferation of ERα-positive breast cancer cells. The impact of DEHP on the chemical therapy in breast cancer is little known. Two breast cancer cell lines, MCF-7 (ERα-dependent) and MDA-MB-231 (ERα-independent) were examined. We found that DEHP impaired the effectiveness of camptothecin (CPT) and alleviated the CPT-induced formation of reactive oxygen species in ERα-positive MCF-7 cells, but not in ERα-negative MDA-MB-231 cells. DEHP also significantly protected MCF-7 cells against the genotoxicity of CPT. Genome-wide DNA methylation profiling revealed that after 48 hours of exposure to 100 μM DEHP, MCF-7 cells exhibited a significant change in their DNA methylation pattern, including hypermethylation of 700 genes and hypomethylation of 221 genes. The impaired therapeutic response to CPT in DEHP-exposed MCF-7 cells is probably mediated by epigenetic changes, especially through Wnt/β-catenin signaling. A zebrafish xenograft model confirmed the disruptive effect of DEHP on CPT-induced anti-growth of MCF-7 cells. In summary, DEHP exposure induces acquired CPT-resistance in breast cancer cells and epigenetic changes associated with Wnt/β-catenin signaling activation are probably depending on an ER-positive status.

Mao S, Zhang J, Guo Y, et al.
Hyperprogression after anti-programmed cell death ligand-1 therapy in a patient with recurrent metastatic urothelial bladder carcinoma following first-line cisplatin-based chemotherapy: a case report.
Drug Des Devel Ther. 2019; 13:291-300 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
Background: Immune checkpoint blockade targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) signaling was approved recently for locally advanced and metastatic urothelial bladder carcinoma (UBC). Some patients experience a very rapid tumor progression, rather than clinical benefit, from anti-PD-L1/PD-1 therapy.
Case presentation: A 58-year-old male diagnosed with non-muscle-invasive bladder cancer 3 years ago received transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy. TURBT was repeated a year later for recurrent and progressive UBC. Following further disease progression, he received a radical cystectomy (RC), pathologically staged as T2bN2M0, and adjuvant cisplatin-containing combination chemotherapy. When his disease progressed to metastatic UBC, he was started on anti-PD-L1 monotherapy and experienced ultrarapid disease progression within 2 months; imaging scans ruled out pseudoprogression. We observed a fourfold increase in tumor growth rate, defined as the ratio of post- to pretreatment rates. Next-generation sequencing of formalin-fixed paraffin-embedded RC tissues showed
Conclusion: Even in cases with PD-L1-positive tumors,

Ciechomska IA
The role of autophagy in cancer - characterization of crosstalk between apoptosis and autophagy; autophagy as a new therapeutic strategy in glioblastoma.
Postepy Biochem. 2018; 64(2):119-128 [PubMed] Related Publications
The Noble Assembly decided to award the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi for his discoveries of mechanisms of autophagy, a fundamental process for degrading and recycling cellular components. His discoveries opened a path to understanding the fundamental importance of autophagy in many physiological processes, such as adaptation to starvation or response to infection. Mutations in autophagy genes can cause disease, and the autophagic process is involved in several conditions including cancer and neurological disease. It shows the importance of autophagy research, as many questions remain open. The main aim of our research presented here was to better understand the role of autophagy in cancer. Here, we present articles concerning correct monitoring autophagy in cancer cells, characterization of the molecular links between autophagy and apoptosis and analysis of autophagy as a new therapeutic strategy in glioma.

Wang Y, Xu Y, Wang X, et al.
RET fusion in advanced non-small-cell lung cancer and response to cabozantinib: A case report.
Medicine (Baltimore). 2019; 98(3):e14120 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
RATIONALE: Lung cancer is a series of gene-driven disease. EGFR, ALK, and ROS1 are 3 major driver genes that play an important role in lung cancer development and precision management. Additionally, rare genetic alterations continue to be discovered and may become novel targets for therapy. The RET gene is one of such rare genetic alteration of non-small cell lung cancer (NSCLC). In this report, we present a RET-positive case that benefited from cabozantinib treatment.
PATIENT CONCERN: A 50-year-old male patient was diagnosed with lung adenocarcinoma 2 years ago, at that time he received palliative surgery of pulmonary carcinoma and completed 4 cycles of chemotherapy with gemcitabine and cisplatin. Six months later, he was hospitalized in our cancer center due to the disease recurrence, presenting with pleural metastasis.
DIAGNOSIS: Gene alteration was examined using the intraoperative specimen by PCR method, and KIF5B/RET gene fusion was detected. Therefore, the patient was diagnosed with late-stage lung adenocarcinoma with RET gene mutation.
INTERVENTIONS: The patient received treatment with cabozantinib from June 2017.
OUTCOMES: Cabozantinib was administered (140 mg orally, once daily) for approximate 9 months, and his disease achieved stable disease (SD). During that period, there were no severe adverse events (AE), except for a grade II rash (CTCAE 4.0).
LESSONS: We found that the RET fusion gene is a novel driver molecular of lung adenocarcinoma in patients without common mutations in such genes as EGFR, ALK, and ROS1. This case report supports a rationale for the treatment of lung adenocarcinoma patients with a RET fusion and provides alternative treatment options for these types of NSCLC patients.

Nie Y, Sun W, Xiao Z, Ye S
Complete response to sunitinib for more than three years in a patient with a jejunum gastrointestinal stromal tumor: A case report.
Medicine (Baltimore). 2019; 98(3):e14060 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
RATIONALE: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is characterized by KIT mutations. Patientsresistant to 1st-line imatinib therapy are usually given sunitinib assecond-line treatment, which provides a median progression-free survival of 8 to 12 months. We report the 1st case of metastatic jejunum GIST with a KIT exon 11 deletion that showed complete response (CR) to sunitinib for more than 3 years.
PATIENT CONCERNS: A 34-year-old man with advanced jejunum GIST was surgically treated upon initial diagnosis, and was histologically found to carry a high recurrence risk. Genetic testing revealed a KIT exon 11 deletion, and adjuvant therapy with imatinib was administered. The imatinib dose was escalated following recurrence in the abdomen, but the mass continued to grow.
DIAGNOSIS: He was diagnosed with abdominal recurrence of GIST based on his medical history and histopathological results.
INTERVENTION: Second-line sunitinib therapy was given.
OUTCOMES: The mass disappeared, and CR was seen following 7 months of sunitinib therapy; this CR was sustained for more than 45 months.
LESSONS: In cases of metastatic jejunum GIST with a KIT exon 11 deletion, sunitinib as second-line therapy can be used to achieve CR for more than 3 years.

Yorita K, Nakagawa H, Miyazaki K, et al.
Infarcted Warthin tumor with mucoepidermoid carcinoma-like metaplasia: a case report and review of the literature.
J Med Case Rep. 2019; 13(1):12 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: Warthin tumor is a common, benign, painless salivary gland neoplasm. Rarely, Warthin tumors show large areas of squamous metaplasia; such Warthin tumors are called metaplastic or infarcted Warthin tumors because they are occasionally accompanied with tumor necrosis. The histological distinction between mucoepidermoid carcinomas and the metaplastic portions of Warthin tumors can be challenging; without a genetic study, mucoepidermoid carcinomas can be misdiagnosed as metaplastic Warthin tumors. We report a case of infarcted Warthin tumor partly showing mucoepidermoid carcinoma-like epithelial metaplasia. Only two cases of infarcted Warthin tumor similar to our case have been reported.
CASE PRESENTATION: A 69-year-old Japanese man presented with a right parotid tumor. He had noticed the swelling on his right buccal region 1 year previously; the lesion had rapidly enlarged, with associated pain, 1 month previously. A radiological examination revealed a mass in the tail of the right parotid gland. Superficial parotidectomy was performed. On histological examination, the mass showed typical focal features of Warthin tumor; other areas showed coagulation necrosis of the tumor. These areas were surrounded by non-oncocytic epithelium comprising squamous and mucinous epithelial cells. Although cellular atypia of the non-oncocytic epithelium was not observed, a mixture of squamous and mucinous cells and lack of abundant lymphoid tissue mimicked low-grade mucoepidermoid carcinoma. Based on the results of fluorescence in situ hybridization, MAML2 gene rearrangement was not present in the typical portions of Warthin tumor and the mucoepidermoid carcinoma-like lesion. Therefore, a metaplastic or infarcted Warthin tumor was diagnosed. Our patient was disease-free 8 months after surgery.
CONCLUSIONS: Clinicians need to know that pain is a clinical symptom of infarcted/metaplastic Warthin tumor. Pathologists should be aware that a metaplastic Warthin tumor can mimic a low-grade mucoepidermoid carcinoma. Our case showed a mucoepidermoid carcinoma-like lesion that was confined near the area of tumor necrosis, and neither cytological atypia nor apparent invasive growth was present. These findings appeared to be histological clues of a metaplastic Warthin tumor rather than a mucoepidermoid carcinoma. Careful clinicopathological evaluation as well as genetic studies are needed to clarify the distinction between mucoepidermoid carcinoma and metaplastic portions of Warthin tumors.

Oliver GR, Blackburn PR, Ellingson MS, et al.
RNA-Seq detects a SAMD12-EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas.
Mol Genet Genomic Med. 2019; 7(3):e00560 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: We describe a patient presenting with pachygyria, epilepsy, developmental delay, short stature, failure to thrive, facial dysmorphisms, and multiple osteochondromas.
METHODS: The patient underwent extensive genetic testing and analysis in an attempt to diagnose the cause of his condition. Clinical testing included metaphase karyotyping, array comparative genomic hybridization, direct sequencing and multiplex ligation-dependent probe amplification and trio-based exome sequencing. Subsequently, research-based whole transcriptome sequencing was conducted to determine whether it might shed light on the undiagnosed phenotype.
RESULTS: Clinical exome sequencing of patient and parent samples revealed a maternally inherited splice-site variant in the doublecortin (DCX) gene that was classified as likely pathogenic and diagnostic of the patient's neurological phenotype. Clinical array comparative genome hybridization analysis revealed a 16p13.3 deletion that could not be linked to the patient phenotype based on affected genes. Further clinical testing to determine the cause of the patient's multiple osteochondromas was unrevealing despite extensive profiling of the most likely causative genes, EXT1 and EXT2, including mutation screening by direct sequence analysis and multiplex ligation-dependent probe amplification. Whole transcriptome sequencing identified a SAMD12-EXT1 fusion transcript that could have resulted from a chromosomal deletion, leading to the loss of EXT1 function. Re-review of the clinical array comparative genomic hybridization results indicated a possible unreported mosaic deletion affecting the SAMD12 and EXT1 genes that corresponded precisely to the introns predicted to be affected by a fusion-causing deletion. The existence of the mosaic deletion was subsequently confirmed clinically by an increased density copy number array and orthogonal methodologies CONCLUSIONS: While mosaic mutations and deletions of EXT1 and EXT2 have been reported in the context of multiple osteochondromas, to our knowledge, this is the first time that transcriptomics technologies have been used to diagnose a patient via fusion transcript analysis in the congenital disease setting.

Biswas A, Chakraborty K, Dutta C, et al.
Engineered Histidine-Enriched Facial Lipopeptides for Enhanced Intracellular Delivery of Functional siRNA to Triple Negative Breast Cancer Cells.
ACS Appl Mater Interfaces. 2019; 11(5):4719-4736 [PubMed] Related Publications
Cytosolic delivery of functional siRNA remains the major challenge to develop siRNA-based therapeutics. Designing clinically safe and effective siRNA transporter to deliver functional siRNA across the plasma and endosomal membrane remains a key hurdle. With the aim of improving endosomal release, we have designed cyclic and linear peptide-based transporters having an Arg-

Yang T, Xu R, Yan B, et al.
Elevation of tumor mutation burden in ROS1-fusion lung adenocarcinoma resistant to crizotinib: A case report.
Medicine (Baltimore). 2018; 97(52):e13797 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
RATIONALE: Although most of non-small cell lung cancer (NSCLC) patients with ROS1-fusions respond to crizotinb, acquired resistance eventually develop. The next-generations of ROS1 inhibitors have made some achievements, but the effects of immunotherapy have not been explored.
PATIENT CONCERNS: A 44-year-old Chinese women presented with cough and dyspnea with a history of advanced lung adenocarcinoma.
DIAGNOSIS: A PET/CT scan revealed primary tumors in bilateral lung lobes and multiple metastases in lymph nodes and bones. And ultrasound-guided left cervical lymph node biopsy revealed the pathological diagnosis was poor differentiated lung adenocarcinoma.
INTERVENTIONS: The patients was started to be treated with 4 cycles of pemetrexed, carboplatin and bevacizumab, followed by one cycle of docetaxel, cisplatin and bevacizumab. As the ROS1-fusion was found by next generation sequencing, the patient received crizotinib treatment about 3 months.
OUTCOMES: After 5 cycles of chemotherapy, CT scans revealed increased size of bilateral lobe nodules indicative of progressive disease (PD). Then the patient received treatment of crizotinib and his progression-free survival reached 3 months. Due to uncontrollable disease progression, the patient expired.
LESSONS: The genetic profile of NSCLC patients might be altered in various therapeutic processes. Thus, repeated genetic testing might be important at each progression. Moreover, immunotherapy might be a powerful weapon to overcome the resistance to Tyrosine kinase inhibitors (TKIs) in future.

Potugari BR, Engel JM, Onitilo AA
Metastatic Prostate Cancer in a
Clin Med Res. 2018; 16(3-4):69-72 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
A man, aged 61 years, with a history of hypogonadism and family history of cancer experienced persistent urinary difficulties with no visible prostate abnormalities. Laboratory testing and diagnostic imaging revealed a primary lesion in the prostate with lymph node involvement and multiple bone metastases. Treatment with androgen-deprivation therapy, 17,20-lyase inhibition, and bisphosphonates for 7 months was unsuccessful in preventing disease progression, but second-line chemotherapy and continued androgen-deprivation therapy improved prostate specific antigen levels. During the patient's second treatment regimen, his daughter received a diagnosis of breast cancer. The patient's daughter underwent genetic testing for oncogenic mutations, and it was discovered that she carried a mutation in

Shams M, Dorgalaleh A, Safarian N, et al.
Inhibitor development in patients with congenital factor VII deficiency, a study on 50 Iranian patients.
Blood Coagul Fibrinolysis. 2019; 30(1):24-28 [PubMed] Related Publications
: Congenital factor VII (FVII) deficiency is a rare bleeding disorder with an estimated prevalence of 1 per 500 000 in the general population. On-demand replacement therapy is the main therapeutic choice in patients with congenital FVII deficiency. Inhibitor formation against exogenous FVII is very rare and can cause challenges in the management of the disorder. The present study was conducted to assess the prevalence of FVII inhibitor in 50 patients with congenital FVII deficiency under on-demand or prophylaxis treatment by recombinant activated FVII. All patients with confirmed congenital FVII deficiency were assessed for inhibitor development in regular intervals. Inhibitor titer was determined by a modified Nijmegen-Bethesda assay. The study results were analyzed by SPSS software. Among all cases, two patients (4%) developed an FVII inhibitor. Case 1 was a 14-year-old boy with severe FVII deficiency (FVII activity <1%) with regular prophylaxis. The patient was a high-responder with high-titer FVII inhibitor (170 Bethesda Unit). This patient, who had a history of intracranial hemorrhage, had undergone brain surgery three times. The second patient was a 70-years old man with on-demand therapy that also developed a high-titer inhibitor (10 Bethesda Unit). This patient had experienced easy bruising and endured a few surgeries for his brain tumor and, finally, succumbed to the disease. Although the inhibitor formation is a rare phenomenon, it may result in a significant challenge to manage the affected patients.

Takuwa H, Tsuji W, Shintaku M, Yotsumoto F
Hormone signaling via androgen receptor affects breast cancer and prostate cancer in a male patient: A case report.
BMC Cancer. 2018; 18(1):1282 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: Male breast cancer (MBC) is rare, accounting for only around 1% of all breast cancers. Most MBCs are hormone-driven. Not only the estrogen receptor (ER), but also other steroid hormone receptors, including the androgen receptor (AR) and progesterone receptor (PgR) are expressed in MBC. AR activation in breast cancer cells facilitates downstream gene expression that drives tumorigenesis in a similar manner to ER. AR-mediated signalling works paradoxically in breast cancer and prostate cancer, and cancer cells expressing the AR are endocrine-sensitive.
CASE PRESENTATION: We describe a case of double cancer of MBC and prostate cancer. A 69-year-old man was referred to our hospital with a lump in his left breast in the 1990s. The patient had cT3N3M0, stage IIIC breast cancer, and underwent a mastectomy and axillary lymph node dissection. Though adjuvant chemotherapy was administered, he experienced pleural metastasis 2 months after the surgery. Two years after the recurrence during endocrine therapy with oral 5-fluorouracil, he complained of frequent urination. Radiological and histological examinations revealed that the patient had cT3N0M0, stage III primary prostate cancer with a prostate-specific antigen (PSA) level of 40.5 ng/mL. Germline mutations in the BRCA1 and BRCA2 genes were not tested. He received multidisciplinary, continuous therapy for both breast and prostate cancer; however, 5 and 3 years after each diagnosis, respectively, he experienced a deep vein thrombosis in his right leg related to the endocrine therapy. Liver metastasis progressed after he stopped breast cancer therapy. However, long-term disease control had been achieved with anti-estrogen therapy for breast cancer and estrogen replacement therapy for prostate cancer.
CONCLUSIONS: Several studies have shown that estrogen exposure after estrogen depletion likely causes apoptosis of ER-positive breast cancer cells. Our findings indicate that this also applies to the environment in male body. AR dominant signaling prevents breast cancer recurrence and metastasis, especially in MBC patients.

Urbanova M, Hirschfeldova K, Obeidova L, et al.
Two Czech patients with familial adenomatous polyposis presenting mosaicism in APC gene.
Neoplasma. 2019; 66(2):294-300 [PubMed] Related Publications
During standard molecular diagnostic procedure, two Czech families with APC (Adenomatous polyposis coli gene) mosaicism have been detected. A woman with attenuated familial adenomatous polyposis (AFAP, OMIM #175100) was recently inspected by next generation sequencing. Standard bioinformatics pipeline, restricted to variants with at least 20% of reads (for germline variants) would miss mutation p.G1412X (NM_000038.5) present in 17% of reads. This novel variant was not present in any of her two children. Another woman with a clinical manifestation of attenuated FAP was tested 16 years ago without conclusive APC mutation found when denaturing gradient gel electrophoresis (DGGE), protein truncation test (PTT), multiplex ligation probe amplification (MLPA) and direct Sanger sequencing were applied. Recent inspection of her son showed clear mutation p.Q1062X (NM_000038.5, NP_000029.2) leading to premature stop codon. This finding led to re-evaluation of this protein position in his mother and detection of mosaicism (11% of allele, 22% of heterozygous cells in blood), which was primarily overlooked. Mutations in both patients were confirmed by allele-specific real time PCR (AS qPCR). In both index patients it was possible to detect and quantify the mosaic allele in biological samples of polyps, adjacent colonic mucosa and buccal swabs. In cases of sporadic appearance of FAP, besides blood we plan to preferably inspect also other samples, where mosaic fraction might be under detection limit of bioinformatics pipelines (<3%). For our future routine NGS sequencing analysis we will apply our in-house somatic variant detection pipeline to minimize the false negative calls when genes with high level of de-novo mutations are analyzed.

Liu X, Liu H, Luo S
Reversal of resistance to chemotherapy following anti-programmed cell death-1 immunotherapy in metastatic lung adenocarcinoma: A case report.
Medicine (Baltimore). 2018; 97(49):e13427 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
RATIONALE: For metastatic non-small cell lung cancer with no epidermal growth factor receptor mutations or anaplastic lymphoma kinase gene rearrangements, programmed cell death-1 (PD-1) blockade is preferentially recommended post first-line chemotherapy. However, still many patients do not respond to these agents. After development of resistance to PD-1 blockade, further evaluation of chemotherapy regimen will be necessary.
PATIENT CONCERNS: A 57-year old man had cough with minimal whitish expectoration. Computed tomography (CT) scans showed that he had an upper lobe mass of his left lung and multiple lymphadenectasis, including mediastinal and hilar lymph nodes, and also to the right intrapulmonary lymph nodes.
DIAGNOSES: The patient was diagnosed with adenocarcinoma after a biopsy was conducted on the upper lobe mass of his left lung.
INTERVENTIONS: The patient received pemetrexed plus cisplatin (Pem-Cis) treatment for 6 cycles and sequential thoracic radiation as a therapeutic schedule. CT demonstrated a confirmed partial response after these treatments. Three months later, the tumors continued to grow. The patient received successive pemetrexed-based chemotherapy regimens; however, these regimens failed to stop tumor progression. The patient subsequently underwent 6 cycles of PD-1 mAb pembrolizumab treatment.
OUTCOMES: Sensitivity of chemotherapy was restored, and the patient displayed a reduction in the size of enlarged mediastinal and hilar lymph nodes after 2 cycles of treatment with Pem-Cis, the initially used chemotherapy regimen.
LESSONS: This outcome suggests that PD-1 blockade holds promise as a treatment strategy for reversion of chemotherapy resistance in refractory lung adenocarcinoma and warrants additional studies.

Chen YQ, Yang TQ, Zhou B, et al.
HOXA5 overexpression promotes osteosarcoma cell apoptosis through the p53 and p38α MAPK pathway.
Gene. 2019; 689:18-23 [PubMed] Related Publications
Osteosarcoma is the most common malignant bone tumor in children and adolescents. Aberrant expression of HOXA5 results in various diseases, including cancers. However, the specific function and molecular mechanism of HOXA5 in osteosarcoma is not fully understood. In the present study, we focused on HOXA5 in U2OS and MG63 cells in vitro. We observed lower expression of HOXA5 in U2OS, MG63, and SaOS2 human osteosarcoma cells, compared with hFOB1.19 human osteoblastic cells. HOXA5 overexpression in U2OS and MG63 cells markedly reduced cell survival and proliferation and elevated cell apoptosis and caspase-3 activity. HOXA5 also activated the p38α MAPK pathway by increasing p53. Treating U2OS and MG63 cells with the p53 inhibitor α-pifithrin or the p38α MAPK inhibitor SB203580 led to higher cell survival and proliferation and lower cell apoptosis, compared with the pcDNA3.1-HOXA5 group. In conclusion, our study showed that the p53 and p38α MAPK signal axis facilitated HOXA5's role in inhibiting growth and stimulating apoptosis of osteosarcoma cells.

Ren W, Sun Q, Wu PY, et al.
Profiles of genomic alterations in primary esophageal follicular dendritic cell sarcoma: A case report.
Medicine (Baltimore). 2018; 97(48):e13413 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
RATIONALE: Follicular dendritic cell (FDC) sarcoma is a rare tumor with FDC differentiation that typically arises within lymph nodes but can also occur extranodally. To date, the primary esophageal FDC sarcoma has not been reported in the English literature.
PATIENT CONCERNS: We described a 67-year-old female who foremostly presented with dysphagia, and the patient was readmitted due to a dry cough and pain of his right shoulder 2 years after initial treatment.
DIAGNOSES: Primary esophageal FDC sarcoma with the right superior mediastinal lymph node metastasis.
INTERVENTIONS: The esophageal tumor was removed by endoscopic submucosal dissection at the first hospitalization. At the second hospitalization 2 years after the initial visit, the tracheal stent loaded with (125) iodine radioactive seeds was placed. The profiles of genetic variations and immunotherapeutic biomarkers were also explored by next-generation sequencing protocol from the patient's blood, esophageal primary, and mediastinal metastatic tumor samples.
OUTCOMES: The patient's symptom transitorily relieved, but she gave up further treatment and died 2 months after the tracheal stent was placed. As for the genomic alterations, we found 9 gene mutations in all the samples, including checkpoint kinase 2(CHEK2), FAT atypical cadherin 1 (FAT1), tumor protein 53 (TP53), DPYD, ERBB2 interacting protein (ERBB2IP), FBXW7, KMT2D, PPP2R1A, TSC2, whereas amplification of MYC was only in the metastatic example. The analysis of clonal evolution and phylogenetic tree showed the propagation and replay of polyclonal esophageal FDC sarcoma. At the same time, the detection of biomarkers for immunotherapy revealed microsatellite stable and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-programmed death (PD-1)/programmed death ligand (PD-L1) immunotherapy outcome. On the contrary, the tumor mutational burdens were 10 mutations per 1 million bases in both the primary and metastatic tumor sample, which ranked the top 23.3% in solid tumors mutational burdens database of Geneseeq and might be a good predictor of the efficacy of anti-PD-1/PD-L1 immunotherapy.
LESSONS: To the best of our knowledge, this case report announced the first case of extranodal primary esophageal FDC sarcoma in the world, and firstly revealed its unique genetic alterations profiles, which might contribute to further in-depth study of this rare disease.

Gruhl SL, Sharma P, Han TS
A family with PTEN mutations with malignancy and an unusually high number of offspring with autism spectrum disorder: a case report.
J Med Case Rep. 2018; 12(1):353 [PubMed] Article available free on PMC after 19/09/2019 Related Publications
BACKGROUND: Cowden's syndrome (OMIM:158350), a rare genetic disorder (incidence ~ 1:250,000), is caused by mutations of the tumor suppressor gene PTEN. In this report, we describe clinical manifestations of a 56-year-old patient diagnosed with Cowden's syndrome and his family with PTEN mutations. The family has an unusually high number of offspring with autism spectrum disorder.
CASE PRESENTATION: Except for his 80-year-old Caucasian father, all of our index case's living Caucasian kindred (three children, brother, and nephew) had PTEN mutations and macrocephaly. Prior to genetic testing, his mother and sister died of breast cancer at 42 and 38 years old, respectively. After PTEN mutation was identified, our patient underwent complete thyroidectomy (histology showing micropapillary carcinoma) and right nephrectomy for renal cell carcinoma. All of his three children (13-year-old son, 11- and 8-year-old daughters) have been diagnosed with autism spectrum disorder. His son and brother underwent total thyroidectomy. His nephew had thyroid nodules. Management of Cowden's syndrome requires clinical examinations and investigations every 6 to 12 months from 18 years old or 5 years before the family's earliest age of cancer diagnosis and should focus on all clinical manifestations associated with PTEN mutations to identify early abnormal changes in skin, breasts, thyroid, endometrium, gut, and kidneys. Input from specialists across different disciplines is necessary.
CONCLUSIONS: We describe a man and his family with PTEN mutations who have increased risk of cancers and an unusually high number of offspring with autism spectrum disorder. Early recognition and close surveillance are vital in order to provide treatment and early screening for asymptomatic at-risk relatives.

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