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1.
Article in English | MEDLINE | ID: mdl-37945347

ABSTRACT

Metastatic porocarcinomas (PCs) are vanishingly rare, highly aggressive skin adnexal tumors with mortality rates exceeding 70%. Their rarity has precluded the understanding of their disease pathogenesis, let alone the conduct of clinical trials to evaluate treatment strategies. There are no effective agents for unresectable PCs. Here, we successfully demonstrate how functional precision medicine was implemented in the clinic for a metastatic PC with no known systemic treatment options. Comprehensive genomic profiling of the tumor specimen did not yield any actionable genomic aberrations. However, ex vivo drug testing predicted pazopanib efficacy, and indeed, administration of pazopanib elicited remarkable clinicoradiological response. Pazopanib and its class of drugs should be evaluated for efficacy in other cases of PC, and the rationale for efficacy should be determined when PC tumor models become available. A functional precision medicine approach could be useful to derive effective treatment options for rare cancers.


Subject(s)
Indazoles , Precision Medicine , Skin Neoplasms , Humans , Sulfonamides/therapeutic use , Pyrimidines/therapeutic use , Skin Neoplasms/drug therapy
2.
Singapore medical journal ; : 139-143, 2018.
Article in English | WPRIM (Western Pacific) | ID: wpr-687890

ABSTRACT

<p><b>INTRODUCTION</b>Sporadic colorectal cancers with BRAF mutations constitute two distinct subgroups of colorectal cancers. Recent studies have linked the presence of the BRAF mutation to a familial inheritance pattern. This was a proof-of-concept study that aimed to examine: (a) the extent of field change in sporadic colorectal cancers with BRAF mutation; and (b) the extent of resection margins required and the pattern of DNA mismatch repair protein loss in these tumours.</p><p><b>METHODS</b>Eight microsatellite instability-high tumours with positive BRAF mutation from an existing histopathological database were selected for BRAF mutation and mismatch repair protein analysis.</p><p><b>RESULTS</b>All the resection margins were negative for BRAF mutation. Three tumours had loss of MLH1 and PMS2 expressions, and five tumours had no protein loss. Six peritumoral tissues were negative and one was positive for BRAF mutation.</p><p><b>CONCLUSION</b>The results suggest that any early field change effect is restricted to the immediate vicinity of the tumour and is not a pan-colonic phenomenon. Current guidelines on resection margins are adequate for BRAF mutation-positive colorectal cancers. Any suggestion of a hereditary link to these tumours is likely not related to germline BRAF gene mutations. The pattern of protein loss reinforces previous findings for the two subgroups of BRAF mutation-positive colorectal cancers.</p>


Subject(s)
Female , Humans , Male , Colorectal Neoplasms , Genetics , Pathology , Microsatellite Instability , Mutation , Neoplasm Metastasis , Peritoneal Neoplasms , Pathology , Proto-Oncogene Proteins B-raf , Genetics , Stomach Neoplasms , Pathology
3.
Am J Cancer Res ; 7(3): 484-502, 2017.
Article in English | MEDLINE | ID: mdl-28401006

ABSTRACT

AT rich interactive domain 1A (ARID1A) is one of the most commonly mutated genes in a broad variety of tumors. The mechanisms that involve ARID1A in ampullary cancer progression remains elusive. Here, we evaluated the frequency of ARID1A and KRAS mutations in ampullary adenomas and adenocarcinomas and in duodenal adenocarcinomas from two cohorts of patients from Singapore and Romania, correlated with clinical and pathological tumor features, and assessed the functional role of ARID1A. In the ampullary adenocarcinomas, the frequency of KRAS and ARID1A mutations was 34.7% and 8.2% respectively, with a loss or reduction of ARID1A protein in 17.2% of the cases. ARID1A mutational status was significantly correlated with ARID1A protein expression level (P=0.023). There was a significant difference in frequency of ARID1A mutation between Romania and Singapore (2.7% versus 25%, P=0.04), suggestive of different etiologies. One somatic mutation was detected in the ampullary adenoma group. In vitro studies indicated the tumor suppressive role of ARID1A. Our results warrant further investigation of this chromatin remodeller as a potential early biomarker of the disease, as well as identification of therapeutic targets in ARID1A mutated ampullary cancers.

4.
Carcinogenesis ; 36(4): 441-51, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25742747

ABSTRACT

Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro.


Subject(s)
Antineoplastic Agents/pharmacology , DEAD-box RNA Helicases/genetics , Drug Resistance, Neoplasm/genetics , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Apoptosis/drug effects , Apoptosis/genetics , Calcium-Binding Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cisplatin/pharmacology , Cytoskeletal Proteins/genetics , DEAD-box RNA Helicases/biosynthesis , DNA Copy Number Variations/genetics , DNA Damage/drug effects , DNA Damage/genetics , DNA Methylation/genetics , Databases, Nucleic Acid , Epirubicin/pharmacology , Gastric Mucosa/cytology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Histones/genetics , Humans , Nerve Tissue Proteins/genetics , Prognosis , RNA Interference , RNA, Small Interfering , Retrospective Studies , Transcription Factors/genetics
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