Genomic profiling of submucosal-invasive gastric cancer by array-based comparative genomic hybridization.
ABSTRACT: Genomic copy number aberrations (CNAs) in gastric cancer have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis. However, involvement of genomic CNAs in the process of submucosal invasion and lymph node metastasis in early gastric cancer is still poorly understood. In this study, to address this issue, we collected a total of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC), analyzed their genomic profiles by array CGH, and compared them between paired samples of mucosal (MU) and submucosal (SM) invasion (23 pairs), and SM invasion and lymph node (LN) metastasis (9 pairs). Initially, we hypothesized that acquisition of specific CNA(s) is important for these processes. However, we observed no significant difference in the number of genomic CNAs between paired MU and SM, and between paired SM and LN. Furthermore, we were unable to find any CNAs specifically associated with SM invasion or LN metastasis. Among the 23 cases analyzed, 15 had some similar pattern of genomic profiling between SM and MU. Interestingly, 13 of the 15 cases also showed some differences in genomic profiles. These results suggest that the majority of SMGCs are composed of heterogeneous subpopulations derived from the same clonal origin. Comparison of genomic CNAs between SMGCs with and without LN metastasis revealed that gain of 11q13, 11q14, 11q22, 14q32 and amplification of 17q21 were more frequent in metastatic SMGCs, suggesting that these CNAs are related to LN metastasis of early gastric cancer. In conclusion, our data suggest that generation of genetically distinct subclones, rather than acquisition of specific CNA at MU, is integral to the process of submucosal invasion, and that subclones that acquire gain of 11q13, 11q14, 11q22, 14q32 or amplification of 17q21 are likely to become metastatic.
Project description:In this study, we investigated CNAs of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC) by 44k oligonucleotide-based array comparative genomic hybridization (array CGH). Overall design: 23 mucosal portion of SMGC vs 23 paired submucosal (SM) portion of SMGC, 9 SM portion vs 9 paired lymph node (LN) metastasis, 12 SMGC with LN metastasis vs 15 SMGC without LN metastasis
Project description:In this study, we investigated CNAs of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC) by 44k oligonucleotide-based array comparative genomic hybridization (array CGH). 23 mucosal portion of SMGC vs 23 paired submucosal (SM) portion of SMGC, 9 SM portion vs 9 paired lymph node (LN) metastasis, 12 SMGC with LN metastasis vs 15 SMGC without LN metastasis
Project description:Abstract Aim Although rectal neuroendocrine tumors (NETs) are considered to be rare low?grade malignancies when lymph node metastasis (LNM) is present, their degree of malignancy is comparable to that of colorectal cancer (CRC). However, it remains unclear as to which patients require radical lymph node dissection. The aim of this study was to elucidate the risk factors for LNM and develop a risk?scoring system for LNM to help determine appropriate therapeutic approaches. Methods In this study, we examined 103 patients with rectal NETs who underwent local resection (n = 55) or radical resection with LN dissection (n = 48). We evaluated each pathological feature, including the depth of submucosal invasion (SM depth) and tumor budding grade. Results According to our univariate analyses and previous reports, the significant five risk factors for LNM were weighted with point values: 2 points for tumor size ? 15 mm and muscularis invasion, and 1 point each for SM depth ? 2000 µm, positive lymphovascular invasion, budding grade 3, and vertical margin. The area under the receiver operating curve for the scoring system was 0.899 (95% CI: 0.843?0.955). When a score of 2 was used as the cut?off value, the sensitivity and specificity for the prediction of LNM were 100% and 72.1%, respectively. Conclusions The risk?scoring system for LNM of rectal NETs showed high diagnostic performance. Using this risk?scoring system, it is possible to predict the risk of LNM and thereby potentially avoid unnecessary surgery. Further prospective external validation studies should be performed. The study was registered in the Japanese Clinical Trials Registry as UMIN000036658. The risk?scoring system for LNM of rectal NETs could predict the risk of LNM and thereby potentially avoid unnecessary surgery.
Project description:<h4>Background/aims</h4>Papillary gastric cancer (GC) is classified as differentiated adenocarcinoma, together with well-differentiated (WD) and moderately differentiated (MD) adenocarcinoma. This study evaluated the risk of lymph node metastasis (LNM) in submucosal (SM) invasive papillary GC compared with other differentiated early GC types.<h4>Methods</h4>This retrospective study involved three tertiary hospitals and enrolled 1,798 lesions with differentiated SM invasive GC treated with curative gastrectomy between March 2001 and December 2012. All pathology slides were reviewed, and clinicopathologic findings associated with LNM, including tumor size, location, gross type, ulceration, depth and width of SM invasion, and lymphovascular invasion (LVI), were analyzed.<h4>Results</h4>The proportion of SM papillary GC was 2.8% (n=51). SM papillary GC was associated with larger tumor size and deeper and wider SM invasion than other differentiated GC types. LNM was significantly higher in the papillary type than in the MD and WD types. LNM was found in 27.5% of SM papillary GC patients (WD: 9.0%, MD: 21.2%). LVI was the only significant risk factor for LNM in SM papillary GC. The depth or width of SM invasion was not associated with LNM in papillary GC. Lower third location or elevated gross appearance was significantly associated with LVI.<h4>Conclusions</h4>SM papillary GC had the highest LNM rate, with features different from those of other differentiated SM invasive GCs. The treatment strategy for SM papillary GC should be carefully approached, especially for lesions located in the lower third or of the elevated gross type.
Project description:Whole exome sequencing and copy number aberration (CNA) analysis were performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84·4%) were clonal in both compartments, 3 (4·7%) were PB-specific and 7 (10·9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0·5-5·3%). Of 41 CNAs, 27 (65·8%) were shared by both compartments and 7 (17·1%) were LN- or PB-specific. Overall, 6 of 9 cases (66·7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23·3-p11·1), del9(p24·3-p13·1) and gain 2(p25·3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse.
Project description:The recent rise in antibiotic and chemotherapeutic resistance necessitates the search for novel drugs. Potential therapeutics can be produced by specialized metabolism gene clusters (SMGCs). We mined for SMGCs in metagenomic samples from Atlantis II Deep, Discovery Deep and Kebrit Deep Red Sea brine pools. Shotgun sequence assembly and secondary metabolite analysis shell (antiSMASH) screening unraveled 2751 Red Sea brine SMGCs, pertaining to 28 classes. Predicted categorization of the SMGC products included those (1) commonly abundant in microbes (saccharides, fatty acids, aryl polyenes, acyl-homoserine lactones), (2) with antibacterial and/or anticancer effects (terpenes, ribosomal peptides, non-ribosomal peptides, polyketides, phosphonates) and (3) with miscellaneous roles conferring adaptation to the environment/special structure/unknown function (polyunsaturated fatty acids, ectoine, ladderane, others). Saccharide (80.49%) and putative (7.46%) SMGCs were the most abundant. Selected Red Sea brine pool sites had distinct SMGC profiles, e.g., for bacteriocins and ectoine. Top promising candidates, SMs with pharmaceutical applications, were addressed. Prolific SM-producing phyla (Proteobacteria, Actinobacteria, Cyanobacteria), were ubiquitously detected. Sites harboring the largest numbers of bacterial and archaeal phyla, had the most SMGCs. Our results suggest that the Red Sea brine niche constitutes a rich biological mine, with the predicted SMs aiding extremophile survival and adaptation.
Project description:We designed a study to investigate genetic relationships between primary tumors of oral squamous cell carcinoma (OSCC) and their lymph node metastases, and to identify genomic copy number aberrations (CNAs) related to lymph node metastasis. For this purpose, we collected a total of 42 tumor samples from 25 patients and analyzed their genomic profiles by array-based comparative genomic hybridization. We then compared the genetic profiles of metastatic primary tumors (MPTs) with their paired lymph node metastases (LNMs), and also those of LNMs with non-metastatic primary tumors (NMPTs). Firstly, we found that although there were some distinctive differences in the patterns of genomic profiles between MPTs and their paired LNMs, the paired samples shared similar genomic aberration patterns in each case. Unsupervised hierarchical clustering analysis grouped together 12 of the 15 MPT-LNM pairs. Furthermore, similarity scores between paired samples were significantly higher than those between non-paired samples. These results suggested that MPTs and their paired LNMs are composed predominantly of genetically clonal tumor cells, while minor populations with different CNAs may also exist in metastatic OSCCs. Secondly, to identify CNAs related to lymph node metastasis, we compared CNAs between grouped samples of MPTs and LNMs, but were unable to find any CNAs that were more common in LNMs. Finally, we hypothesized that subpopulations carrying metastasis-related CNAs might be present in both the MPT and LNM. Accordingly, we compared CNAs between NMPTs and LNMs, and found that gains of 7p, 8q and 17q were more common in the latter than in the former, suggesting that these CNAs may be involved in lymph node metastasis of OSCC. In conclusion, our data suggest that in OSCCs showing metastasis, the primary and metastatic tumors share similar genomic profiles, and that cells in the primary tumor may tend to metastasize after acquiring metastasis-associated CNAs.
Project description:Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n=178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n=142; RJH set, n=104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients.
Project description:Background/Aims:The accurate assessment of the depth of invasion of early gastric cancer (EGC) is critical to determine the most appropriate treatment option. However, it is difficult to distinguish shallow submucosal (SM1) invasion from deeper submucosal (SM2) invasion. We investigated the diagnostic performance of endoscopic ultrasonography (EUS) using a miniature probe for EGC with suspected SM invasion. Methods:From April 2008 to June 2018, EGCs with suspected SM invasion were analyzed retrospectively. The EGCs examined by a 20 MHz high-frequency miniature probe was included in our study. Esophago-gastric junction cancers and patients treated by chemotherapy before resection were excluded. The sensitivity and specificity for the detection of SM2 invasion by EUS were compared with those of white light imaging (WLI). Additionally, factors related to depth underestimation or overestimation were investigated using multivariate analysis. Results:A total of 278 EGCs in 259 patients were included in the final analysis. The sensitivity and specificity for SM2 or deeper by EUS were 73.7% (87/118) and 74.4% (119/160), respectively. The sensitivity and specificity by WLI were 47.5% (56/118) and 68.1% (109/160), respectively. The sensitivity of EUS was significantly superior to that of conventional endoscopy (p<0.01). Multivariate analysis revealed that an anterior location of the EGC was an independent risk factor for underestimation by EUS (odds ratio, 3.3; 95% confidence interval, 1.1 to 9.8; p=0.03). Conclusions:The depth diagnostic performance for EGCs with suspected SM invasion using EUS was satisfactory and superior to that of conventional endoscopy. Additionally, it is important to recognize factors that may lead to misdiagnosis in those lesions.
Project description:Little is known concerning the prognostic significance of the degree of lymphatic vessel invasion in pancreatic head cancer. To address this gap in knowledge, we retrospectively examined 60 patients with locally advanced, surgically resectable pancreatic head cancer who underwent pancreaticoduodenectomy and lymph node (LN) dissection.All cases were histopathologically diagnosed as ductal adenocarcinoma, stage II (25 pT3N0 cases, 35 pT3N1 cases). The following variables were investigated: age; sex; neoadjuvant therapy; adjuvant therapy; tumor size; tumor grade; invasion into the serosa, retropancreatic tissue, duodenum, bile duct, portal venous system and perineural area; cut margins; LN metastasis; and the number of invaded lymphatic vessels (LVI-score).Univariate analysis demonstrated that LN metastasis and an LVI-score ?5 were significantly associated with poor disease-free survival. Multivariate Cox regression analysis confirmed that LN metastasis and an LVI-score ?7 were significantly associated with poor disease-free survival. Additionally, LVI-scores ?9 and ?10 were comparable to or surpassed the significance of LN metastasis based on the hazard ratio. Univariate analysis demonstrated that tumor size >30?mm, duodenal invasion, LN metastasis and an LVI-score ?2 were significantly associated with poor overall survival. Multivariate Cox regression analysis confirmed that LN metastasis and LVI-scores ?9 and ?10 were significantly associated with poor overall survival, and an LVI-score ?10 was comparable to or surpassed the significance of LN metastasis based on the hazard ratio.Our study strongly suggests that a high degree of lymphatic vessel invasion is associated with a poor prognosis in patients with locally advanced, surgically resectable pancreatic head cancer.