NODAL

Gene Summary

Gene:NODAL; nodal growth differentiation factor
Aliases: HTX5
Location:10q22.1
Summary:The protein encoded by this gene is a member of the TGF-beta superfamily. Studies of the mouse counterpart suggested that this gene may be essential for mesoderm formation and subsequent organization of axial structures in early embryonic development. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:nodal homolog
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

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 (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: NODAL (cancer-related)

Schmid CA, Robinson MD, Scheifinger NA, et al.
DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.
J Exp Med. 2015; 212(5):775-92 [PubMed] Article available free on PMC after 04/11/2015 Related Publications
The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton's tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.

He HL, Lee YE, Chen HP, et al.
Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer.
Exp Mol Pathol. 2015; 98(3):338-45 [PubMed] Related Publications
Genes associated with protein folding have been found to have certain prognostic significance in a subset of cancers. The aim of this study is to evaluate the clinical impact of DNAJC12 expression in patients with rectal cancers receiving neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Through data mining from a public transcriptomic dataset of rectal cancer focusing on genes associated with protein folding, we found that DNAJC12, a member of the HSP40/DNAJ family, was the most significant such gene correlated with the CCRT response. We further evaluated the expression of DNAJC12 by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancers. From this set, we statistically analyzed the association of DNAJC12 expression with various clinicopathological factors, tumor regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of DNAJC12 was significantly associated with advanced pre- and post-treatment tumor status (P<0.001), advanced pre- and post-treatment nodal status (P<0.001), increased vascular invasion (P=0.015), increased perineural invasion (P=0.023) and lower tumor regression grade (P=0.009). More importantly, high expression of DNAJC12 was found to be correlated with poor prognosis for OS (P=0.0012), DFS (P<0.0001) and LRFS (P=0.0001). In multivariate analysis, DNAJC12 overexpression still emerged as an independent prognosticator for shorter OS (P=0.040), DFS (P<0.001) and LRFS (P=0.016). The data indicate that DNAJC12 overexpression acts as a negative predictive factor for the response to neoadjuvant CCRT and was significantly associated with shorter survival in patients with rectal cancers receiving neoadjuvant CCRT followed by surgery.

Cappellesso R, Fassan M, Hanspeter E, et al.
HER2 status in gastroesophageal cancer: a tissue microarray study of 1040 cases.
Hum Pathol. 2015; 46(5):665-72 [PubMed] Related Publications
Among patients with gastric cancer (GC) and gastroesophageal cancer (G-EC), HER2 amplification identifies those who may benefit from trastuzumab. HER2 status assessment, however, is influenced by preanalytic, analytic, and postanalytic variables. In a series of 5426 microarray cancer tissue cores obtained from 1040 GC/G-ECs (824 GC, 216 G-EC) and 720 synchronous nodal metastases, we evaluated both the performances of 2 different immunohistochemistry (IHC) protocols and the HER2 status intratumor variability. The prevalence of HER2 amplification and protein overexpression were assessed by chromogenic in situ hybridization and by 2 IHC protocols (CB11 and 4B5). HER2 was amplified in 114 (11%) of 1040 cases; in 6 (5.3%) of 114 cases, gene amplification only involved nodal metastasis. HER2 amplification prevailed in intestinal-type (P = .001) and low-grade (P < .001) tumors, showing no correlation with patients' age/sex, tumor location, stage, and Ming histotype. Overall, 12.5% and 13.7% of cases IHC scored 2+/3+ using the CB11-IHC and the 4B5-IHC protocol, respectively. HER2 amplification was not associated with protein overexpression (score 0/1+) in 11.4% and 6.2% of cases using the CB11-IHC and the 4B5-IHC protocol, respectively. The 4B5-IHC protocol proved more sensitive than CB11-IHC (93.9% versus 88.6%) and just as specific (96.1% versus 96.9%). Tested by chromogenic in situ hybridization, intratumor HER2 status was "substantially" consistent in different tissue cores obtained from the same case (κ = 0.78). Similar results were obtained for HER2 protein expression (CB11-IHC, κ = 0.78, and 4B5-IHC, κ = 0.83). Immunohistochemistry testing, however, fails in identifying about 10% of HER2-amplified cancers, potentially excluding these patients from anti-HER2 therapy.

Yuksel UM, Dilek G, Dogan L, et al.
The relationship between CSE1L expression and axillary lymph node metastasis in breast cancer.
Tumori. 2015 Mar-Apr; 101(2):194-8 [PubMed] Related Publications
AIM: CSE1L is the human homologue to the yeast gene CSE1 and CSE1L is a gene related to cancer progression. Thus, CSE1L may regulate the invasion and metastasis of breast cancer. The aim of this study is to show the relationship between CSE1L and axillary lymph node metastasis.
METHODS: Sixty-six breast cancer patients were evaluated according to patient and tumor characteristics. Immunohistochemistry was carried out on formalin-fixed, paraffin-embedded archival breast tumor tissues. The results of CSE1L staining were analyzed according to the percentage of immunoreactive cells.
RESULTS: There were 29 patients without axillary lymph node metastasis and 37 patients with nodal metastasis. The mean age of the patients was 50.6 ± 11.3 years. Age, tumor size, nuclear grade and hormone receptor status were similar in the axillary lymph node positive and negative groups. There was a statistically significant relationship between cytoplasmic CSE1L expression and axillary lymph node metastasis. However, nuclear CSE1L expression did not have any effect on axillary lymph node metastasis.
CONCLUSIONS: Cytoplasmic CSE1L overexpression may be a valuable tool for prognosis of breast cancer in future.

Kang BW, Kim JG, Lee SJ, et al.
Expression of aquaporin-1, aquaporin-3, and aquaporin-5 correlates with nodal metastasis in colon cancer.
Oncology. 2015; 88(6):369-76 [PubMed] Related Publications
OBJECTIVES: The clinical significance of aquaporin-1 (AQP1), aquaporin-3 (AQP3), and aquaporin-5 (AQP5) expression was analyzed in a large number of patients with colon cancer.
METHODS: AQP1, AQP3, and AQP5 expression was investigated based on the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery. Scores were given to the staining intensity and percentage of positive cells, and the staining score was defined as the sum of these scores then used to categorize the AQP expression as negative, weakly AQP-positive, or strongly AQP-positive.
RESULTS: A total of 298 (61.3%) patients were identified as strongly AQP1-positive (staining score ≥ 6), while 38 (7.8%) were strongly AQP3-positive and 145 (29.8%) were strongly AQP5-positive. The overexpression of AQP1, AQP3, and AQP5 was significantly correlated with lymph node metastasis in a multivariate logistic analysis (AQP1, p = 0.026; AQP3, p = 0.023; AQP5, p = 0.003). While the multivariate survival analysis, which included age, histology, TNM stage, and CEA level showed that the expression of AQP1, AQP3, and AQP5 had no effect on the overall survival and disease-free survival.
CONCLUSIONS: The current study found a significant correlation between AQP1, AQP3, and AQP5 expression and lymph node metastasis in patients with surgically resected colon cancer.

Uccini S, Al-Jadiry MF, Scarpino S, et al.
Epstein-Barr virus-positive diffuse large B-cell lymphoma in children: a disease reminiscent of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly.
Hum Pathol. 2015; 46(5):716-24 [PubMed] Related Publications
Pediatric Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare disease in nonimmunocompromised hosts. In a review of 231 cases of malignant lymphoma (87 Hodgkin lymphoma and 144 non-Hodgkin lymphoma) occurring in Iraqi children, 7 cases (5% of NHLs) were classified as EBV+ DLBCL. Six children presented with nodal disease, and 1 presented with extranodal localization (bone). In all cases, the disease was at an advanced clinical stage (III/IV). Evidence of immunodeficiency (Evans syndrome and selective IgA deficiency) was observed in a single case. Two cases were "monomorphic" with immunoblastic histology, and 5 cases were "polymorphic" with histologic aspects reminiscent of nodular lymphocyte-predominant Hodgkin lymphoma (2 cases) and of CD30+ classical Hodgkin lymphoma (3 cases). In all cases, tumor cells were EBV infected (EBER+/LMP-1+), were medium-large B-cells (CD20+/CD79a+/PAX-5+/BOB-1+/OCT-2+) of non-germinal center (non-GC) origin (CD10-/MUM-1+), and had high proliferative activity (50%-70%). Chromosomal translocations involving BCL2, MYC, and IGH genes were not observed. IGH monoclonality could be demonstrated in 3 of 3 investigated cases. Six cases of EBV-negative DLBCL (4% of NHL) were present in the same series. All had monomorphic histology with centroblastic/immunoblastic morphology; 3 cases were of GC type and 3 of non-GC type. Our findings indicate that in Iraq, DLBCLs are 9% of NHLs. Moreover, 2 different types of the disease do exist; the EBV-positive cases, with strong histologic and immunohistochemical resemblance with EBV+ DLBCL of the elderly, and the EBV-negative cases, which are similar to the pediatric DLBCL usually observed in Western populations.

Pham-Ledard A, Cowppli-Bony A, Doussau A, et al.
Diagnostic and prognostic value of BCL2 rearrangement in 53 patients with follicular lymphoma presenting as primary skin lesions.
Am J Clin Pathol. 2015; 143(3):362-73 [PubMed] Related Publications
OBJECTIVES: To study the diagnostic value of BCL2 rearrangement in follicle center lymphoma (FCL) presenting as primary skin lesions, evaluate its prevalence and the prognostic value in primary cutaneous FCL (PCFCL), and assess prognostic factors in PCFCL.
METHODS: Fifty-three patients with a cutaneous presentation of FCL without a history of nodal lymphoma were selected retrospectively. Clinical and histologic data were collected together with staging and follow-up data. A fluorescence in situ hybridization (FISH) test for BCL2 split probes was performed on skin biopsy specimens.
RESULTS: Initial staging procedures identified 47 PCFCLs and six cases of secondary skin involvement of FCL (SSIFCL). FISH detected seven cases carrying a BCL2 rearrangement: four (8.5%) of 47 PCFCLs and three (50%) of six SSIFCLs. These seven cases coexpressed BCL2 and CD10. In PCFCL, cutaneous relapse rate was 42.6%. A small/medium centrocytic cell population was associated with a higher probability of skin relapse in univariate (P = .008) and multivariate (P = .028) analysis, and BCL2 rearrangement detection was associated with secondary extracutaneous spreading (P = .05).
CONCLUSIONS: We observed that BCL2 rearrangement in PCFCL is rare, associated with initial positivity of staging (diagnostic value) or with secondary extracutaneous spreading (prognostic value). In selected cases with BCL2-CD10 coexpression, FISH testing could detect patients with poor outcome and require closer monitoring.

Samdani T, Schultheis M, Stadler Z, et al.
Lymph node yield after colectomy for cancer: is absence of mismatch repair a factor?
Dis Colon Rectum. 2015; 58(3):288-93 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Nodal staging is crucial in determining the use of adjuvant chemotherapy for colon cancer. The number of metastatic lymph nodes has been positively correlated with the number of lymph nodes examined. Current guidelines recommend that at minimum 12 to 14 lymph nodes be assessed. In some studies, mismatch repair deficiency has been associated with lymph node yield.
OBJECTIVE: The purpose of this work was to determine whether mismatch repair-deficient colorectal tumors are associated with increased lymph node yield.
DESIGN: We queried an institutional database to analyze colectomy specimens with immunohistochemistry for mismatch repair genes in patients treated for colorectal cancer between 1999 and 2012. Before 2006, immunohistochemistry was performed at the request of an oncologist or surgeon. After 2006, it was routinely performed for patients <50 years of age. We measured the association of clinical and pathologic features with lymph node quantity. Fourteen predictors and confounders were jointly analyzed in a multivariable linear regression model.
SETTINGS: The study was conducted at a single tertiary care institution.
PATIENTS: Tissue specimens from 256 patients were reviewed.
MAIN OUTCOME MEASURES: The correlation of tumor, patient, and operative variables to the yield of mesenteric lymph nodes was measured.
RESULTS: Of 256 colectomy specimens reviewed, 94 had mismatch repair deficiency. On univariate analysis, mismatch repair deficiency was associated with lower lymph node yield, older patient age, right-sided tumors, and poor differentiation. The linear regression model identified 5 variables with independent relationships to lymph node yield, including patient age, specimen length, lymph node ratio, perineural invasion, and tumor size. A positive correlation was observed with tumor size, specimen length, and perineural invasion. Tumor location had a more complex, nonlinear, quadratic relationship with lymph node yield; proximal tumors were associated with a higher yield than more distal lesions. Mismatch repair deficiency was not independently associated with lymph node yield.
LIMITATIONS: Mismatch repair immunohistochemistry based on patient age, family history, and pathologic features may reduce the generalizability of these results. Our sample size was too small to identify variables with small measures of effect. The retrospective nature of the study did not permit a true assessment of the extent of mesenteric resection.
CONCLUSIONS: Patient age, length of bowel resected, lymph node ratio, perineural invasion, tumor size, and tumor location were significant predictors of lymph node yield. However, when controlling for surgical and pathologic factors, mismatch repair protein expression did not predict lymph node yield.

Noorlag R, van Kempen PM, Stegeman I, et al.
The diagnostic value of 11q13 amplification and protein expression in the detection of nodal metastasis from oral squamous cell carcinoma: a systematic review and meta-analysis.
Virchows Arch. 2015; 466(4):363-73 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Despite improvements in both diagnostic and therapeutic strategies, the prognosis of oral squamous cell carcinoma (OSCC) has not changed significantly over the last decades. Prognosis of OSCC particularly depends on the presence of nodal metastasis in the neck. Therefore, proper determination of the nodal status is pivotal for appropriate treatment. Unfortunately, current available imaging techniques (magnetic resonance imaging or ultrasound even with fine needle aspiration of suspected lymph nodes (LNs)) fail to detect occult nodal disease accurately. Clinicians in head and neck oncology urgently need new diagnostic tools to reliably determine the presence of nodal metastasis of the neck. Gain of the chromosomal region 11q13 is one of the most prominent genetic alterations in head and neck cancer and is associated with poor prognosis and metastasis. The aim of this systematic review and meta-analysis was to determine the diagnostic value of either 11q13 amplification or amplification/protein overexpression of individual genes located on 11q13 to detect nodal metastasis in OSCC. A search was conducted in Pubmed, EMBASE, and Cochrane, and 947 unique citations were retrieved. Two researchers independently screened all articles and only 18 were found to meet our inclusion criteria and were considered of sufficient quality for meta-analysis. Pooled results of those show that both amplification of CCND1 and protein overexpression of cyclin D1 significantly correlate with lymph node metastasis (LNM) in OSCC. In addition, amplification of CCND1 shows a negative predictive value of 80 % in the detection of LNM in early stage OSCCs which are clinically lymph node negative although this evidence is sparse and should be validated in a larger homogeneous cohort of T1-2 OSCC.

Shaker O, Maher M, Nassar Y, et al.
Role of microRNAs -29b-2, -155, -197 and -205 as diagnostic biomarkers in serum of breast cancer females.
Gene. 2015; 560(1):77-82 [PubMed] Related Publications
Micro-RNAs (miRs) are known to be differentially expressed in the serum of cancer patients and controls, and can thus be used as biomarkers for cancer screening. We detected the expression level of miR-29b-2, 155, 197 and 205 in the serum of female breast cancer patients and healthy controls to detect whether serum level of this chosen micro-RNAs could detect patients with breast cancer and also to detect difference in level of micro-RNAs between non-metastatic cases and metastatic cases, also we tried to detect any relation between level of micro-RNAs and the stage of the tumor, the size of tumor, nodal affection, the presence of metastasis and also the site of metastasis. Serum samples were collected from 130 female patients, 80 with non-metastatic breast cancer, 20 with metastatic breast cancer and 30 healthy controls. Real-time quantitative PCR was used to detect the expression level of miR-29b-2, -155, -197 and -205. The expression level of miR-29b-2, -155, -197 and -205 was significantly increased in the serum of breast cancer patients. miR-29b-2, -155, -197 and -205 may be useful as a blood-based biomarker for breast cancer screening.

Kato S, Asano N, Miyata-Takata T, et al.
T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases.
Am J Surg Pathol. 2015; 39(4):462-71 [PubMed] Related Publications
Among Epstein-Barr virus (EBV)-positive cytotoxic T/NK-cell lymphoma, there are only a few reports on the clinicopathologic features of patients with primary nodal presentation (nodal EBV cytotoxic T-cell lymphoma [CTL]). Here, we compared the clinicopathologic profiles of 39 patients with nodal EBV CTL with those of 27 cases of "extranasal" NK/T-cell lymphoma of nasal type (ENKTL), especially addressing their T-cell receptor (TCR) phenotype. Histologically, 22 of 39 nodal EBV CTL cases (56%) were unique in having centroblastoid appearance, which was contrasted with the lower incidence of this feature in ENKTL (15%, P=0.001). In contrast, pleomorphic appearance was more frequently seen in ENKTL than in nodal EBV CTL (67% vs. 23%, P=0.001). Thirty-three of 39 nodal EBV CTL cases (85%) were of T-cell lineage on the basis of TCR expression and/or TCRγ gene rearrangement; in detail, 18 cases (46%) were TCRβ positive (αβ T), 5 (13%) were TCRγ and/or δ positive (γδ T), and 10 (26%) were TCR-silent type with clonal TCRγ gene rearrangement but no expression of TCRβ, γ, or δ. These results were clearly contrasted by a lower incidence of T-cell lineage in ENKTL (7 cases, 26%, P<0.001). Notably, the survival time of the 5 nodal lymphoma patients with γδ T-cell phenotype was within 3 months, which was inferior to those of αβ T and TCR-silent types (P=0.003), and 3 of those with available clinical information were all found to be associated with autoimmune diseases. These data suggest that nodal EBV CTL is distinct from ENKTL.

Battistella M, Romero M, Castro-Vega LJ, et al.
The High Expression of the microRNA 17-92 Cluster and its Paralogs, and the Downregulation of the Target Gene PTEN, Is Associated with Primary Cutaneous B-Cell Lymphoma Progression.
J Invest Dermatol. 2015; 135(6):1659-67 [PubMed] Related Publications
The oncogenic microRNA (miR) 17-92 cluster has a causative role in the lymphomagenesis of nodal B-cell lymphomas, by activating proliferation and inhibiting apoptosis. Here we analyzed primary cutaneous B-cell lymphomas for the miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25. In 22 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL-LT) compared with 22 primary cutaneous follicle center lymphomas (PCFCLs), we found that miR-20a and miR-106a were overexpressed. Multivariate Cox analysis showed that higher miR-20a and miR-20b expression levels were associated with shorter disease-free and overall survival, independently from histological type. Gene expression profiling also showed a downregulation of 8 candidate target genes of miR-20a, miR-20b, and miR-106a in PCLBCL-LT compared with PCFCL. Among the candidate target genes, PTEN, NCOA3, and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative reverse transcriptase-PCR on CD20-positive laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with shorter disease-free survival (DFS), independently from the histological type. Altogether, this molecular and bioinformatic study of 44 patient skin biopsy samples showed that the oncogenic miR-17-92 cluster and its paralogs were involved in cutaneous B-cell lymphoma progression, and that the downregulation of the target gene PTEN was associated with shorter DFS.

Ieni A, Barresi V, Caltabiano R, et al.
Discordance rate of HER2 status in primary gastric carcinomas and synchronous lymph node metastases: a multicenter retrospective analysis.
Int J Mol Sci. 2014; 15(12):22331-41 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: The assessment of human epidermal growth factor receptor 2 (HER2) gene amplification is essential in order to identify those patients affected by advanced gastric cancer who may benefit from Trastuzumab targeted therapy.
MATERIALS AND METHODS: With the aim to investigate the concordance rate in HER2 status between primary gastric carcinoma (GC) and synchronous lymphnode metastases, we investigated HER2 status in a cohort of 108 surgical formalin-fixed paraffin-embedded specimens of GC and matched synchronous metastatic lymph nodes collected from three different units of Anatomic Pathology in southern of Italy. Fleiss-Cohen weighted k statistics were used to assess the concordance rate of HER2 status.
RESULTS: HER2 amplification was observed in 17% of primary GCs and the overall concordance rate with corresponding nodal metastases was 90.74%. Changes in HER2 status between primary GC and matched synchronous metastases were evidenced in 10 (9.26%) cases. Of these, 6 cases were HER2 amplified in the primary GC and not amplified in the metastases, while 4 were HER2 not amplified in the primary tumour and amplified in the lymph node metastases.
CONCLUSIONS: Although at present the simultaneous determination of HER2 in advanced gastric cancer and corresponding metastatic lymph nodes is not mandatory, the possibility that the synchronous metastases of GC have a different HER2 status from that of the primary tumour is of remarkable significance; Indeed this may have influence on the therapeutic management and prognosis of the patients.

Chai YJ, Kim YA, Jee HG, et al.
Expression of the embryonic morphogen Nodal in differentiated thyroid carcinomas: Immunohistochemistry assay in tissue microarray and The Cancer Genome Atlas data analysis.
Surgery. 2014; 156(6):1559-67; discussion 1567-8 [PubMed] Related Publications
BACKGROUND: Nodal, an embryonic morphogen, plays a role in tumorigenesis of melanoma, breast, and prostate cancer; however, its role in thyroid carcinoma is unknown. We examined Nodal expression in thyroid tumors by immunohistochemistry assay and The Cancer Genome Atlas (TCGA) analysis.
METHODS: An immunohistochemistry assay was performed in a tissue microarray comprising 128 classic papillary thyroid carcinomas (PTC), 58 follicular thyroid carcinomas (FTC), 19 follicular variants of PTC (FVPTC), 57 follicular adenomas (FA), 54 adenomatous goiters (AG), and 5 normal thyroid tissues. The TCGA database was examined to evaluate the expression of Nodal mRNA in normal thyroid and PTC.
RESULTS: The proportion of tumors showing negative Nodal expression in PTC, FTC, FVPTC, FA, and AG was 0%, 1.7%, 0%, 14%, and 41%, respectively. For the diagnosis of malignant tumors, the sensitivity, specificity, positive predictive value, and negative predictive value of positive Nodal staining was 99%, 27%, 72%, and 97%, respectively. High Nodal expression was associated with older age and BRAF mutation in PTC. TCGA analysis revealed PTC had greater Nodal mRNA expression than normal thyroid (P = .012).
CONCLUSION: Nodal staining might be useful "rule-out test" for the diagnosis of malignant thyroid tumor. Nodal may be associated with the tumorigenesis of thyroid malignancy.

Uziel O, Yosef N, Sharan R, et al.
The effects of telomere shortening on cancer cells: a network model of proteomic and microRNA analysis.
Genomics. 2015; 105(1):5-16 [PubMed] Related Publications
Previously, we have shown that shortening of telomeres by telomerase inhibition sensitized cancer cells to cisplatinum, slowed their migration, increased DNA damage and impaired DNA repair. The mechanism behind these effects is not fully characterized. Its clarification could facilitate novel therapeutics development and may obviate the time consuming process of telomere shortening achieved by telomerase inhibition. Here we aimed to decipher the microRNA and proteomic profiling of cancer cells with shortened telomeres and identify the key mediators in telomere shortening-induced damage to those cells. Of 870 identified proteins, 98 were differentially expressed in shortened-telomere cells. 47 microRNAs were differentially expressed in these cells; some are implicated in growth arrest or act as oncogene repressors. The obtained data was used for a network construction, which provided us with nodal candidates that may mediate the shortened-telomere dependent features. These proteins' expression was experimentally validated, supporting their potential central role in this system.

Chen G, Li G, Luo M, et al.
Clinical significance of SPRR1A expression in progesterone receptor-positive breast cancer.
Tumour Biol. 2015; 36(4):2601-5 [PubMed] Related Publications
Small proline-rich repeat protein 1A (SPRR1A) is a marker for terminal squamous cell differentiation. Previous studies showed that SPRR1A expression increases in squamous cell carcinoma of the skin, but decreases in esophageal squamous cell carcinoma. This study focuses on the expression of SPRR1A protein in breast cancers (BCs) in China. A total of 111 patients with histologically confirmed BC, who underwent radical surgery between January 2006 and September 2007 in China Medical University, were enrolled. The relationship between SPRR1A expression and clinicopathological factors as well as BC prognoses was also determined. Overall, SPRR1A expression was detected in more than half of the BC specimens by immunohistochemistry (56/111, 53.8%), but there was no significant difference between age groups (≥50 vs. <50 years) in terms of SPRR1A expression (P = 0.915), as well as no differences between SPRR1A expression and the clinical stage (0-I vs. II-III) or nodal status (P = 0.234 and 0.632, respectively). Moreover, human epidermal growth factor receptor 2 overexpression was not correlated with SPRR1A expression, whereas Ki67 was associated with SPRR1A expression (P = 0.155 and 0.028, respectively). Interestingly, SPRR1A expression was significantly associated with progesterone receptor-positive (P = 0.010) rather than estrogen receptor-positive (0.778) BCs. The 5-year survival rate in patients did not differ with the presence or absence of SPRR1A expression (P = 0.753), whereas the combination of SPRR1A expression, progesterone receptor status, and menopausal status allowed identification of a subgroup of BC patients with a good long-term prognosis. Thus, the SPRR1A status might play an important role in the prognosis of postmenopausal breast carcinoma patients, especially that of progesterone receptor-positive subgroups.

Knief J, Gebauer N, Bernard V, et al.
Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.
J Clin Endocrinol Metab. 2015; 100(2):754-62 [PubMed] Related Publications
CONTEXT: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored.
OBJECTIVE: Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations.
DESIGN: A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data.
RESULTS: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively.
CONCLUSIONS: Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.

Galván JA, García-Martínez J, Vázquez-Villa F, et al.
Validation of COL11A1/procollagen 11A1 expression in TGF-β1-activated immortalised human mesenchymal cells and in stromal cells of human colon adenocarcinoma.
BMC Cancer. 2014; 14:867 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: The human COL11A1 gene has been shown to be up-regulated in stromal cells of colorectal tumours, but, so far, the immunodetection of procollagen 11A1, the primary protein product of COL11A1, has not been studied in detail in human colon adenocarcinomas. Some cancer-associated stromal cells seem to be derived from bone marrow mesenchymal cells; the expression of the COL11A1 gene and the parallel immunodetection of procollagen 11A1 have not been evaluated in these latter cells, either.
METHODS: We used quantitative RT-PCR and/or immunocytochemistry to study the expression of DES/desmin, VIM/vimentin, ACTA2/αSMA (alpha smooth muscle actin) and COL11A1/procollagen 11A1 in HCT 116 human colorectal adenocarcinoma cells, in immortalised human bone marrow mesenchymal cells and in human colon adenocarcinoma-derived cultured stromal cells. The immunodetection of procollagen 11A1 was performed with the new recently described DMTX1/1E8.33 mouse monoclonal antibody. Human colon adenocarcinomas and non-malignant colon tissues were evaluated by immunohistochemistry as well. Statistical associations were sought between anti-procollagen 11A1 immunoscoring and patient clinicopathological features.
RESULTS: Procollagen 11A1 was immunodetected in human bone marrow mesenchymal cells and in human colon adenocarcinoma-associated spindle-shaped stromal cells but not in colon epithelial or stromal cells of the normal colon. This immunodetection paralleled, in both kinds of cells, that of the other mesenchymal-related biomarkers studied: vimentin and alpha smooth muscle actin, but not desmin. Thus, procollagen 11A1(+) adenocarcinoma-associated stromal cells are similar to "activated myofibroblasts". In the series of human colon adenocarcinomas here studied, a high procollagen 11A1 expression was associated with nodal involvement (p = 0.05), the development of distant metastases (p = 0.017), and advanced Dukes stages (p = 0.047).
CONCLUSION: The immunodetection of procollagen 11A1 in cancer-associated stromal cells could be a useful biomarker for human colon adenocarcinoma characterisation.

Farr D, Khan SA
Local therapy for breast cancer in the molecular era: relevant or relic?
Oncology (Williston Park). 2014; 28(11):918-28 [PubMed] Related Publications
Local therapy (surgery and radiation) is an essential component of breast cancer treatment. Yet, based on clinical trial results dating from the 1980s, the magnitude of local therapy interventions has been decreasing. Now, with the emergence of tailored systemic therapies, their increasing use in the neoadjuvant setting, and their high rates of pathologic complete response (pCR), the relevance of local therapy is being questioned. However, given our present inability to assess pathologic response without surgery, the low pCR rates in common subtypes of breast cancer, and the survival advantages with nodal radiation, local therapy remains not only relevant but crucial to a comprehensive breast cancer treatment plan. In the future, as gene profiling of individual patient tumors progresses and allows for precise tailoring of therapy, it is conceivable that surgery and/or radiation would not be required in some patients. However, the notion that brief, low-morbidity local therapy options, which synergize with prolonged and potentially morbid systemic regimens, would not be relevant for most patients is beyond the horizon at the moment.

Matsuda I, Shimizu Y, Okamoto T, Hirota S
Follicular lymphoma mimicking marginal zone lymphoma in lymph node: a case report.
Int J Clin Exp Pathol. 2014; 7(10):7076-81 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Nodal follicular lymphoma (FL) is typically composed of follicular or nodular proliferation of small cleaved lymphoid cells, presumably derived from germinal center (GC) B cells. The hallmark of FL is t(14;18)(q32;q21) chromosomal translocation, which juxtaposes anti-apoptotic gene BCL2 to immunoglobulin heavy chain (IGH) promoter. Reflecting this background, FL cells are immunohistochemically positive for BCL2 as well as GC B cell markers CD10 and BCL6. It is known that low grade B-cell lymphomas, including FL, chronic lymphocytic leukemia/small lymphocytic lymphoma, and marginal zone lymphoma, are sometimes associated with marginal zone differentiation or plasmacytic differentiation. The marginal zone differentiation obscures the morphological differences among these, providing diagnostic challenges for histopathologists. In this paper, we present a case of FL, originally mimicking marginal zone lymphoma in the axillary lymph node. Subsequent bone marrow biopsy showed paratrabecular infiltration of small to medium-sized lymphoid cells. Immunohistochemical analysis of the bone marrow biopsy together with histopathology and flow cytometry of the axillary lymph node led to a final diagnosis of FL with marginal zone differentiation in the axillary lymph node and its bone marrow infiltration. Our case illustrates and reconfirms the importance of clinicopathological correlation which leads to a correct diagnosis.

Wong H, Lau S, Cheung P, et al.
Lobular breast cancers lack the inverse relationship between ER/PR status and cell growth rate characteristic of ductal cancers in two independent patient cohorts: implications for tumor biology and adjuvant therapy.
BMC Cancer. 2014; 14:826 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Although invasive lobular carcinoma (ILC) of the breast differs from invasive ductal carcinoma (IDC) in numerous respects - including its genetics, clinical phenotype, metastatic pattern, and chemosensitivity - most experts continue to manage ILC and IDC identically in the adjuvant setting. Here we address this discrepancy by comparing early-stage ILC and IDC in two breast cancer patient cohorts of differing nationality and ethnicity.
METHODS: The clinicopathologic features of 2029 consecutive breast cancer patients diagnosed in Hong Kong (HK) and Australia (AUS) were compared. Interrelationships between tumor histology and other clinicopathologic variables, including ER/PR and Ki67, were analysed.
RESULTS: Two hundred thirty-nine patients were identified with ILC (11.8%) and 1790 patients with IDC. AUS patients were older (p <0.001) and more often postmenopausal (p <0.03) than HK patients. As expected, ILC tumors were lower in grade and proliferative rate, and more often ER-positive and HER2-negative, than IDC (p <0.002); yet despite this, ILC tumors were as likely as IDC to present with nodal metastases (p >0.7). Moreover, whereas IDC tumors exhibited a strongly negative relationship between ER/PR and Ki67 status (p <0.0005), ILC tumors failed to demonstrate any such inverse relationship (p >0.6).
CONCLUSION: These data imply that the primary adhesion defect in ILC underlies a secondary stromal-epithelial disconnect between hormonal signaling and tumor growth, suggesting in turn that this peritumoral feedback defect could reduce both the antimetastatic (adjuvant) and tumorilytic (palliative) efficacy of cytotoxic therapies for such tumors. Hence, we caution against assuming similar adjuvant chemotherapeutic survival benefits for ILC and IDC tumors with similar ER and Ki67, whether based on immunohistochemical or gene expression assays.

Rudolph A, Shi H, Försti A, et al.
Repeat polymorphisms in ESR2 and AR and colorectal cancer risk and prognosis: results from a German population-based case-control study.
BMC Cancer. 2014; 14:817 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Evidence has accumulated which suggests that sex steroids influence colorectal cancer development and progression. We therefore assessed the association of repeat polymorphisms in the estrogen receptor β gene (ESR2) and the androgen receptor gene (AR) with colorectal cancer risk and prognosis.
METHODS: The ESR2 CA and AR CAG repeat polymorphisms were genotyped in 1798 cases (746 female, 1052 male) and 1810 controls (732 female, 1078 male), matched for sex, age and county of residence. Colorectal cancer risk associations overall and specific for gender were evaluated using multivariate logistic regression models adjusted for sex, county of residence and age. Associations with overall and disease-specific survival were evaluated using Cox proportional hazard models adjusted for established prognostic factors (diagnosis of other cancer after colorectal cancer diagnosis, detection by screening, treatment with adjuvant chemotherapy, tumour extent, nodal status, distant metastasis, body mass index, age at diagnosis and year of diagnosis) and stratified for grade of differentiation. Heterogeneity in gender specific associations was assessed by comparing models with and without a multiplicative interaction term by means of a likelihood ratio test.
RESULTS: The average number of ESR2 CA repeats was associated with a small 5% increase in colorectal cancer risk (OR = 1.05, 95% CI 1.01-1.10) without significant heterogeneity according to gender or tumoural ESR2 expression. We found no indication for an association between the AR CAG repeat polymorphisms and risk of colorectal cancer. The ESR2 CA and AR CAG repeat polymorphisms were not associated with overall survival or disease specific survival after colorectal cancer diagnosis.
CONCLUSIONS: Higher numbers of ESR2 CA repeats are potentially associated with a small increase in colorectal cancer risk. Our study does not support an association between colorectal cancer prognosis and the investigated repeat polymorphisms.

Gebauer N, Thorns C, Bernard V, et al.
MicroRNA profiling of low-grade and transformed nodal marginal zone lymphoma reveals a similar signature pattern distinct from diffuse large B cell lymphoma.
Acta Haematol. 2015; 133(2):214-20 [PubMed] Related Publications
BACKGROUND/AIMS: As critical post-transcriptional regulators of gene expression, microRNAs are involved in several cellular processes of vital impact including cell growth and apoptosis. Many hematologic malignancies exhibit distinct microRNA signatures. MicroRNA implication in the pathogenesis of nodal marginal zone lymphoma (NMZL), however, remains widely elusive.
METHODS: Comprehensive morphologic, immunophenotypic and cytogenetic studies were carried out on a cohort of NMZL (n = 30) incorporating indolent as well as transformed MZL. In addition, microRNA signatures were generated, employing a quantitative real-time polymerase chain reaction approach. These were then compared to signatures from cases of diffuse large B cell lymphoma (DLBCL) alongside reactive lymph node controls.
RESULTS: While microRNA signatures of low-grade and transformed NMZL did not differ significantly, several microRNAs were differentially expressed between transformed NMZL and DLBCL, hinting at molecularly distinct mechanisms of lymphomagenesis and indicating the biological disparity of transformed NMZL from DLBCL.
CONCLUSION: In the light of the unresolved issue regarding the classification of marginal zone-derived transformed B-cell neoplasms, microRNAs may be a valuable aid in discriminating NMZL from DLBCL.

Park SJ, Kim SM, Hong YS, et al.
TFAP2E methylation status and prognosis of patients with radically resected colorectal cancer.
Oncology. 2015; 88(2):122-32 [PubMed] Related Publications
OBJECTIVES: This study investigates the clinical significance of the gene encoding AP-2ε (TFAP2E) in colorectal cancer (CRC) patients undergoing curative resection.
METHODS: A single-institution cohort of 248 patients who underwent curative resection of stage I/II/III CRCs between March and December 2004 was enrolled, and 193 patients whose tumors were available for the determination of the TFAP2E methylation status were included in the analysis.
RESULTS: TFAP2E hypermethylation was detected in 112 patients (58%) and was significantly associated with distally located CRCs, low pathologic T stage (T1/T2), and stage I tumors. After a median follow-up of 86.3 months, the patients with TFAP2E hypermethylation tended to show better relapse-free survival (RFS) and overall survival (OS) than the patients with TFAP2E hypomethylation (5-year RFS rate: 90 vs. 80%, p = 0.063; 6-year OS rate: 88 vs. 80%, p = 0.083). Multivariate analysis showed that the pathologic nodal stage and TFAP2E methylation status were independent prognostic factors for RFS and OS, and they remained significant factors in the subgroup analysis that included 154 patients with stage II/III CRCs who had received adjuvant chemotherapy.
CONCLUSIONS: TFAP2E hypermethylation is associated with good clinical outcomes and may be considered as an independent prognostic factor in patients with curatively resected CRCs.

Yang J, Hawkins OE, Barham W, et al.
Myeloid IKKβ promotes antitumor immunity by modulating CCL11 and the innate immune response.
Cancer Res. 2014; 74(24):7274-84 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a BRAF(V600E/PTEN(-/-)) allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8(+) T cell-mediated tumor cell lysis. Depleting macrophages or CD8(+) T cells in mice with wild-type IKKβ myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8(+) T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβ(CA)) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance.

Song JY, Pittaluga S, Dunleavy K, et al.
Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations.
Am J Surg Pathol. 2015; 39(2):141-56 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorder. It is hypothesized that these patients have dysregulated immune surveillance of EBV. We reviewed the biopsies of 55 patients with LYG who were referred for a prospective trial at the National Cancer Institute (1995 to 2010) and evaluated the histologic, immunohistochemical, in situ hybridization, and molecular findings of these biopsies in conjunction with clinical information. Grading of the lesions was based on morphologic features and the number of EBV-positive B cells. The median age was 46 years (M:F 2.2:1). Clinically, all patients had lung involvement (100%), with the next most common site being the central nervous system (38%). No patient had nodal or bone marrow disease. All patients had past EBV exposure by serology but with a low median EBV viral load. We reviewed 122 biopsies; the most common site was lung (73%), followed by skin/subcutaneous tissue (17%); other sites included kidney, nasal cavity, gastrointestinal tract, conjunctiva, liver, and adrenal gland. Histologically, the lesions showed angiocentricity, were rich in T cells, had large atypical B cells, and were positive for EBV. Grading was performed predominantly on the lung biopsy at diagnosis; they were distributed as follows: LYG grade 1 (30%), grade 2 (22%), and grade 3 (48%). Necrosis was seen in all grades, with a greater degree in high-grade lesions. Immunoglobulin gene rearrangement studies were performed, and a higher percentage of clonal rearrangements were seen in LYG grade 2 (50%) and grade 3 (69%) as compared with grade 1 (8%). LYG is a distinct entity that can usually be differentiated from other EBV-associated B-cell lymphoproliferative disorders on the basis of the combination of clinical presentation, histology, and EBV studies. Grading of these lesions is important because it dictates the treatment choice.

Moorchung N, Kunwar S, Ahmed KW
An evaluation of nuclear factor kappa B expression in colorectal carcinoma: an analysis of 50 cases.
J Cancer Res Ther. 2014 Jul-Sep; 10(3):631-5 [PubMed] Related Publications
CONTEXT: There is a rising trend in the incidence of (colorectal carcinoma) colorectal cancer (CRC) in India. Nuclear factor kappa B (NFkB) is a transcription factor which belongs to the Rel family. It has an impact on phenomena such as apoptosis, tumor progression and differentiation.
AIMS: (1) To evaluate the grade and stage in 50 cases of colorectal carcinoma. (2) To evaluate the NFkB translocation into the nucleus of the cells. (3) To compare the benign and malignant areas with the degree of NFkB translocation and compare the translocation with the grade and pathological stage.
SUBJECTS AND METHODS: The grade and stage of the tumors was evaluated. NFkB staining was performed on the tissues. The results of the immunostaining were analyzed semi quantitatively as a percentage of positive cells.
STATISTICAL ANALYSIS USED:  Statistical Package for Social Sciences 13.0 statistical package program (SPSS, Lead Technologies Inc, USA) for windows was used. Correlation was carried out using the Pearson's correlation co-efficient and the Chi-square test.
RESULTS: There were 29 males (58%) and 21 females (42%). Most of the cases were well-differentiated adenocarcinomas (58%). There was a significant difference between NFkB translocation in the epithelial cells and lymphocytes in the benign and malignant areas (P - 0.04 and P - 0.001 respectively). There was a significant correlation between the grade of NFkB staining in the malignant epithelial cells with the tumor and nodal status (P - 0.001 and P - 0.001).
CONCLUSIONS: It is likely that NFkB is an important factor in the pathogenesis of CRC. Further studies including therapeutic intervention using strategies which prevent activation of NFkB in colorectal carcinoma patients will tell if we could alter the course of the disease favorably.

Halpenny DF, Riely GJ, Hayes S, et al.
Are there imaging characteristics associated with lung adenocarcinomas harboring ALK rearrangements?
Lung Cancer. 2014; 86(2):190-4 [PubMed] Related Publications
INTRODUCTION: 5% of lung adenocarcinomas harbor rearrangements of the anaplastic lymphoma kinase (ALK) gene. This study compared computed tomography (CT) imaging features in patients with ALK rearrangements and those with EGFR mutations.
MATERIAL/METHODS: 30 patients with ALK rearrangements were studied. 97 patients with epidermal growth factor receptor (EGFR) mutations were used as controls. Features assessed included size and location of thoracic lymphadenopathy, and the size, contour, consistency and location of the primary tumor.
RESULTS: 127 lung adenocarcinomas were examined. 30 (24%) tumors harbored ALK rearrangements, 97 (76%) tumors harbored EGFR mutations. ALK tumors had larger thoracic lymphadenopathy than the control group (p=0.005). Both readers identified 17 (57%) patients in the ALK group with lymph nodes >1.5cm. Reader 1 identified 19 (20%) patients in the EGFR group with lymph nodes >1.5cm, and reader 2 identified 18 (19%) (kappa 0.969). Patients with ALK rearrangements were more likely to have multifocal lymphadenopathy. Reader 1 identified 22 (73%) ALK patients versus 35 (36%) EGFR patients with multifocal thoracic nodal enlargement, while reader 2 identified 20 (67%) ALK patients versus 30 (31%) EGFR patients (kappa 0.953). 92% of ALK positive lesions were solid.
CONCLUSION: ALK positive lung adenocarcinomas are more likely than EGFR mutant lung adenocarcinomas to be associated with larger volume, multifocal thoracic lymphadenopathy. While routine testing for ALK should be standard, the presence of such characteristics in a solid tumor should further prompt testing for ALK rearrangement.

Ye J, Zhou Y, Weiser MR, et al.
Immunohistochemical detection of ARID1A in colorectal carcinoma: loss of staining is associated with sporadic microsatellite unstable tumors with medullary histology and high TNM stage.
Hum Pathol. 2014; 45(12):2430-6 [PubMed] Related Publications
AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation.

Rakhshani N, Kalantari E, Bakhti H, et al.
Evaluation of HER-2/neu overexpression in gastric carcinoma using a tissue microarray.
Asian Pac J Cancer Prev. 2014; 15(18):7597-602 [PubMed] Related Publications
BACKGROUND: Amplification and overexpression of human epidermal growth factor receptor 2 (HER2 / neu) oncogene has considerable prognostic value in breast and gastric cancers. This study aimed to evaluate the frequency, overexpression pattern, clinical significance, and concordance between the results for protein expression and gene amplification of HER-2/neu in gastric and gastro-esophageal junction carcinomas.
MATERIALS AND METHODS: In this study, 101 gastric tissue samples which were included in tissue microarray were immunohistochemically examined for overexpression of HER2/neu. Chromogenic in situ hybridization (CISH) was used for HER-2/neu amplification. The correlation of HER2/neu amplification with clinicopathological parameters was also assessed. In addition, concordance between CISH and IHC was detected.
RESULTS: This study demonstrated a significant difference in the overexpression of HER2/neu in gastric tumors. The overexpression of HER2/neu was significantly higher in intestinal type, poorly differentiated grade, large size (5 cm≤) and positive nodal involvement tumors (p-value=0.041, 0.015, 0.038 and 0.071, respectively). Also, amplification of HER2/neu according to CISH test, had a significant positive correlation with tumor size and tumor type (p-value=0.018 and 0.058, respectively).Concordance between CISH and IHC was 76.9% in 101 evaluable samples.
CONCLUSIONS: IHC/CISH differences were attributed to basolateral membranous immunoreactivity of glandular cells resulting in incomplete membranous reactivity and/or a higher rate of tumor heterogeneity in gastric cancers compared to breast cancers. Therefore, this can be a potential marker for targeted therapy of malignant gastric tumors.

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