SOX11+ Large B-Cell Neoplasms: Cyclin D1-Negative Blastoid/Pleomorphic Mantle Cell Lymphoma or Large B-Cell Lymphoma?

Large or blastoid B-cell neoplasms that are SOX11+ are a diagnostic dilemma and raise a differential diagnosis of cyclin D1-negative blastoid/pleomorphic mantle cell lymphoma (MCL) versus diffuse large B-cell lymphoma (DLBCL) or blastoid high-grade B-cell lymphoma (HGBL) with aberrant SOX11 expression. Here we report a study cohort of 13 SOX11+ large/blastoid B-cell neoplasms. Fluorescence in situ hybridization analysis was negative for CCND1 rearrangement in all 13 cases; 1 of 8 (12.5%) cases tested showed CCND2 rearrangement and 2 (25%) cases had extracopies of CCND2. Gene expression profiling showed that the study group had a gene expression signature similar to cyclin D1+ blastoid/pleomorphic MCL but different from DLBCL. Principal component analysis revealed that the cohort cases overlapped with cyclin D1+ blastoid/pleomorphic MCL but had minimal overlap with DLBCL. All patients in the cohort had clinicopathologic features similar to those reported for patients with cyclin D1+ MCL. We also performed a survey of SOX11 expression in a group of 85 cases of DLBCL and 24 cases of blastoid HGBL. SOX11 expression showed a 100% specificity and positive predictive value for the diagnosis of MCL. Overall, the results support the conclusion that large or blastoid B-cell neoplasms that are positive for SOX11 are best classified as cyclin D1-negative blastoid/pleomorphic MCL, and not as DLBCL or blastoid HGBL. We also conclude that SOX11 is a specific marker for the diagnosis of MCL, including cyclin D1-negative blastoid/pleomorphic MCL cases and should be performed routinely on blastoid/large B-cell neoplasms to help identify potential cases of cyclin D1-negative blastoid/pleomorphic MCL.

Clinical impact of 5'MYC or 3'MYC gain/loss detected by FISH in patients with aggressive B-cell lymphomas.

FISH analysis using MYC break-apart probes is a widely used technique to assess for MYC rearrangement (MYC-R). Occasionally, FISH results in atypical signal patterns, such as gain or loss of 5'MYC or 3'MYC. The clinical impact and/or relationship of these atypical signal patterns to MYC-R are unknown. In this study, we assessed 35 patients who had aggressive B-cell lymphomas and exhibited atypical FISH signal patterns: 3'MYC deletion (n = 16) or 3'MYC deletion plus 5'MYC amplification (n = 5), 5'MYC gain (n = 10), 5'MYC deletion (n = 3), and 3'MYC gain (n = 1). For comparison, we also included 9 patients who showed an unbalanced MYC-R. Patients with 5'MYC gain showed MYC expression and were often refractory to chemotherapy (n = 7) or had early relapse (n = 2). By contrast, lymphomas with 3'MYC deletion were negative or had low expression of MYC (16 of 18), and patients often responded to chemotherapy (16 of 19). The median event-free survival was 24, 6, and 4 months for patients with 3'MYC deletion, 5'MYC gain and unbalanced MYC-R, respectively (p = 0.0048). We conclude that 5'MYC gain is associated with MYC expression and a poorer prognosis and likely represents an unbalanced MYC-R. By contrast, 3'MYC deletions are not associated with MYC expression or a poorer prognosis and this finding may be unrelated to MYC-R.

MET Expression Level in Lung Adenocarcinoma Loosely Correlates with MET Copy Number Gain/Amplification and Is a Poor Predictor of Patient Outcome.

MET amplification has been associated with shorter survival in cancer patients, however, the potential correlation of MET overexpression with either MET amplification or patient outcome is controversial. The aim of this study was to address these questions by correlating MET expression level with MET copy number and patient outcome in a cohort of 446 patients who had a lung adenocarcinoma: 88 with MET amplification, 118 with polysomy 7, and 240 with negative results by fluorescence in situ hybridization. MET expression assessed by immunohistochemistry was semi-quantified by expression level: absent (0+), weak (1+), moderate (2+) and strong (3+); or by H-score: 0-99, 100-199, and ≥200. MET expression level or H-score was positively but weakly correlated with MET copy number or MET/CEP7 ratio. Strong expression of MET (3+ or H-score ≥ 200) was associated with a shorter overall survival, but it was not an independent hazard for survival by multivariant analysis. We conclude that MET expression is loosely correlated with MET copy number gain/amplification. Strong expression of MET does not independently predict patient outcome.

CD2-negative lymphoma-associated T-cells: a potential mechanism of immune-evasion in diffuse large B-cell lymphoma.

CD2 is a costimulatory protein expressed in all mature T/NK-cells, in particular memory T-cells. CD58 (or LFA-3) is the receptor for CD2 and is ubiquitously expressed. CD2-CD58 interaction has key functions in T-cell activation and organization of the immunological synapse between T- and antigen-presenting cells. Cancer cells have developed multiple mechanisms to evade immune surveillance. Loss of CD58 expression is one frequently reported in diffuse large B-cell lymphomas (DLBCL). On the other hand, in non-hematological neoplasms, tumor infiltrating lymphocytes (TILs) with reduced expression of CD2 have been associated with defective cytotoxicity and T-cell exhaustion. Here, we reported a case of DLBCL involving the jejunal mucosa associated with a rim of cytotoxic reactive T-cells with features of immune evasion (CD2- and TCR-) and T-cell exhaustion (PD1 + high). This case likely exemplifies a previously unrecognized immune evasion mechanism in lymphoma involving a decreased CD2 expression in the lymphoma-associated T-cells.

MET Amplification (MET/CEP7 Ratio ≥ 1.8) Is an Independent Poor Prognostic Marker in Patients With Treatment-naive Non-Small-cell Lung Cancer.

INTRODUCTION: The MET pathway is a promising target in patients with non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization analysis has become a standard method to detect MET amplification. However, no consensus has been reached regarding the definition of MET amplification. We aimed to find clinically meaningful cutoffs for MET amplification that could be used as a prognostic marker and/or indication for MET inhibitor therapy. PATIENTS AND METHODS: We reviewed the fluorescence in situ hybridization results of MET/CEP7 (centromere of chromosome 7) for 2260 patients with treatment-naive NSCLC from 2014 to 2019. Clinical and pathologic data were collected from the medical records. Log-rank tests and Cox proportional hazard models were used to estimate the overall survival (OS) among patients with different MET/CEP7 ratios and/or MET copy numbers. RESULTS: Of the 2260 patients, 130 (5.8%) had had a MET/CEP7 ratio of ≥ 1.8 and 13 (0.6%) had had a ratio of ≥ 5.0. Of these 130 patients with a MET/CEP7 ratio of ≥ 1.8, 123 (95%) also had a MET copy number of ≥ 5. In general, a higher MET copy number and higher MET/CEP7 ratio were associated with advanced tumor stage. The OS was significantly shorter when the MET copy number was ≥ 10 and/or when the MET/CEP7 ratio was ≥ 1.8. A MET/CEP7 ratio of ≥ 1.8 remained a significant hazard to OS on multivariate analysis (hazard ratio, 1.63; P = .019). CONCLUSIONS: Patients with a MET copy number of ≥ 10 and/or MET/CEP7 ratio of ≥ 1.8 showed significantly poorer survival, and a MET/CEP7 ratio of ≥ 1.8 was an independent poor prognostic factor.

Acquired MET amplification in non-small cell lung cancer is highly associated with the exposure of EGFR inhibitors and may not affect patients' outcome.

MET amplification has been associated with shorter survival in cancer patients and thought to represent one of two major mechanisms for developing resistance to therapy with EGFR inhibitors. We retrospectively studied 99 patients who had non-small cell lung cancer (NSCLC) and had at least two FISH analyses for MET/CEP7 at different time points during the course of disease. Four (4%) patients showed MET amplification in the initial diagnostic biopsy, and 16 (16%) patients acquired MET amplification in the follow-up biopsy specimens. Acquired MET amplification was highly associated with EGFR inhibitor treatment. Except for EGFR and TP53 mutations, other gene mutations were rare in the patients with MET amplification. Patients with acquired MET amplification showed no significant survival difference comparing to the patients who did not show MET amplification.

Coexistent genetic alterations involving ALK, RET, ROS1 or MET in 15 cases of lung adenocarcinoma.

In lung cancer, targetable activating alterations in cancer genes, such as EGFR, ALK, RET, ROS1 and MET, are usually mutually exclusive. Rare lung cancer cases with coexistent alterations of EGFR and ALK or EGFR mutations with RET or ROS1 rearrangements have been reported. In this study, we report 15 patients (3 men and 12 women; 14 Caucasians and 1 African American) with ages ranging from 43 to 81 years (median 60 years) with lung adenocarcinoma in which coexistent alterations of two cancer-associated genes, including ALK, ROS1, or RET rearrangement or MET amplification were present. The combination of alterations detected by fluorescence in situ hybridization included ALK combined with ROS1 (n=4), ALK with MET (n=3), ALK with RET (n=1); RET with MET (n=4), RET with ROS1 (n=2), and ROS1 combined with MET (n=1). The frequencies of involvement were similar for all 4 genes, 53% for both ALK and MET (n=8), 47% for both RET and ROS1 (n=7). Activating gene mutations were also detected by next-generation sequencing for TP53 (n=6), EGFR (n=5), KRAS (n=3) and STK11 (n=2). Nine patients reported a smoking history (8 heavy and 1 light) and 6 patients were non-smokers. These findings suggest the need for assessing a panel of genes in lung cancer. Since targetable agents are available for each of these activating alterations, treatment with more than one targeted agent may be beneficial for this rare group of patients.

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations.

ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case-control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (P<0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.42-2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case-control analysis comparing NSOC probands with controls (OR=1.58; 95% CI=1.12-2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI=1.38-2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface.

Identification of IRF6 gene variants in three families with Van der Woude syndrome.

Van der Woude syndrome is the most common cause of syndromic orofacial clefting. It is characterised by the presence of lip pits, cleft lip and/or cleft palate. It is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Several mutations in the interferon regulatory factor 6 (IRF6) gene have been found in VWS families, suggesting that this gene is the primary locus. We screened for mutations in this gene in three families in our population. There was a recurrent nonsense mutation within exon 9 of the gene for a Malay family consisting of five affected members with different presentations. We also found a co-segregating rare polymorphism which would result in a non-synonymous change 23 bases downstream of the nonsense mutation. This polymorphism was present in <1% of the Malay subjects screened, but was not found among the Chinese and Indians in our population. For another family, a 396C-->T mutation (R45W in the DNA-binding domain) was found in the proband, although the possibility of a genetic defect elsewhere could not be excluded because his mother and twin sister (both unaffected) also had this variant. In the third case with complete absence of family history, a de novo deletion spanning the whole IRF6 gene was detected in the child with VWS. This case of haploinsufficiency caused disruption of orofacial development but not other organ systems as the child has no other medical or developmental abnormalities despite the deletion of at least five other genes.

Suicide in Hong Kong: a case-control psychological autopsy study.

BACKGROUND: The relative contribution of psychosocial and clinical risk factors to suicide among Chinese populations is an important issue. In Hong Kong, this issue requires vigorous examination in light of a 50% increase in suicide rate between 1997 and 2003. METHOD: Using a case-control psychological autopsy method, 150 suicide deceased were compared with 150 living controls matched by age and gender. Semi-structured interviews were conducted with the next-of-kin of the subjects. Data were collected on a wide range of potential risk and protective factors, including demographic, life event, clinical and psychological variables. The relative contribution of these factors towards suicide was examined in a multiple logistic regression model. RESULTS: Six factors were found to significantly and independently contribute to suicide: unemployment, indebtedness, being single, social support, psychiatric illness, and history of past attempts. CONCLUSIONS: Both psychosocial and clinical factors are important in suicides in Hong Kong. They seem to have mediated suicide risk independently. In addition, socio-economic adversities seem to have played a relatively important role in the increasing suicide rate in Hong Kong.