Partial Trisomy 16q21-q24.3 with Novel Cardiac Manifestation of Left Ventricular Noncompaction Cardiomyopathy: A Case Report

Partial trisomy 16q is most often a consequence of malsegregation from a balanced parental translocation involving chromosome 16q. It is characterized by nonspecific craniofacial dysmorphic features, hypotonia, developmental delay, psychomotor retardation, and systemic manifestations of cardiac defect, renal abnormalities, and lung abnormalities. The survival of these patients depends upon the extent and severity of the organs involved. The present literature is replete with cases of partial trisomy 16q having structural cardiac defects. However, in the present report we describe a novel finding of myocardial disease in the form of left ventricular noncompaction (LVNC) cardiomyopathy associated with this genetic condition.

The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill PTEN mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.

Chromosome 16q Located Genes CDH1, CDH13 and ADAMTS18 Are Correlated and Frequently Methylated But Not Associated With DNMTs levels In Human Lymphoma

Hypermethylation of promoter contributes to the transcriptional repression of a number of cancer associated genes. In lymphoma, the promoter hypermethylation of many tumor suppressor genes (TSGs), such as p16, has been already known. Using methylation-specific PCR (MSP) and quantitative real-time PCR (qRT-PCR), we examined promoter methylation status and mRNA expression levels of E-cadherin (CDH1), H-cadherin (CDH13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS18) which are putative TSGs located on chromosome 16q, and also examined the mRNA expression levels of DNA methyltransferases (DNMT1, 3A and 3B) and studied the correlation between these different tested parameters in 36 of lymphomas [included 29 diffuse large B cell (DLBCL) and seven mantle cell lymphoma (MCL)] and 16 non-malignant lymphoid tissues after obtaining informed consent. The expression of DNMTs mRNA were significantly higher in lymphomas compared to non-malignant tissues (p<0.05). Promoter hypermethylation of CDH1, CDH13, and ADAMTS18 was detected in 31/36 (86%), 33/36 (91.6%) and 28/36 (77.7%) of lymphoma, respectively. The expression of CDH1 and ADAMTS18 was significantly reduced in the patients with hypermethylated promoter when compared to unmethylated (p<0.01 and p<0.05, respectively), while no significant difference was found in CDH13. CDH1 and ADAMTS18 expressions were significantly reduced in lymphomas compared to non-malignant tissues (p<0.01), while CDH13 showed no significant difference. Notably, there was significant positive correlation between the expression levels of CDH1 and CDH13 (r = 0.735, p<0.01) (Fig. 1A). Moreover, ADAMTS18 expression showed significant positive correlation with both CDH1 and CDH13 expression levels (r = 0.625, p<0.01; r = 0.720, p<0.01, respectively) (Fig. 1B, C). Also there was significant negative correlation between the expression levels of DNMT3A and 3B with ADAMTS18 (r = -0.396, p<0.01; r = -0.364, p<0.01, respectively), but not with CDH1 and CDH13 (Fig. 2A and B). We could not find any correlation between the levels of DNMTs mRNA and the methylation status of CDH1, CDH13 and ADAMTS18. We examined the effect of 5-Aza-2-deoxycytidine (5-aza-dC) treatment on CDH1, CDH13 and ADAMTS18 expression levels and their methylated promoters in 3 of lymphoma cell lines (Raji, CTB-1 and SLVL) and one patient primary DLBCL cell line. We found that 5-aza-dC treatment of CDH1, CDH13 and ADAMTS18-methylated cell lines led to restoration of their expression levels (Fig. 3A, B, and C). Our results showed that CDH1, CDH13 and ADAMTS18, tumor suppressor genes adjacently located at chromosome 16q, are remarkably correlated and frequently methylated in human lymphoma and their methylation could not be explained solely by the expression level of DNMTs mRNA. Disclosures: No relevant conflicts of interest to declare.