Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis. Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated. Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in , and were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as and were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors. Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients. .
IL-13 minor T and A alleles for rs1295686 and rs20541, respectively, were associated with significantly higher risk of asthma in the Saudi Arabian population.
Non-alcoholic fatty liver disease (NAFLD) is a common chronic condition caused by the accumulation of fat in the liver. NAFLD may range from simple steatosis to advanced cirrhosis, and affects more than 1 billion people around the world. To date, there has been no effective treatment for NAFLD. In this study, we evaluated the expression of 4 candidate NAFLD biomarkers to assess their possible applicability in the classification and treatment of the disease. Twenty-six obese subjects, who underwent bariatric surgery, were recruited and their liver biopsies obtained. Expression of 4 candidate biomarker genes, PNPLA3 , COL1A1 , PPP1R3B , and KLF6 were evaluated at gene and protein levels by RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. A significant increase in the levels of COL1A1 protein ( P = .03 ) and PNPLA3 protein ( P = .0 3) were observed in patients with fibrosis-stage NAFLD compared to that in patients with steatosis-stage NAFLD. However, no significant differences were found in abundance of PPP1R3B and KLF6 proteins or at the gene level for any of the candidate. This is the first study, to our knowledge, to report on the expression levels of candidate biomarker genes for NAFLD in the Saudi population. Although PNPLA3 and PPP1R3B had been previously suggested as biomarkers for steatosis and KLF6 as a possible marker for the fibrosis stage of NAFLD, our results did not support these findings. However, other studies that had linked PNPLA3 to fibrosis in advanced NAFLD supported our current finding of high PNPLA3 protein in patients with fibrosis. Additionally, our results support COL1A1 protein as a potential biomarker for the fibrosis stage of NAFLD, and indicate its use in the screening of patients with NAFLD. Further studies are required to validate the use of COL1A1 as a biomarker for advanced NAFLD in a larger cohort.
Background: Hereditary thrombocythemia (HT) has been reported in Japanese and African populations in association with S505N, and N35K c-Mpl mutations, respectively. A novel Pro106Leu germ-line mutation in the c-Mpl gene has recently been shown to be associated with HT in Arabic population. Clinical and bone marrow (BM) features of Pro106Leu mutation are largely unknown. Methods: The molecular genetic databases at two tertiary hospitals in Riyadh, King Abdulaziz medical city (KAMC) and King Saud University medical city (KSUMC), were searched to identify all patients (pts) with MPL Pro106Leu mutation. Clinical and pathological data were retrospectively collected. BM aspiration and biopsy were independently reviewed retrospectively by two consultant hematopathologists and agreement was reached by a consensus review. Simple descriptive statistics were used to summarize the results. A univariate subgroup analysis, comparing the hematologic parameters between the homozygous and heterozygous genotypes was conducted using Pearson Chi-Square and t-tests. Results: A total of 115 pts with Pro106Leu MPL mutation were included, 86 (75%) from KAMC and 29 (25%) from KSUMC. All pts were ethnically Arabs. Median age was 33 years (yrs) (range: 0.4-68), 65 (56.5%) were female, and 31 (27%) were pediatric pts (age <18 yrs). MPL Pro106Leu mutation was homozygous in 87 (75.7%) pts, and heterozygous in 28 (24.3%). Spleen was enlarged in 3 (3%) pts, not documented in 15 (13%), and normal in 97 (84%). History of bleeding was documented among 11 (10%) pts. Thrombosis history was positive in 5 (4%) pts only, unavailable in 6 (5%), and negative in 104 (90%). Family history of thrombocytosis was reported in 46 (40%), but family history was not documented in 20 (17%). Common comorbidities include: autoimmune disease in 33 (29%), diabetes 21 (18%), and hypertension 20 (17%). Reasons for MPL testing was: abnormal routine blood work 79 (69%), family history of thrombocytosis 23 (20%), or others 13 (11%). Thrombocytosis [platelet (plt) counts > 450 x109/L] was documented in 107 (93%) pts, normal in 4 (3.5%), and low in 4 (3.5%) at the time of diagnosis of Pro106Leu mutation. See figure 1. The median plt count at the time of diagnosis of MPL Pro106Leu mutation was 667 x 109/L (range: 13-1473). The median mean plt volume was 8 fL (range 6.1-10.2), white blood cell count 8.4 x 109/L (2.46-68.35), absolute neutrophil count 5 x 109/L (1.01- 21.19), hemoglobin 132 gm/L (85-148), mean corpuscular volume 84.1 fL (57-117.3), mean corpuscular hemoglobin 27.7 pg (18-37.5), mean corpuscular hemoglobin concentration 327 g/dL (300-351), and red cell distribution width 13.6 (10.9-22.8). Ferritin less than 30 was seen in 40 (35%) pts, 27 of whom were women. No ferritin done in 14 pts. Iron stores (based on bone marrow, ferritin and iron saturation) were adequate in 56 (49%), inadequate in 49 (43%), and not documented in 10 (9%). BCR-ABL, JAK2 and CALR were only detected in 1 pt each. One pt was not tested for CALR mutation. All other pts were negative for the three mutations. Out of all 115 pts, 33 (29%) had an evaluable BM. BM cellularity ranged from 20-100 %, 12/33 (36%) were hypocellular, 17/33 (52%) normocellular, and 4/33 (12%) hypercellular. Megakaryocyte (meg) morphology revealed dysplastic changes in 20 (60%) (hypolobated megs or with separated lobes), only 7 (21%) of cases had cloudlike megs but none had staghorn or giant megs as described in essential thrombocythemia. BM megs were increased in 29 (87%). Small size megs were seen in 15/33 (45%). Clustering of megs was seen in the majority of the cases 30/33 (90%) of whom, 29(87%) had loose and 20 (60%) dense clusters. On univariate analysis (see tables 1-2), homozygous genotype was associated with higher plt count. Total of 65 (57%) pts were prescribed aspirin, and 16 (14%) hydroxyurea. At the time of last follow-up 114 (99%) of pts were alive. The median follow-up was 7.8 yrs from the time of thrombocytosis (ranged from 0-24.8). No case developed disease progression to myelofibrosis. One pt was diagnosed with T-lymphoblastic lymphoma and later died from treatment complications and another pt was diagnosed with CML. Conclusion: Pro106Leu mutation is associated with marked thrombocytosis at a younger age with a low risk of thrombosis. Homozygous genotype is associated with a significantly higher plt count. BM usually shows either normo- or hypocellular marrow with increased megs proliferation, and clustering. Disclosures No relevant conflicts of interest to declare.
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