A novel germline SMAD4 variant detected in a Japanese family with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia.

Juvenile polyposis syndrome (JPS) is an autosomal dominant, inherited disorder caused by pathogenic germline variants of mainly SMAD4 or BMPR1A genes. Some patients with JPS, especially with SMAD4 variants, also develop hereditary, hemorrhagic telangiectasia (HHT). HHT is also an autosomal dominant inherited disorder. Herein, we identified a novel germline pathogenic variant of the SMAD4 in a Japanese family with JPS and HHT. A six-base pair deletion in the SMAD4 gene (NM_005359.6:c.1495_1500delTGCATA) was identified in the patients. Two amino acids are deleted from SMAD4 protein (p.Cys499_Ile500del), which are located in MSH2 domain essential for the binding with SMAD3. This is a novel variant that has not been registered in any database surveyed. Amino acid structural analysis predicted significant changes in the secondary and three-dimensional structures in the vicinity of the two amino acids' deletion. The variant is classified as 'Likely Pathogenic' according to the American College of Medical Genetics and Genomics guidelines.

Impact of Second-line Chemotherapy on Prognosis: Response of Advanced Gastric Cancer to Taxanes Plus Ramucirumab.

BACKGROUND/AIM: The impact of clinical response to taxanes plus ramucirumab (RAM) on overall survival (OS) has not been clarified for advanced gastric cancer (AGC), although this type of therapy is already in use as second-line chemotherapy (CTx). This study aimed to investigate the prognostic impact of the clinical response to taxanes plus ramucirumab (RAM) for AGC patients. PATIENTS AND METHODS: This study included AGC patients treated with paclitaxel (PTX) or nab-paclitaxel (nab-PTX) and RAM. A retrospective analysis of response and survival rates in consecutive medical records of patients was performed. RESULTS: Forty-two patients were enrolled. Median progression-free survival and OS were 5.4 months [95% confidence interval (CI)=4.440-6.361] and 11.8 months (95% CI=8.648-15.019), respectively. In Cox-hazard multivariate analysis, peritoneal metastasis [hazard ratio (HR)=2.830; 95% CI=1.320-6.067; p=0.008], and disease control rate (HR=0.310; 95% CI=0.129-0.741; p=0.008) were independent factors. CONCLUSION: The response to taxanes plus RAM CTx had an impact on the survival of patients with AGC.

Methylation status and long-fragment cell-free DNA are prognostic biomarkers for gastric cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) detected before surgery disappears after complete surgical resection of the cancer. Residual ctDNA indicates minimal residual disease (MRD), which is a cause of recurrence. The presence of long-fragment circulating cell-free DNA (cfDNA) or methylated cfDNA also implies the presence of cancer. In this study, we evaluated the prognostic value of cfDNA methylation and long-fragment cfDNA concentration in gastric cancer patients undergoing curative surgery METHODS: Ninety-nine gastric cancer patients were included. Peripheral blood samples were collected before and 1 month after surgery. In patients administered chemotherapy, samples were collected before starting chemotherapy. qPCR was performed to detect long- and short-fragment LINE-1. A plasma HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay to determine the concentration of HpaII small fragments was performed using ligation-mediated PCR and HpaII was quantified as the HpaII:MspI ratio to detect methylation levels of cfDNA. RESULTS: Overall survival (OS) of patients with low methylation levels before starting treatment was significantly worse than that of patients with high methylation levels (P = 0.006). In the 90 patients who underwent curative surgery, recurrence-free survival (RFS) and OS of patients with low methylation levels before surgery were worse than those with high methylation levels (P=0.08 and P = 0.11, respectively). RFS and OS of patients with high concentrations of long-fragment LINE-1 after surgery were significantly worse than those with low concentrations of long-fragment LINE-1 (P = 0.009, P = 0.04). CONCLUSIONS: Pre-surgical low methylation levels of LINE-1 are a negative prognostic factor. Post-surgical high concentrations of long-fragment LINE-1 indicate MRD and a high risk of recurrence.