ABSTRACT
Poly(ADP-ribose) polymerase inhibitors have been shown dramatic responses in patients with BRCAness. However, clinical studies have been limited to breast cancer patients with germline mutations. Here, we describe a patient with metastatic breast cancer who had a rare BRCA1 somatic mutation (BRCA1 c.4336G>T (p.E1446*)) detected by cell-free DNA analysis after failing standard therapies. This tier III variant of unknown significance was predicted to be a pathogenic variant in our assessment, leading us to consider off-label treatment with olaparib. The patient responded well to olaparib for several months, with a decrease in allele frequency of this BRCA1 somatic mutation in cell-free DNA. Olaparib resistance subsequently developed with an increase in the allele frequency and new BRCA1 reversion mutations. To our knowledge, this is the first report confirming BRCA1 c.4336G>T (p.E1446*) as a mutation sensitive to olaparib in breast cancer and describing the dynamic changes in the associated mutations using liquid biopsy.
ABSTRACT
Purpose@#Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib. @*Materials and Methods@#In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted next-generation sequencing platform which included 106 genes. @*Results@#A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of –31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of ≥ 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly. @*Conclusion@#Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib.
ABSTRACT
PURPOSE: RNA editing generates protein diversity by altering RNA sequences in coding regions without changing the overall DNA sequence. Adenosine-to-inosine (A-to-I) RNA editing events have recently been reported in some types of cancer, but they are rare in human colorectal cancer (CRC). Therefore, this study was conducted to identify diverse RNA editing in CRC. MATERIALS AND METHODS: We compared transcriptome data of 39 CRC samples and paired adjacent tissues from The Cancer Genome Atlas database to identify RNA editing patterns in CRC, focusing on canonical A-to-I RNA edits in coding sequence regions. We investigated nonsynonymous RNA editing patterns by comparing tumor and normal tissue transcriptome data. RESULTS: The number of RNA edits varied from 12 to 42 per sample. We also observed that hypoand hyper-RNA editing patterns were distinguishable within the samples. We found 10 recurrent nonsynonymous RNA editing candidates in nine genes (PDLIM, NEIL1, SRP9, GLI1, APMAP, IGFBP7, ZNF358, COPA, and ZNF587B) and validated some by Sanger sequencing and the inosine chemical erasing assay. We further showed that editing at these positions was performed by the adenosine deaminase acting on RNA 1 enzyme. Most of these genes are hypoedited in CRC, but editing of GLI1 was increased in cancer tissues compared with normal tissues. CONCLUSION: Our results show that nonsynonymous RNA editing patterns can be used to identify CRC patients and could serve as novel biomarkers for CRC.
Subject(s)
Humans , Adenosine Deaminase , Base Sequence , Biomarkers , Clinical Coding , Colorectal Neoplasms , Genome , Inosine , RNA Editing , RNA , TranscriptomeABSTRACT
Coronary artery aneurysm is a rare disorder. It is defined as abnormal dilatation of coronary artery with diameter exceeding 1.5 times the adjacent normal segments. The incidence of coronary aneurysm is 2.6% in Caucasians and 0.25% in Asians. Over half of the former were associated with atherosclerotic coronary artery disease. However, 70 percents of the latter were nonobstructive coronary artery aneurysms. Coronary artery fistula is a rare disorder. It has been identified in only 0.2% of routine cardiac angiographic studies conducted over a 10-year period. The clinical spectrums are various, asymtomatic, asymptomatic murmur, dyspnea on exertion, fatigue, and congestive heart failure. The right coronary artery (56%) and left coronary artery(36%) are mainly involved in the origin site of congenital coronary artery fistula. The draining site of fistula are right ventricle(39%), right atrium(33%), and pulmonary artery(20%) and so on. This 54 years-old woman had intermittent chest tightness and an abnormal mediastinal shadow on chest roentgenogram and chest C-T examination, which was diagnosed as a mediastinal mass such as teratoma. We performed the operation under left anterolateral thoracotomy for mass excision. However, we knew the mass had the pulsating arterial blood flow through a fine needle puncture of the mass and that it was attached to the left ventricle. We believed the excision of mass on beating heart would be very dangerous. Therefore, we closed the wound without excising the mass. After several days, we performed an echocardiography and coronary angiography, We knew it was cardiac tumor. Incidentally, the patient had a tortuous coronary fistula from the right coronary artery to pulmonary trunk. Using cardiopulmonary bypass with moderate systemic hypothermia, the mass was resected and the fistula was clipped with surgical clips. Pathology of the specimen was a giant coronary arterial aneurysm.