scholarly journals Metastatic colorectal cancer and severe hypocalcemia following irinotecan administration in a patient with X-linked agammaglobulinemia: a case report

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Mingming Li ◽  
Wei Chen ◽  
Xiaomeng Sun ◽  
Zhipeng Wang ◽  
Xun Zou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Drug Monitoring ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Drug Monitoring ◽  
Treatment Cycle ◽  
Germline Mutations ◽  
Therapeutic Drug ◽  
Immune Disorder ◽  
Whole Exome

Abstract Background X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Therefore, gene sequencing, therapeutic drug monitoring and any possible measurement to predict DRT should be considered before determining the course of chemotherapy for XLA patients with CRC. Case presentation In this study, we reported a 21-year-old male who developed metastatic CRC in the context of XLA. Since the whole exome sequencing and therapeutic drug monitoring did not reveal any predictive markers of DRT, we applied standard first-line chemotherapy to the patient. However, progressive disease occurred after the fifth treatment cycle. Therefore, the administration of oxaliplatin was changed to irinotecan as second-line therapy. After that, the patient firstly suffered from severe hypocalcemia and eventually died due to metastatic CRC after the eighth treatment cycle. The overall survival time was 7.5 months. Conclusions This study reported the first written record of a Chinese XLA patient with metastatic CRC and severe hypocalcemia. Whole exome sequencing and bioinformatic analysis indicated the somatic mutations in ABCA6, C6 and PAX3 genes might contribute to the early-onset and metastasis CRC. Besides, a number of germline mutations in genes related to calcium metabolism (CACNA2D4, CD36, etc.) and the administration of irinotecan were speculated to be the causes of severe hypocalcemia. We therefore suggested that in order to avoid severe DRT, clinicians should take genetic background and therapeutic drug monitoring into consideration while planning chemotherapy treatment for XLA patients with CRC.

Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors

2021 ◽  
Author(s):  
Juan Chen ◽  
Yan Li ◽  
Jianlei Wu ◽  
Yakun Liu ◽  
Shan Kang
Keyword(s):  
Germ Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Peripheral Blood ◽  
Copy Number ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Germline Mutations ◽  
Deletion Region ◽  
Whole Exome

Abstract Background Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. Methods The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes corresponding to copy number alterations (CNA) deletion and duplication region, functional annotation of was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region. Results In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YST). Moreover, POU5F1 was the most significant mutated gene with mutation frequency > 10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region) was found in 2 YST and nuclear staining in 2 dysgerminomas (DG) tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I-like receptor, Toll-like receptor, NF-kappa B and Jak–STAT. KRT4, RPL14, PCSK6, PABPC3 and SARM1 mutations were detected in both peripheral blood and tumor samples. Conclusions Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.

Whole-Exome Sequencing-Based Approach for Germline Mutations in Patients with Inborn Errors of Immunity

2020 ◽  
Vol 40 (5) ◽  
pp. 729-740 ◽  
Author(s):  
Tsubasa Okano ◽  
Kohsuke Imai ◽  
Takuya Naruto ◽  
Satoshi Okada ◽  
Motoi Yamashita ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Germline Mutations ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Whole Exome

scholarly journals Whole exome sequencing analysis of urine trans-renal tumour DNA in metastatic colorectal cancer patients

ESMO Open ◽  
2019 ◽  
Vol 4 (6) ◽  
pp. e000572
Author(s):  
Giovanni Crisafulli ◽  
Benedetta Mussolin ◽  
Andrea Cassingena ◽  
Monica Montone ◽  
Alice Bartolini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Weight ◽  
Metastatic Colorectal Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Information ◽  
Renal Tumour ◽  
Low Molecular Weight ◽  
Sequencing Analysis ◽  
Whole Exome

BackgroundThe analysis of circulating free tumour DNA (ctDNA) in blood, commonly referred as liquid biopsy, is being used to characterise patients with solid cancers. Tumour-specific genetic variants can also be present in DNA isolated from other body fluids, such as urine. Unlike blood, urine sampling is non-invasive, can be self-performed, and allows recurrent longitudinal monitoring. The features of tumour DNA that clears from the glomerular filtration barrier, named trans-renal tumour DNA (trtDNA), are largely unexplored.Patients and methodsSpecimens were collected from 24 patients with KRAS or BRAF mutant metastatic colorectal cancer (mCRC). Driver mutations were assessed by droplet digital PCR (ddPCR) in ctDNA from plasma and trtDNA from urine. Whole exome sequencing (WES) was performed in DNA isolated from tissue, plasma and urine.ResultsOut of the 24 CRC cases, only four had sufficient DNA to allow WES analyses in urine and plasma. We found that tumour alterations primarily reside in low molecular weight fragments (less than 112 bp). In patients whose trtDNA was more than 2.69% of the urine derived DNA, cancer-specific molecular alterations, mutational signatures and copy number profiles identified in urine DNA are comparable with those detected in plasma ctDNA.ConclusionsWith current technologies, WES analysis of trtDNA is feasible in a small fraction of mCRC patients. Tumour-related genetic information is mainly present in low molecular weight DNA fragments. Although the limited amounts of trtDNA poses analytical challenges, enrichment of low molecular weight DNAs and optimised computational tools can improve the detection of tumour-specific genetic information in urine.

Identification of Two New DBA Genes, RPS27 and RPL27, by Whole-Exome Sequencing in Diamond-Blackfan Anemia Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 984-984 ◽  
Author(s):  
Etsuro Ito ◽  
Kenichi Yoshida ◽  
Yusuke Okuno ◽  
Aiko Sato-Otsubo ◽  
Tsutomu Toki ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Germline Mutations ◽  
Steroid Treatment ◽  
Single Amino Acid ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Diamond Blackfan Anemia ◽  
Whole Exome ◽  
Increased Risk

Abstract Abstract 984 Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome, characterized by red blood cell aplasia, macrocytic anemia, and increased risk of malignancy. Approximately 90% of patients present during the first year of life or in early childhood. About 40–50% of DBA cases are familial with autosomal dominant, while the remainder is sporadic cases whose mode of inheritance is largely unknown. Although anemia is the most prominent feature of DBA, up to 40% of patients also accompany other symptoms including growth retardation and/or a variety of congenital malformations. Recent studies have shown that the disease could be associated with heterozygous mutations in ribosomal protein (RP) genes, including six small subunit RP genes RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 as well as four large subunit RP genes RPL5, RPL11, RPL26, and RPL35A, which collectively account for about 50% of patients with DBA. In addition, germline mutations in the GATA1 gene encoding a hematopoietic transcription factor, have been also reported in two DBA families. However, it is clear that the molecular etiology of many DBA cases remains to be covered. To identify new mutations that are responsible for DBA, we performed whole-exome sequencing on 40 DBA patients with no documented mutations/deletions involving known DBA genes. After excluding all variants registered in the 1000 Genomes Project, or dbSNP131, or found in our inhouse SNP database, we searched for non-synonymous mutations involving RP genes as possible candidate for novel DBA genes. In this study, we identified probable pathogenic mutations in two novel RP genes, RPS27 and RPL27 in two patients. The first case was a 1-year-old girl who harbored a single nucleotide substitution at the splice acceptor site in intron 1 of RPL27 (c.-2–1G>A), which results in splicing error. She had atrial septal defect and pulmonary stenosis, and responded to steroid treatment. The second case was a 2-year-old girl carrying a frameshift deletion of RPS27 (c.90delC, p.Tyr31ThrfsX5), leading to a premature truncation. This patient had no abnormalities and responded to steroid treatment. An additional five missense SNVs affecting single cases was identified in five genes, including RPL3L, RPL8, RPL13, RPL18A, and RPL31, together with two in-frame deletions of RPL6 and RPL14 in two patients, which cause deletion of a single amino-acid. However, the pathological significance in these 7 cases is uncertain. In the remaining 31 patients, no mutations were detected in RP genes. In conclusion, we identified novel germline mutations of RP genes that could be responsible for DBA, further confirming the concept that the RP genes are common targets of germline mutations in DBA patients and also suggested the presence of non-RP gene targets for DNA. Disclosures: No relevant conflicts of interest to declare.

Familial AML With Germline CEBPA Mutations: Extended Clinical Outcomes and Analysis Of Secondary Mutations Using Whole Exome Sequencing

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 740-740
Author(s):  
Kiran Tawana ◽  
Aline Renneville ◽  
Jun Wang ◽  
Panayiotis Georgiades ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Clinical Outcomes ◽  
Whole Exome Sequencing ◽  
Germline Mutations ◽  
Whole Exome ◽  
Disease Episode ◽  
Cebpa Mutations ◽  
Tumor Dna

Abstract Background Germline mutations in the N-terminal of CCAAT/enhancer binding protein α (CEBPA) are a feature of autosomal dominant AML. Despite the strong penetrance of these mutations, the age of disease onset varies considerably and is usually precipitated by acquiring a C-terminal mutation. Although biallelic CEBPA-mutations in sporadic AML are associated with favorable clinical outcomes, little is known about long-term survival or the secondary molecular events linked with familial cases. Aims We sought to establish the long term clinical outcomes in familial CEBPA-mutated AML and to examine the patterns of secondary mutations associated with leukemic transformation. Methods and Results Disease specific and follow up information was collected in 16 affected patients, from 7 pedigrees, published between 2004 and 2011. In 94% of patients (n=15), at least 3 years follow up was achieved. All pedigrees had a germline N-terminal CEBPA mutation and 17 of 18 documented disease episodes had an acquired C-terminal mutation. The age at AML diagnosis varied from 2-39 years (median 24.5 yrs) with a single asymptomatic carrier detected (now 23 yrs). With the exception of 1 patient diagnosed in 1963, all cases received combination chemotherapy at diagnosis. Additional consolidation comprised autologous stem cell transplantation (SCT, n=3) and allogeneic SCT in 1 patient failing to achieve CR post induction therapy. Ten patients had at least 1 further disease episode, the first recurrence presenting after a median of 2.1 years (range 0.5-14 yrs), 5 continued in CR and 1 patient was lost to follow up. In 3 out of 4 patients, where CEBPA was screened at recurrence, the acquired C-terminal mutations differed from diagnosis, signifying new episodes of AML. The median overall survival (OS) for the entire cohort was 20 years (1.1-46 yrs, n=16) and 17.3 years for patients with multiple disease episodes, reflecting durable responses to second line therapies. To identify potential co-operating mutations in CEBPA pedigrees, whole exome sequencing (WES) was performed in 7 tumor samples from 5 patients across 3 pedigrees, all with the germline mutation p.P23fs (Figure 1). All tumor DNA samples were sequenced with matched remission or skin DNA as a germline control. The number of acquired mutations in familial tumors was similar to sporadic disease, with 10-22 (median=14) non-synonymous tier 1 mutations per sample. In addition to the acquired C-terminal CEBPA mutation, these included established AML loci such as EZH2, TET2, WT1, GATA2, NRAS, CSF3R and the recently identified cohesin complex gene, SMC3. Of note, FLT3-ITD, NPM1 and DNMT3A mutations were absent in all tumors. A minimum of 2 established mutations were identified in each tumor and, at present, we can only speculate on which additional mutations are ‘driver' or ‘passenger' events. Reflecting findings in sporadic AML, biallelic CEBPA and GATA2 mutations co-occurred in both siblings from Pedigree 1 and were subsequently identified by Sanger sequencing in the child III.2 (Figure 1). All 3 patients continue in long term remission following chemotherapy. We were able to trace the clonal evolution in patient I.2 (Pedigree 3) by WES of 3 consecutive tumor samples which arose over a 17 year period. At diagnosis (Dx) the patient received induction and consolidation chemotherapy and remained disease free for 14 years. The second disease episode (R1) was treated with chemotherapy followed by autologous SCT and the third presentation (R2) was chemo-refractory. Tumor DNA from R2 was clonally related to Dx, sharing 7 identical mutations, including the original C-terminal CEBPA deletion. In contrast, R1 appeared molecularly distinct from Dx and R2, most likely representing a new clone which was subsequently eradicated with treatment. Conclusion This is the first report of long term clinical outcomes in familial CEBPA-mutated AML. Although many patients experienced disease recurrence, our extended follow up showed that OS remained favorable despite multiple episodes of disease. Assessment of C-terminal CEBPA mutations provided a unique insight into the recurrence of AML, with some patients appearing to develop completely new leukemic episodes. Although the penetrance of germline mutations is high, healthy carriers and late onset disease are noted, emphasizing the need for clinical vigilance and screening of all related potential SCT donors. Disclosures: No relevant conflicts of interest to declare.

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