scholarly journals Clinical Implications of Pathogenic Germline Variants in Small Intestine Neuroendocrine Tumors (SI-NETs)

2021 ◽  
pp. 808-816
Author(s):  
Kimberly Perez ◽  
Matthew H. Kulke ◽  
Anu Chittenden ◽  
Chinedu Ukaegbu ◽  
Kristina Astone ◽  
...  
Keyword(s):  
Small Intestine ◽  
Neuroendocrine Tumors ◽  
Susceptibility Gene ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Inherited Susceptibility ◽  
Germline Variant ◽  
Hereditary Susceptibility ◽  
Generation Sequencing ◽  
Independent Cohort

PURPOSE An inherited basis for presumed sporadic neuroendocrine tumor (NET) has been suggested by evidence of familial clustering of NET and a higher incidence of second malignancies in patients and families with NET. To further investigate a potential heritable basis for sporadic neuroendocrine tumors, we performed multigene platform germline analysis to determine the frequency of hereditary susceptibility gene variants in a cohort of patients with sporadic small intestine NET (SI-NET). METHODS We performed a multigene platform germline analysis with Invitae's 83-gene, next-generation sequencing panel using DNA from 88 individuals with SI-NET from a clinically annotated database of patients with NET evaluated at Dana-Farber Cancer Institute (DFCI) who are considered high risk for inherited variants. Additionally, we evaluated the prevalence of pathogenic variants in an unselected cohort of patients with SI-NET who underwent testing with Invitae. RESULTS Of the 88 patients in the DFCI cohort, a pathogenic germline variant was identified in eight (9%) patients. In an independent cohort of 120 patients with SI-NET, a pathogenic germline variant was identified in 13 (11%) patients. Pathogenic variants were identified in more than one patient in the following genes: ATM, RAD51C, MUTYH, and BLM. Somatic testing of tumors from the DFCI cohort was suboptimal because of insufficient coverage of all targeted exons, and therefore, analysis was limited. CONCLUSION We demonstrate a 9%-11% incidence of pathogenic germline variants in genes associated with inherited susceptibility for malignancy not previously described in association with SI-NET. The association of these germline variants with neuroendocrine carcinogenesis and risk is uncertain but warrants further characterization.

scholarly journals Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

2021 ◽  
Vol 13 ◽  
pp. 175883592110337
Author(s):  
Fleur van der Sijde ◽  
Zakia Azmani ◽  
Marc G. Besselink ◽  
Bert A. Bonsing ◽  
Jan Willem B. de Groot ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Germline Variant ◽  
Early Tumor ◽  
Disease Stages ◽  
Generation Sequencing ◽  
Independent Cohort

Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control ( n = 30) or progressive disease ( n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.

scholarly journals Genetic and Clinical Profiles of Pheochromocytoma and Paraganglioma: A Single Center Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaosen Ma ◽  
Ming Li ◽  
Anli Tong ◽  
Fen Wang ◽  
Yunying Cui ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Exon 2 ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Single Center Study ◽  
Clinical Profiles ◽  
Generation Sequencing

Pheochromocytoma/paraganglioma (PPGL) has a high genetic heterogeneity with 40% germline variants in known pathogenic genes. Data in Chinese on this aspect are scanty. To detect the genetic and clinical profile of Chinese PPGL patients, we examined the variants of 12 known germline pathogenic genes (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127, and KIF1B) by next-generation sequencing and Sanger sequencing in 314 Chinese PPGL subjects. Twenty nine percent of Chinese PPGL patients had germline variants and SDHB was the most frequently mutated (14.6%). The most frequent SDHB variants were in exon 2, exon 7, and IVS 7. Pathogenic variants were more likely to occur in metastatic PPGL patients, paragangliomas, and patients under 30, with the ratio being 50.7% (35/69), 35.9% (56/156), and 49.5% (52/105), respectively. Our cohort included 314 patients from a single setting. The genetic and clinical features of Chinese PPGL patients were unique in some aspects compared to their non-Chinese counterparts. Identification of genotype-phenotype relation can serve as an effective tool for genetic prioritization and clinical decision-making.

Analysis of germline mutations in Chinese colorectal cancer patients with next-generation sequencing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13651-e13651
Author(s):  
Jing Gao ◽  
Hua Ren ◽  
Haiyan Liao ◽  
Luo Hai ◽  
Yuwei Cong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Lynch Syndrome ◽  
Genetic Susceptibility ◽  
Susceptibility Gene ◽  
Germline Mutations ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Gene Testing ◽  
Generation Sequencing

e13651 Background: Colorectal cancer (CRC) remains one of the leading causes of morbidity and mortality around the world. Familial cancer syndromes are common in CRC, inherited syndromes including Lynch syndrome (LS), familial adenomatous polyposis (FAP), and MutY human homolog (MUTYH)-associated polyposis (MAP) were well defined. But still, there are not well-established evidence between other several genes and CRC risk. Expanded multi-gene testing may be an alternative to find out the underlying mechanism for genetic susceptibility. Our study aims to assess the germline alternation landscape of Chinese CRC patients. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 381 genes on tissues from patients with CRC between January 01, 2017 and December 02, 2019 in 3D Medicines database. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: 1360 CRC patients were included for analysis, in which 95 (7.0%) patients harbored pathogenic (80/95) and likely pathogenic (15/95) germline mutations in 28 cancer predisposition genes. 33 subjects had pathogenic variants associated with Lynch syndrome (15 mutations in MLH1, 9 mutations in MSH2, 6 mutations in MSH6, 3 mutations in PMS2, respectively). 8 subjects had pathogenic variants associated with FAP (3 APC), MAP (3 MUTYH) and Li-Fraumeni syndrome (2 TP53). In addition, 14 pathogenic mutations in moderate penetrance genes (5 ATM, 3 BLM and 6 CHEK2) were found. The frequency of pathogenic BRCA mutations were 1 alternation in BRCA1 and 3 alternations in BRCA2. Conclusions: 7.0 % of patients with Chinese CRC carried germline cancer susceptibility gene mutations. Multi-gene testing would provide references for assessing genetic susceptibility and managing increased surveillance.

scholarly journals Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Do Hyeon Cha ◽  
Heon Yung Gee ◽  
Raul Cachau ◽  
Jong Mun Choi ◽  
Daeui Park ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Kidney Injury ◽  
Genetic Identification ◽  
Diagnostic Screening ◽  
Renal Hypouricemia ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Causal Variants ◽  
Coding Variants ◽  
Independent Cohort

Abstract Differentiating between inherited renal hypouricemia and transient hypouricemic status is challenging. Here, we aimed to describe the genetic background of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis using two founder variants in primary screening. We selected all cases (N = 31) with extreme hypouricemia (<1.3 mg/dl) from a Korean urban cohort of 179,381 subjects without underlying conditions. WES and corresponding downstream analyses were performed for the discovery of rare causal variants for hypouricemia. Two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) were identified in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. Four novel coding variants in SLC22A12, p.Asn136Lys, p.Thr225Lys, p.Arg284Gln, and p.Glu429Lys, were additionally identified. In silico studies predict these as pathogenic variants. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of Korean patients with monogenic hypouricemia. Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

scholarly journals Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2704
Author(s):  
Sally Yepes ◽  
Nirav N. Shah ◽  
Jiwei Bai ◽  
Hela Koka ◽  
Chuzhong Li ◽  
...  
Keyword(s):  
Internal Control ◽  
Susceptibility Gene ◽  
Copy Number Variants ◽  
Bone Cancer ◽  
Chinese Patients ◽  
European Ancestry ◽  
Unknown Etiology ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Pathogenic Variants

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

scholarly journals One4Two®: An Integrated Molecular Approach to Optimize Infertile Couples’ Journey

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 60
Author(s):  
Valeria D’Argenio ◽  
Federica Cariati ◽  
Rossella Tomaiuolo
Keyword(s):  
Disease Genes ◽  
Diagnostic Efficacy ◽  
Whole Process ◽  
Pathogenic Variants ◽  
Limiting Step ◽  
Number Of Genes ◽  
Infertile Couples ◽  
Next Generation Sequencing Ngs ◽  
And Diffusion ◽  
Generation Sequencing

The current diagnostic path of infertile couples is long lasting and often ineffective. Genetic tests, in particular, appear as a limiting step due to their jeopardized use on one side, and to the limited number of genes evaluated on the other. In this context, the development and diffusion, also in routine diagnostic settings, of next generation sequencing (NGS)-based methods for the analyses of several genes in multiple subjects at a time is improving the diagnostic sensitivity of molecular analyses. Thus, we developed One4Two®, a custom NGS panel to optimize the diagnostic journey of infertile couples. The panel validation was carried out in three steps analyzing a total of 83 subjects. Interestingly, all the previously identified variants were confirmed, assessing the analytic sensitivity of the method. Moreover, additional pathogenic variants have been identified underlying the diagnostic efficacy of the proposed method. One4Two® allows the simultaneous analysis of infertility-related genes, disease-genes of common inherited diseases, and of polymorphisms related to therapy outcome. Thus, One4Two® is able to improve the diagnostic journey of infertile couples by simplifying the whole process not only for patients, but also for laboratories and reproduction specialists moving toward an even more personalized medicine.

scholarly journals A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
P. Loza ◽  
A. Irmejs ◽  
Z. Daneberga ◽  
E. Miklasevics ◽  
E. Berga-Svitina ◽  
...  
Keyword(s):  
Literature Review ◽  
Local Spectrum ◽  
Single Family ◽  
Baltic Region ◽  
Breast And Ovarian Cancer ◽  
Pathogenic Variants ◽  
Common Founder ◽  
The Baltic ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Several recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRCA1/2 genes. The aim of current study is to analyze the spectrum of the BRCA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic region. Methods We present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRCA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRCA1/2 using next generation sequencing (NGS). Local spectrum of the BRCA1/2 PV was compared with the Baltic region by performing a literature review. Results Founder PV c.5266dupC, c.4035delA or c.181 T > G was detected in 369/9543 (3.9%) cases. Other BRCA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRCA1 variants c.5117G > A (p.Gly1706Glu), c.4675G > A (p.Glu1559Lys), c.5503C > T (p.Arg1835*) and c.1961delA (p.Lys654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRCA1 PV and six BRCA2 PV were each found in single family. Conclusions By combining three studies by our group of the same cohort in Latvia, frequency of the BRCA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three “historical” founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRCA1/2 sequencing. In relative numbers, c.5117G > A is currently the third most frequent PV of the BRCA1 in population of Latvia, overcoming previously known third most common founder variant c.181 T > G. In addition to three BRCA1 founder PV, a total of five recurrent BRCA1 and two recurrent BRCA2 PV have been reported in population of Latvia so far. Many of the BRCA1/2 PV reported in Latvia are shared among other populations of the Baltic region.

First Ex Vivo Results of Beta-Radioguided Surgery in Small Intestine Neuroendocrine Tumors with Y-90-DOTATOC

2021 ◽  
Author(s):  
Emilio Bertani ◽  
Francesco Collamati ◽  
Marzia Colandrea ◽  
Riccardo Faccini ◽  
Nicola Fazio ◽  
...  
Keyword(s):  
Small Intestine ◽  
Neuroendocrine Tumors ◽  
Ex Vivo ◽  
Radioguided Surgery
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