Cancer Predisposition Genetic Analysis in Children with Brain Tumors Treated at a Single Institution in Japan

Oncology ◽  
2021 ◽  
Author(s):  
Hiroko Fukushima ◽  
Ryoko Suzuki ◽  
Yuni Yamaki ◽  
Sho Hosaka ◽  
Masako Inaba ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Rare Variants ◽  
Clinical Information ◽  
Japanese Patients ◽  
Pediatric Brain Tumors ◽  
Cancer Predisposition ◽  
Children With Cancer ◽  
White Children ◽  
Pathogenic Variants ◽  
Predisposition Genes

Brain tumors affect one-third of all children with cancer. Approximately 10% of children with cancer carry variants in cancer predisposition genes. However, germline analyses in large cohorts of Asian children have not been reported. Thirty-eight Japanese patients with pediatric brain tumors were included in this study (19 boys, 19 girls). DNA was extracted from the patients’ peripheral blood, and cancer-associated genes were analyzed using targeted resequencing. Rare variants with allele frequencies <0.1% in the general population and variants suspected to be pathogenic were extracted and analyzed. Pathogenic variants were found in 7 patients (18%): 2 nonsense variants of CHEK2 and FANCI; 2 frameshift deletions in SMARCB1 and PTCH1; and 3 missense variants of TSC1, WRN, and MLH1. The median age at diagnosis was 9.1 years, and three of the 7 patients had a family history of cancer. One patient diagnosed with basal cell nevus syndrome, also called Gorlin syndrome, developed a second neoplasm, and another with an SMARCB1 variant and an atypical teratoid/rhabdoid tumor developed a thyroid adenomatous nodule. This is the first cancer-related germline analysis with detailed clinical information reported in Japanese children with brain tumors. The prevalence was almost equivalent to that in white children.

scholarly journals Expanding cancer predisposition genes with ultra-rare cancer-exclusive human variations

2020 ◽  
Author(s):  
Roni Rasnic ◽  
Nathan Linial ◽  
Michal Linial
Keyword(s):  
Genetic Predisposition ◽  
Rare Variants ◽  
Genetic Alterations ◽  
Cancer Predisposition ◽  
Rare Cancer ◽  
Uk Biobank ◽  
Independent Evidence ◽  
High Penetrance ◽  
Predisposition Genes ◽  
The Uk

AbstractIt is estimated that up to 10% of cancer incidents are attributed to inherited genetic alterations. Despite extensive research, there are still gaps in our understanding of genetic predisposition to cancer. It was theorized that ultra-rare variants partially account for the missing heritable component. We harness the UK BioBank dataset of ∼500,000 individuals, 14% of which were diagnosed with cancer, to detect ultra-rare, possibly high-penetrance cancer predisposition variants. We report on 115 cancer-exclusive ultra-rare variations (CUVs) and nominate 26 variants with additional independent evidence as cancer predisposition variants. We conclude that population cohorts are valuable source for expanding the collection of novel cancer predisposition genes.

scholarly journals Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site

EP Europace ◽  
2019 ◽  
Vol 21 (11) ◽  
pp. 1725-1732 ◽  
Author(s):  
Greg J Mellor ◽  
Pankaj Panwar ◽  
Andrea K Lee ◽  
Christian Steinberg ◽  
Julie A Hathaway ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Rare Variants ◽  
Clinical Information ◽  
Long Qt ◽  
T Wave ◽  
Pathogenic Variants ◽  
Loop Region ◽  
Wave Morphology ◽  
History Of ◽  
Qt Syndrome

Abstract Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

scholarly journals Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Kana Kitayama ◽  
Tomoya Ishiguro ◽  
Masaki Komiyama ◽  
Takayuki Morisaki ◽  
Hiroko Morisaki ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Clinical Information ◽  
Japanese Patients ◽  
Kinase Domain ◽  
Single Family ◽  
Serine Threonine Kinase ◽  
Blood Leukocytes ◽  
Pathogenic Variants ◽  
Japanese Cohort ◽  
Recurrent Epistaxis

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. Methods Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. Results In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. Conclusions In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

scholarly journals Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

2021 ◽  
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Katherine L. Nathanson ◽  
Jeffrey N. Weitzel ◽  
David E. Goldgar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lobular Carcinoma ◽  
Population Based ◽  
Cancer Predisposition ◽  
Clinical Cohort ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Multigene Panel

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

scholarly journals Germline Pathogenic Variants in Homologous Recombination and DNA Repair Genes in an Asian Cohort of Young-Onset Colorectal Cancer

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Ming Ren Toh ◽  
Jian Bang Chiang ◽  
Siao Ting Chong ◽  
Sock Hoai Chan ◽  
Nur Diana Binte Ishak ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Predisposition ◽  
Colorectal Cancers ◽  
Dna Repair Genes ◽  
Young Onset ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Repair Genes

Abstract Background Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. Methods We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. Results In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C>T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. Conclusion A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.

Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10581-10581
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Susan M. Domchek ◽  
Jeffrey N. Weitzel ◽  
David Goldgar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Population Based ◽  
Cancer Predisposition ◽  
Clinical Cohort ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Multigene Panel Testing ◽  
Multigene Panel

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected controls in both cohorts and between women with ILC and IDC in the clinical cohort. Results: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analyses, CDH1 and BRCA2 PVs were associated with high risks of ILC (Odds ratio (OR) > 4), and CHEK2, ATM and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2 and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

scholarly journals Cancer predisposition genes in Japanese children with rhabdomyosarcoma

2021 ◽  
Author(s):  
Hiroko Fukushima ◽  
Ryoko Suzuki ◽  
Yuni Yamaki ◽  
Sho Hosaka ◽  
Masako Inaba ◽  
...  
Keyword(s):  
Soft Tissue Sarcomas ◽  
Clinical Information ◽  
Cancer Predisposition ◽  
Japanese Children ◽  
Drug Induced ◽  
Female Ratio ◽  
First Report ◽  
Missense Variants ◽  
Predisposition Genes

Background: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. Germline mutations in cancer predisposition genes have been detected in approximately 10% of pediatric cancers. However, the genetic background of RMS is still unclear, especially in Asian children. Procedure: DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Results: Twenty patients participated in this study. The median age at diagnosis was 5.0 years. The male-to-female ratio was 3:2. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Five pathogenic variants were found in four patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of LIG4 and MEN1. Two of the four patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. This is the first report of germline cancer-related gene variants with detailed clinical information in Japanese children with RMS. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. Conclusions: When this is the first report of the germline genetic analysis of Japanese children with RMS, the frequency of the variant was almost equivalent to that of previous reports from Western countries. Unbiased exon sequencing may be useful to clarify the pathogenesis of RMS in children and in predicting the clinical course of these patients.

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