scholarly journals Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Cell Reports ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 239-254.e6 ◽  
Author(s):  
Theo A. Knijnenburg ◽  
Linghua Wang ◽  
Michael T. Zimmermann ◽  
Nyasha Chambwe ◽  
Galen F. Gao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Cancer Genome Atlas ◽  
Molecular Landscape ◽  
Genome Atlas

scholarly journals Response to Comment on “DNA damage is a pervasive cause of sequencing errors, directly confounding variant identification”

Science ◽  
2018 ◽  
Vol 361 (6409) ◽  
pp. eaat0958 ◽  
Author(s):  
Lixin Chen ◽  
Pingfang Liu ◽  
Thomas C. Evans ◽  
Laurence M. Ettwiller
Keyword(s):  
Dna Damage ◽  
Oxidative Damage ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Sequencing Errors ◽  
Cancer Genome Atlas ◽  
Genome Atlas ◽  
Variant Identification

Following the Comment of Stewart et al., we repeated our analysis on sequencing runs from The Cancer Genome Atlas (TCGA) using their suggested parameters. We found signs of oxidative damage in all sequence contexts and irrespective of the sequencing date, reaffirming that DNA damage affects mutation-calling pipelines in their ability to accurately identify somatic variations.

scholarly journals Comment on “DNA damage is a pervasive cause of sequencing errors, directly confounding variant identification”

Science ◽  
2018 ◽  
Vol 361 (6409) ◽  
pp. eaas9824 ◽  
Author(s):  
Chip Stewart ◽  
Ignaty Leshchiner ◽  
Julian Hess ◽  
Gad Getz
Keyword(s):  
Dna Damage ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Sample Processing ◽  
Sequencing Errors ◽  
Cancer Genome Atlas ◽  
P 752 ◽  
Genome Atlas ◽  
Variant Identification

Chen et al. (Reports, 17 February 2017, p. 752) highlight an important problem of sequencing artifacts caused by DNA damage at the time of sample processing. However, their manuscript contains several errors that led the authors to incorrect conclusions. Moreover, the same sequencing artifacts were previously described and mitigated in The Cancer Genome Atlas and other published sequencing projects.

Whole exome sequencing–based analysis to identify DNA damage repair deficiency as a major contributor to gliomagenesis in adult diffuse gliomas

2020 ◽  
Vol 132 (5) ◽  
pp. 1435-1446 ◽  
Author(s):  
Ege Ülgen ◽  
Özge Can ◽  
Kaya Bilguvar ◽  
Yavuz Oktay ◽  
Cemaliye B. Akyerli ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Gene Mutations ◽  
The Cancer Genome Atlas ◽  
Mutational Load ◽  
Mutational Signatures ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Whole Exome ◽  
Diffuse Gliomas

OBJECTIVEProcesses that cause or contribute to cancer, such as aging, exposure to carcinogens, or DNA damage repair deficiency (DDRd), create predictable and traceable nucleotide alterations in one’s genetic code (termed “mutational signatures”). Large studies have previously identified various such mutational signatures across cancers that can be attributed to the specific causative processes. To gain further insight into the processes in glioma development, the authors analyzed mutational signatures in adult diffuse gliomas (DGs).METHODSTwenty-five DGs and paired blood samples were whole exome sequenced. Somatic mutational signatures were identified using 2 different methods. Associations of the signatures with age at diagnosis, molecular subset, and mutational load were investigated. As DDRd-related signatures were frequently observed, germline and somatic DDR gene mutations as well as microsatellite instability (MSI) status were determined for all samples. For validation of signature prevalence, publicly available data from The Cancer Genome Atlas (TCGA) were used.RESULTSEach tumor had a unique combination of signatures. The most common signatures were signature 1 (88%, aging related), signature 3 (52%, homologous recombination related), and signature 15 (56%, mismatch repair related). Eighty-four percent of the tumors contained at least 1 DDRd signature. The findings were validated using public TCGA data. The weight of signature 1 positively correlated with age (r = 0.43) while cumulative weight of DDRd signatures negatively correlated with age (r = −0.16). Each subject had at least 1 germline/somatic alteration in a DDR gene, the most common being the risk single nucleotide polymorphism rs1800734 in MLH1. The rs1800734-AA genotype had a higher cumulative DDRd weight as well as higher mutational load; TP53 was the most common somatically altered DDR gene. MSI was observed in 24% of the tumors. No significant associations of MSI status with mutational load, rs1800734, or the cumulative weight of DDRd signatures were identified.CONCLUSIONSCurrent findings suggest that DDRd may act as a fundamental mechanism in gliomagenesis rather than being a random, secondary event.

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

scholarly journals The construction and analysis of ceRNA networks in invasive breast cancer: a study based on The Cancer Genome Atlas

2018 ◽  
Vol Volume 11 ◽  
pp. 1-11 ◽  
Author(s):  
Chundi Gao ◽  
Huayao Li ◽  
Jing Zhuang ◽  
HongXiu Zhang ◽  
Kejia Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Invasive Breast Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Genome Atlas
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