Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

Wolff, Roger K.; Hoffman, Michael D.; Wolff, Erica; Herrick, Jennifer S.; Sakoda, Lori C.; Samowitz, Wade S.; Slattery, Martha L.

doi:10.1002/gcc.22539

“…Reduced obscurins expression level has been reported in breast cancer and depletion of obscurins leads to disruption of cell-cell contacts and acquisition of a mesenchymal phenotype that leads to enhanced tumorigenesis, migration and invasiveness (46). In colorectal carcinoma, OBSCN mutation was found early in carcinogenesis and was considered an early driver of carcinogenesis (54). In contrast, OBSCN was not considered as a cancer driver gene in another study (50).…”

Section: Discussionmentioning

confidence: 98%

Whole‐exome sequencing revealed mutational profiles of giant cell glioblastomas

Shi

¹

,

Li

²

,

Kwan

³

et al. 2019

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Giant cell glioblastoma (gcGBM) is a rare histological variant of GBM, accounting for about 1% of all GBM. The prognosis is poor generally though gcGBM does slightly better than the other IDH‐wild‐type GBM. Because of the rarity of the cases, there has been no comprehensive molecular analysis of gcGBM. Previously, single‐gene study identified genetic changes in TP53, PTEN and TERT promoter mutation in gcGBM. In this report, we performed whole‐exome sequencing (WES) to identify somatically acquired mutations and copy number variations (CNVs) in 10 gcGBM genomes. We also examined TERT promoter mutation and MGMT methylation in our cohort. On top of the reported mutations, WES revealed ATRX, PIK3R1, RB1 and SETD2 as the recurrent mutations in gcGBM. Notably, one tumor harbored a mutation in MutS homolog 6 (MSH6) that is a key mismatch repair (MMR) gene. This tumor demonstrated hypermutation phenotype and showed an increased number of somatic mutations. TERT promoter mutation and MGMT methylation were observed in 20% and 40% of our samples, respectively. In conclusion, we described relevant mutation profiling for developing future targeted therapies in gcGBM.

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“…Of these, BIRC6 exhibited a role in resistance to apoptosis (Chen et al., ; Hao et al., ). The gene has been suggested to be a prognosis predictor in colorectal cancer (Hu et al., ) and BIRC6 mutations have been found in colorectal adenomas (Zhou et al., ) and are common in carcinomas (Wolff et al., ). NCOA7/ERAP140 is a nuclear receptor coactivator that binds to the estrogen receptor among others.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in 51 early onset non‐familial CRC cases

Thutkawkorapin

¹

,

Lindblom

²

,

Tham

³

2019

Molec Gen & Gen Med

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Background Colorectal cancer ( CRC ) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi‐allelic autosomal recessive pathogenic variants. Methods The cohort was whole exome sequenced ( WES ) at 100× coverage. Both a dominant‐ and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young‐onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss‐of‐function) or allele frequency. Results We identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS 2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes ( BMPR 1A , BRIP 1 , and SRC ) , three truncating variants in possibly novel cancer genes ( CLSPN , SEC 24B , SSH 2 ) and four candidate missense variants in ACACA , NR 2C2 , INPP 4A, and DIDO 1 . We also identify five possible autosomal recessive candidate genes: ATP 10B , PKHD 1 , UGGT 2 , MYH 13 , TFF 3 . Conclusion Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

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“…The other 84% of cases were classified as microsatellite stable (MSS) and exhibited a higher frequency of somatic copy number alterations, suggesting chromosomal and subchromosomal defects (Network, 2012). The most frequently identified gene mutations in CRC tumors occur in APC, TP53, and KRAS (Huang et al, 2018;Wolff et al, 2018;Yaeger et al, 2018). Recent analysis of TCGA data identified mutations associated with DNA damage response genes and found that cases in the colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) datasets carried mutations in several DNA damage response and repair (DDR) genes (Knijnenburg et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Exploiting DNA repair defects in colorectal cancer

Reilly

¹

,

Novara

²

,

Nicolantonio

³

et al. 2019

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Colorectal cancer ( CRC ) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC . At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRC s. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma ( TCGA ‐ COAD ) and Rectal Adenocarcinoma ( TCGA ‐ READ ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly( ADP )‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA 1 and/or BRCA 2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA 1/ BRCA 2 mutations but exhibiting BRCA ‐ like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK 1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRC s to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients.

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Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

Cited by 60 publications

References 31 publications

Whole‐exome sequencing revealed mutational profiles of giant cell glioblastomas

Whole‐exome sequencing revealed mutational profiles of giant cell glioblastomas

Exome sequencing in 51 early onset non‐familial CRC cases

Exploiting DNA repair defects in colorectal cancer

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