Exome sequencing reveals frequent inactivating mutations in<i>ARID1A, ARID1B, ARID2</i>and<i>ARID4A</i>in microsatellite unstable colorectal cancer

Cajuso, Tatiana; Hänninen, Ulrika A.; Kondelin, Johanna; Gylfe, Alexandra E.; Tanskanen, Tomas; Katainen, Riku; Pitkänen, Esa; Ristolainen, Heikki; Kaasinen, Eevi; Taipale, Minna; Taipale, Jussi; Böhm, Jan; Renkonen–Sinisalo, Laura; Mecklin∥, Jukka–Pekka; Järvinen, Heikki; Tuupanen, Sari; Kilpivaara, Outi; Vahteristo, Pia

doi:10.1002/ijc.28705

Cited by 108 publications

(93 citation statements)

References 48 publications

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“…Furthermore, we observed the presence of a relatively lower proportion of driver events in at-risk mucosa compared with adenomas, and these events were identified in genes previously reported to be spurious (20) or not related to colorectal carcinogenesis (such as CDC27, PLEKNH1 , and PHOX2B ), thus suggesting that these drivers detected in at-risk mucosa are not biologically effective or may be “false positives” (as drivers). Only 2 genes found mutated in the at-risk mucosa samples, WNT11 (31) and ARID1B (32), have been previously reported to play a role in colorectal carcinogenesis, thus indicating that these mucosa samples have already acquired a growth advantage.…”

Section: Discussionmentioning

confidence: 97%

Genomic Landscape of Colorectal Mucosa and Adenomas

Borràs

Lucas

Chang

et al. 2016

Cancer Prevention Research

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Purpose The molecular basis of the adenoma to carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. Experimental Design We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Results Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer-driver genes (APC, KRAS, FBXW7, TCF7L2) and allelic imbalances in chromosomes 5, 7 and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. Conclusions The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis.

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Section: Discussionmentioning

confidence: 97%

Genomic Landscape of Colorectal Mucosa and Adenomas

Borràs

Lucas

Chang

et al. 2016

Cancer Prevention Research

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“…ARID2 has been suggested to be tumor suppressive in hepatocellular carcinoma, with a mutation rate of 6.5%. ARID2 is mutated in 13% of colorectal cancer patients with microsatellite instability [30]. ARID2is also mutated in 18.2% of hepatocellular carcinoma cases, leading to inactivation of the coding protein [31].…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing to identify somatic mutations in peritoneal metastatic gastric adenocarcinoma: A preliminary study

Liu

Zhu

et al. 2016

Oncotarget

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Peritoneal metastasis occurs in more than half of patients with unresectable or recurrent gastric cancer and is associated with the worst prognosis. The associated genomic events and pathogenesis remain ambiguous. The aim of the present study was to characterize the mutation spectrum of gastric cancer with peritoneal metastasis and provide a basis for the identification of new biomarkers and treatment targets. Matched pairs of normal gastric mucosa and peritoneal tissue and matched pairs of primary tumor and peritoneal metastasis were collected from one patient for whole-exome sequencing (WES); Sanger sequencing was employed to confirm the somatic mutations. G>A and C>T mutations were the two most frequent transversions among the somatic mutations. We confirmed 48somatic mutations in the primary site and 49 in the peritoneal site. Additionally, 25 non-synonymous somatic variations (single-nucleotide variants, SNVs) and 2 somatic insertions/deletions (INDELs) were confirmed in the primary tumor, and 30 SNVs and 5 INDELs were verified in the peritoneal metastasis. Approximately 59% of the somatic mutations were shared between the primary and metastatic site. Five genes (TP53, BAI1, THSD1, ARID2, and KIAA2022) verified in our study were also mutated at a frequency greater than 5%in the COSMIC database. We also identified 9genes (ERBB4, ZNF721, NT5E, PDE10A, CA1, NUMB, NBN, ZFYVE16, and NCAM1) that were only mutated in metastasis and are expected to become treatment targets. In conclusion, we observed that the majority of the somatic mutations in the primary site persisted in metastasis, whereas several single-nucleotide polymorphisms occurred de novo at the second site.

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“…The apparent reasoning behind this was that based on his germline ARID1B mutation and inferred CSS diagnosis, he was thought to be susceptible to infection and based on the findings of somatic ARID1B mutations in cancer [Stephens et al, 2012;Kadoch et al, 2013;Khursheed et al, 2013;Cajuso et al, 2014] he was considered at an increased risk of neoplasia. Immunodeficiencies have been reported in other ID syndromes, such as the 22q11 deletion syndrome.…”

Section: Article American Journal Of Medical Genetics Part C (Seminarmentioning

confidence: 98%

The ARID1B phenotype: What we have learned so far

Santen

Clayton‐Smith²

2014

American J of Med Genetics Pt C

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Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.

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Exome sequencing reveals frequent inactivating mutations inARID1A, ARID1B, ARID2andARID4Ain microsatellite unstable colorectal cancer

Cited by 108 publications

References 48 publications

Genomic Landscape of Colorectal Mucosa and Adenomas

Genomic Landscape of Colorectal Mucosa and Adenomas

Whole-exome sequencing to identify somatic mutations in peritoneal metastatic gastric adenocarcinoma: A preliminary study

The ARID1B phenotype: What we have learned so far

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