Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

Yang, Ian A.; Sethi, Nilay; Hinoue, Toshinori; Schneider, Barbara; Cherniack, Andrew D.; Sanchez‐Vega, Francisco; Seoane, José A.; Farshidfar, Farshad; Bowlby, Reanne; Islam, Mirazul; Kim, Jaegil; Chatila, Walid K.; Akbani, Rehan; Kanchi, Rupa S.; Rabkin, Charles S.; Willis, Joseph E.; Wang, Linghua; McCall, Shannon J.; Mishra, Lopa; Ojesina, Akinyemi I.; Bullman, Susan; Pedamallu, Chandra Sekhar; Lazar, Alexander J.; Sakai, Ryo; Thórsson, Vésteinn; Bass, Adam J.; Laird, Peter W.

doi:10.1016/j.ccell.2018.03.010

Cited by 439 publications

(477 citation statements)

References 99 publications

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“…Remarkably, the high rate of segmental aUPD in STAD and ESCA suggests higher levels of structural CIN in these cancer types compared to COAD and READ, which agrees with a previous study showing more focal amplification events in the upper than in the lower GI tract . Furthermore, most GI cancers contain aneuploid genomes . Our experimental and computational assessment of the genome ploidy confirmed that highly aneuploid tumors display an increased number of aUPD compared to near‐diploid tumors, affecting both whole chromosomes and segments of chromosomes.…”

Section: Discussionsupporting

confidence: 90%

“…36 Furthermore, most GI cancers contain aneuploid genomes. 37 Our experimental and computational assessment of the genome ploidy confirmed that highly aneuploid tumors display an increased number of aUPD compared to near-diploid tumors, affecting both whole chromosomes and segments of chromosomes. In fact, whole chromosome UPD may originate from pre-or postzygotic chromosome segregation defects.…”

Section: Discussionsupporting

confidence: 55%

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Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers

Torabi

Erola

Álvarez-Mora

et al. 2018

Intl Journal of Cancer

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Somatically acquired uniparental disomies (aUPDs) are frequent events in solid tumors and have been associated with cancer‐related genes. Studies assessing their functional consequences across several cancer types are therefore necessary. Here, we aimed at integrating aUPD profiles with the mutational status of cancer‐related genes in a tumor‐type specific manner. Using TCGA datasets for 1,032 gastrointestinal cancers, including colon (COAD), rectum (READ), stomach (STAD), esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), we show a non‐random distribution of aUPD, suggesting the existence of a cancer‐specific landscape of aUPD events. Our analysis indicates that aUPD acts as a “second hit” in Knudson's model in order to achieve biallelic inactivation of tumor suppressor genes. In particular, APC , ARID1A and NOTCH1 were recurrently inactivated by the presence of homozygous mutation as a consequence of aUPD in COAD and READ, STAD and ESCC, respectively. Furthermore, while TP53 showed inactivation caused by aUPD at chromosome arm 17p across all tumor types, copy number losses at this genomic position were also frequent. By experimental and computationally inferring genome ploidy, we demonstrate that an increased number of aUPD events, both affecting the whole chromosome or segments of it, were present in highly aneuploid genomes compared to near‐diploid tumors. Finally, the presence of mosaic UPD was detected at a higher frequency in DNA extracted from peripheral blood lymphocytes of patients with colorectal cancer compared to healthy individuals. In summary, our study defines specific profiles of aUPD in gastrointestinal cancers and provides unequivocal evidence of their relevance in cancer.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 55%

Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers

Torabi

Erola

Álvarez-Mora

et al. 2018

Intl Journal of Cancer

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“…Our analyses suggest that roughly 20% of all FGFR2 ‐altered GEA have at least one coexisting genomic event predicted to decrease the sensitivity to FGFR2‐directed therapies. Recurrent RTK coamplifications are relatively unique to GEA among tubular gastrointestinal cancers, and our results are consistent with studies of other RTKs of interest . The frequency of coexisting alterations is a cautionary tale for developing FGFR2‐directed therapies, particularly monotherapies, in GEA and suggests a need for comprehensive baseline genomic characterization .…”

Section: Discussionsupporting

confidence: 85%

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

Klempner

Madison²,

Pujara

et al. 2019

The Oncologist

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Background With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2‐altered GEA. We examined FGFR2 alteration frequency and frequency of co‐occurring alterations in GEA. Subjects, Materials, and Methods A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture‐based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. Results We identified a total of 269 (4.0%) FGFR2‐altered cases consisting of FGFR2‐amplified (amp; 193, 72% of FGFR2‐altered), FGFR2‐mutated (36, 13%), FGFR2‐rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co‐occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2‐altered GEA. Co‐occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2‐altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild‐type samples. Conclusion FGFR2‐altered GEA is a heterogenous subgroup with approximately 20% of FGFR2‐altered samples harboring concurrent RTK alterations. Putative co‐occurring modifiers of FGFR2‐directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. Implications for Practice Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2‐altered GEA parallels the heterogeneity findings in HER2‐amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.

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“…First, EBV‐positive tumors are often biased to men, and MSI‐positive GC typically affects elders . Second, longstanding accumulation of DNA methylations are thought to underlie MSI tumors, suppressing the expression of gene sets including MLH1 …”

Section: Discussionmentioning

confidence: 99%

“…19 Second, longstanding accumulation of DNA methylations are thought to underlie MSI tumors, suppressing the expression of gene sets including MLH1. 19,42 Does any type of gene amplification characterize GCYA? The Cancer Genome Atlas analysis indicated that the amplification of genes related to the RTK signaling pathways are frequently observed in the CIN subtype.…”

Section: Discussionmentioning

confidence: 99%

Enrichment of CLDN18‐ARHGAP fusion gene in gastric cancers in young adults

et al. 2019

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Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease, and diffuse‐type histology. Comprehensive molecular analyses of gastric cancers have led to molecular‐based classifications and to specific and effective treatment options. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here, we studied 146 gastric cancer patients diagnosed at the age of 40 years or younger at the Cancer Institute Hospital (Tokyo, Japan). Tumor specimens were examined for Helicobacter pylori infection, Epstein‐Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications, and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and FISH. Although only a small number of cases were positive for Epstein‐Barr virus and microsatellite instability (n = 2 each), we repeatedly found tumors with gene fusion between a tight‐junction protein claudin, CLDN18 , and a regulator of small G proteins, ARHGAP , in as many as 22 cases (15.1%), and RNA sequencing identified 2 novel types of the fusion. Notably, patients with the CLDN18‐ARHGAP fusion revealed associations between aggressive disease and poor prognosis, even when grouped by their clinical stage. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age‐onset gastric cancers, and its presence could contribute to their aggressive characteristics.

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Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas

Cited by 439 publications

References 99 publications

Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers

Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers

FGFR2-Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape

Enrichment of CLDN18‐ARHGAP fusion gene in gastric cancers in young adults

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