Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis

Liu, Wenjin; Snell, Jeff M.; Jeck, William R.; Hoadley, Katherine A.; Wilkerson, Matthew D.; Parker, Joel S.; Patel, Nirali M.; Mlombe, Yohannie; Mulima, Gift; Liomba, N. George; Wolf, Lindsey L.; Shores, Carol G.; Gopal, Satish; Sharpless, Norman E.

doi:10.1172/jci.insight.88755

Cited by 50 publications

(59 citation statements)

References 45 publications

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“…Apart from copy number aberrations, mutational analyses have shown recurrent inactivating mutations in TP53, and NOTCH1 as well as activating events in PIK3CA [10,11,15]. A single genomic study, performed on African patients from Malawi, recapitulated patterns of gene mutations and copy number changes (gains of CCND1, TP63, MYC, ERBB2, EGFR, MYCL1 and losses of CDKN2A/CDKN2B), similar to those observed in Asian and North American ESCC patients [16]. Of note, gene expression patterns from transcriptome sequence analysis in this African cohort highlighted three distinct ESCC subgroups that tended to reflect exposure to differing environmental factors [16].…”

Section: Introductionmentioning

confidence: 55%

“…A single genomic study, performed on African patients from Malawi, recapitulated patterns of gene mutations and copy number changes (gains of CCND1, TP63, MYC, ERBB2, EGFR, MYCL1 and losses of CDKN2A/CDKN2B), similar to those observed in Asian and North American ESCC patients [16]. Of note, gene expression patterns from transcriptome sequence analysis in this African cohort highlighted three distinct ESCC subgroups that tended to reflect exposure to differing environmental factors [16]. The diversity in the genomic landscape observed in this study strongly warrants the expansion of genomic investigations in other African countries with high ESCC incidence in order to infer etiologic factors and identify markers of disease with a potential for early detection and improved therapeutic interventions.…”

Section: Introductionmentioning

confidence: 66%

“…CCND1 encodes a protein which promotes cell cycle progression. Gain thereof and associated increased expression is well described in a variety of cancer types including head and neck squamous cell carcinoma and ESCC [13][14][15][16]30].…”

Section: Gainsmentioning

confidence: 99%

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Landscape of copy number aberrations in esophageal squamous cell carcinoma from a high endemic region of South Africa

2020

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Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with one of the highest world incidences in the Eastern Cape region of South Africa. Several genome wide studies have been performed on ESCC cohorts from Asian countries, North America, Malawi and other parts of the world but none have been conducted on ESCC tumors from South Africa to date, where the molecular pathology and etiology of this disease remains unclear. We report here tumor associated copy number changes observed in 51 ESCC patients' samples from the Eastern Cape province of South Africa. Methods: We extracted tumor DNA from 51 archived ESCC specimens and interrogated tumor associated DNA copy number changes using Affymetrix® 500 K SNP array technology. The Genomic Identification of Significant Targets in Cancer (GISTIC 2.0) algorithm was applied to identify significant focal regions of gains and losses. Gains of the top recurrent cancer genes were validated by fluorescence in situ hybridization and their protein expression assessed by immunohistochemistry. Results: Twenty-three significant focal gains were identified across samples. Gains involving the CCND1, MYC, EGFR and JAG1 loci recapitulated those described in studies on Asian and Malawian cohorts. The two most significant gains involved the chromosomal sub-bands 3q28, encompassing the TPRG1 gene and 11q13.3 including the CTTN, PPFIA1and SHANK2 genes. There was no significant homozygous loss and the most recurrent hemizygous deletion involved the B3GAT1 gene on chromosome 11q25. Focal gains on 11q13.3 in 37% of cases (19/51), consistently involved CTTN and SHANK2 genes. Twelve of these cases (23,5%), had a broader region of gain that also included the CCND1, FGF19, FGF4 and FGF3 genes. SHANK2 and CTTN are co-amplified in several cancers, these proteins interact functionally together and are involved in cell motility. Immunohistochemistry confirmed both Shank2 (79%) and cortactin (69%) protein overexpression in samples with gains of these genes. In contrast, cyclin D1 (65%) was moderately expressed in samples with CCND1 DNA gain. Conclusions:This study reports copy number changes in a South African ESCC cohort and highlights similarities and differences with cohorts from Asia and Malawi. Our results strongly suggest a role for CTTN and SHANK2 in the pathogenesis of ESCC in South Africa.

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Section: Introductionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 66%

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Landscape of copy number aberrations in esophageal squamous cell carcinoma from a high endemic region of South Africa

2020

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“…Evidence produced by TCGARN supports the contention that different populations may display slightly different mutation profiles . Furthermore, in the only large‐scale genomic analysis performed on ESCC subjects from sub‐Saharan Africa (59 ESCC cases from Malawi), the authors were unable to show the typical mutational signature associated with tobacco smoking, but identified an unusual mutational signature previously observed in a small number of oropharyngeal squamous carcinoma cases . These observations underscore the need to perform a more detailed genomic analysis of ESCC cases located in those regions that have been poorly sampled.…”

Section: Genomics Mutations and Deregulated Pathwaysmentioning

confidence: 90%

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

Talukdar

Pietro

Secrier

et al. 2018

Annals of the New York Academy of Sciences

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Esophageal cancer (EC) is one of the most lethal cancers and a public health concern worldwide, owing to late diagnosis and lack of efficient treatment. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are main histopathological subtypes of EC that show striking differences in geographical distribution, possibly due to differences in exposure to risk factors and lifestyles. ESCC and EAC are distinct diseases in terms of cell of origin, epidemiology, and molecular architecture of tumor cells. Past efforts aimed at translating potential molecular candidates into clinical practice proved to be challenging, underscoring the need for identifying novel candidates for early diagnosis and therapy of EC. Several major international efforts have brought about important advances in identifying molecular landscapes of ESCC and EAC toward understanding molecular mechanisms and critical molecular events driving the progression and pathological features of the disease. In our review, we summarize recent advances in the areas of genomics and epigenomics of ESCC and EAC, their mutational signatures and immunotherapy. We also discuss implications of recent advances in characterizing the genome and epigenome of EC for the discovery of diagnostic/prognostic biomarkers and development of new targets for personalized treatment and prevention.

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“…With the recent technological advances in next‐generation sequencing, human ESCC samples from North and South America, China, Japan, Vietnam, and Malawi have been sequenced . ESCC shares similar genomic profiles with head and neck SCC and lung SCC, but not with esophageal adenocarcinoma, suggesting common etiological factors .…”

Section: Gene Mutations and Nrf2 Hyperactivation In Human Esccmentioning

confidence: 99%

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Paiboonrungruan

Yan

et al. 2018

Annals of the New York Academy of Sciences

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Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. Here, we review the current understanding of the functions of the nuclear factor erythroid-derived 2-like 2 (NRF2) signaling pathway in the esophagus. Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in human ESCC. As a consequence, NRF2 ESCC is more resistant to chemoradiotherapy and associated with poorer survival than NRF2 ESCC. Mechanistically, we believe NRF2, functioning as a transcription factor, causes an esophageal phenotype through regulation of gene transcription. We discuss metabolism, mitochondria, proteasomes, and several signaling pathways as downstream players that may contribute to an esophageal phenotype due to NRF2 hyperactivation. Finally, strategies are proposed to target the NRF2 signaling pathway for therapy of NRF2 ESCC.

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Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis

Cited by 50 publications

References 45 publications

Landscape of copy number aberrations in esophageal squamous cell carcinoma from a high endemic region of South Africa

Landscape of copy number aberrations in esophageal squamous cell carcinoma from a high endemic region of South Africa

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

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