Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma.

Esophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are of African descent. African American ESCC (AA ESCC) is particularly aggressive, and its biological underpinnings remain poorly understood. We sought to identify the genomic abnormalities by conducting whole exome sequencing of 10 pairs of matched AA esophageal squamous cell tumor and control tissues. Genomic analysis revealed diverse somatic mutations, copy number alterations (SCNAs), and potential cancer driver genes. Exome variants created two subgroups carrying either a high or low tumor mutation burden. Somatic mutational analysis based on the Catalog of Somatic Mutations in Cancer (COSMIC) detected SBS16 as the prominent signature in the high mutation rate group suggesting increased DNA damage. SBS26 was also detected, suggesting possible defects in mismatch repair and microsatellite instability. We found SCNAs in multiple chromosome segments, encoding MYC on 8q24.21, PIK3CA and SOX2 on 3q26, CCND1, SHANK2, CTTN on 11q13.3, and KRAS on 12p12. Amplifications of EGFRvIII and EGFRvIVa mutants were observed in two patients, representing a novel finding in ESCC that has potential clinical relevance. This present exome sequencing, which to our knowledge, represents the first comprehensive exome analysis exclusively in AA ESCC, and highlights novel mutated loci that might explain the aggressive nature of AA ESCC and lead to the development of diagnostic and prognostic markers as well as therapeutic targets.

African-American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks.

BACKGROUND: Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), the subtype that shows marked variation in geographic frequency. The molecular architecture of African-American ESCC is still poorly understood. It is unclear why African-American ESCC is more aggressive and the survival rate in these patients is worse than those of other ethnic groups. METHODS: To begin to define genetic alterations that occur in African-American ESCC we conducted microarray expression profiling in pairs of esophageal squamous cell tumors and matched control tissues. RESULTS: We found significant dysregulation of genes encoding drug-metabolizing enzymes and stress response components of the NRF2- mediated oxidative damage pathway, potentially representing key genes in African-American esophageal squamous carcinogenesis. Loss of activity of drug metabolizing enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence and aggressiveness of ESCC in this ethnic group. To determine whether certain genes are uniquely altered in African-American ESCC we performed a meta-analysis of ESCC expression profiles in our African-American samples and those of several Asian samples. Down-regulation of TP53 pathway components represented the most common feature in ESCC of all ethnic groups. Importantly, this analysis revealed a potential distinctive molecular underpinning of African-American ESCC, that is, a widespread and prominent involvement of the NRF2 pathway. CONCLUSION: Taken together, these findings highlight the remarkable interplay of genetic and environmental factors in the pathogenesis of African-American ESCC.

Palliative ethanol injections of unresectable advanced esophageal carcinoma combined with chemoradiation.

Combined chemoradiation therapy has proven to be an effective treatment for unresectable esophageal cancer. Nonsurgical endoscopic palliation of local disease has become feasible with neodymium:yttrium-aluminum-garnet laser, BICAP tumor probe, and metallic stents. Alternatively, endoscopic injections of ethanol are safe, inexpensive, and useful for palliation of malignant dysphagia. Two patients with unresectable squamous cell carcinoma of the esophagus were treated with 1 mL of absolute (95 g/L) alcohol injections once a week for 4 weeks, followed by chemoradiation therapy consisting of concomitant 5-fluorouracil 300 mg/m/d and radiation therapy (total of 60 Gy over 6 weeks). One patient had a complete response but died of alcoholism 25 months after diagnosis without evidence of tumor recurrence. The other patient had a partial response but died 16 months after diagnosis from disease progression. We conclude that tumor ablation by ethanol injection for palliation combined with chemoradiation may be a low-cost alternative for advanced unresectable esophageal cancer.

Analysis of Sciellin (SCEL) as a candidate gene in esophageal squamous cell carcinoma.

BACKGROUND: The aim of this study was to investigate whether a candidate gene, Sciellin (SCEL), mapping to the chromosome 13q21-q31 is mutated in esophageal cancer. MATERIALS AND METHODS: The coding region and intron-exon junctions of SCEL were sequenced in 13 esophageal squamous cell cancers and matching normal esophageal samples to detect mutations. RESULTS: Three single nucleotide polymorphisms were detected in SCEL of which two were silent mutations (L640L and H654H) and one missense mutation (R366K). CONCLUSION: Single nucleotide polymorphisms were detected in both matching tumor and normal esophageal tissues but no disease-associated mutations suggesting that SCEL is not a major factor in esophageal squamous cell carcinogenesis.

Endoscopic Nd:YAG laser with aggressive multimodality therapy for locally advanced esophageal cancer.

BACKGROUND: Laser therapy of esophageal carcinoma has been limited to management of malignant dysphagia. To investigate its cytoreductive potential, Nd:YAG laser tumor debulking was added to multimodality therapy. METHODS: From 1994-1998, 29 patients with advanced locoregional esophageal carcinoma were enrolled in a prospective experimental study of high-dose neoadjuvant chemoradiotherapy together with endoscopic Nd:YAG laser photoablation. Comparisons were made to a retrospective cohort of 31 patients treated from 1990 to 1994 who underwent similar neoadjuvant chemoradiotherapy without laser debulking. RESULTS: Laser dosage ranged from 3457 to 67,443 J (mean 21,832 [SD 16,999]) delivered in 1 to 6 (mean 2.6 [1.4]) treatment sessions. Actuarial analysis showed improved survival in the laser-treated group versus the reference group (30.1 months vs. 16.5 months; p = 0.047). Multivariable analysis of the impact of age, T-stage, N-stage, completion of neoadjuvant therapy, and laser debulking that included all patients in both treatment groups showed completion of therapy to be the most significant variable associated with survival. There were 3 complications related to laser therapy. Relief of dysphagia was achieved in 19 of 29 patients (66%) in the laser group versus 13 of 31 (42%) in the reference group. CONCLUSIONS: Malignant dysphagia may be more effectively treated by the addition of Nd:YAG laser therapy to aggressive multimodality therapy. Improved survival with the addition of laser debulking warrants longer follow-up and a prospective comparative trial.