Etiology Of Esophageal Cancer Research Articles

Esophageal Cancer: Etiology, Modern Treatment Methods and Future Directions

Esophageal cancer (EC) is globally recognized as the sixth most often diagnosed cancer and the eighth most frequent cancer in terms of total occurrence. At the time of diagnosis, it exhibits a notable fatality rate and poor healing outcomes. Esophageal squamous cell carcinoma (ESCC) is commonly brought on by carcinogens entering and exiting the esophageal mucosa directly, such as via mechanical stress, alcohol intake, smoking, and obesity. The main pathophysiologic pathway for esophageal adenocarcinoma (EAC) is chronic gastroesophageal reflux disease (GERD). The treatment of different types of EC varies. The primary strategy for treating locally advanced malignancies is surgery, with the inclusion of neoadjuvant chemotherapy or radiotherapy for combination management. The purpose of adding chemotherapy in EC is to lower the tumor stage, reduce the risk of the tumor, and facilitate subsequent targeted therapy. In this paper, we will discuss the etiology of EC, modern treatment methods and future directions.

Clinicopathological profile and survival analysis of esophageal carcinoma: A retrospective study in a tertiary care hospital in Northeast India

ABSTRACT Background: Esophageal cancer (EC) is an extremely aggressive tumor with one of the highest geographic, ethnic, and gender variations. Various factors including tobacco consumption, unhealthy diet, and socioeconomic status have been implicated in the etiology of EC. Despite the advent of modern treatments, the prognosis of EC is dismal. This study has been undertaken to review the clinical and pathologic profiles, treatment approach, and survival pattern in patients with EC in a tertiary care hospital in northeast India. Materials and Methods: A retrospective descriptive study was done with 179 EC patients presented to our department between January 2013 and December 2020. Statistical analysis was done by using IBM Statistical Package for the Social Sciences version 21. P- value <0.05 was considered significant. Results: The majority of the patients presented in the sixth decade of life from rural areas with male to female ratio of 3.7:1. Dysphagia was the most common presenting feature. High incidence of tobacco and alcohol use was found. Mid-esophagus is the most common site and squamous cell carcinoma is the most common type. Fifty-two (29.1%) and 71 (39.6%) patients presented in stages III and IV, respectively. Twenty-four (13.4%) patients presented with metastatic disease, the lung being the most common site. Patients were treated with surgery, chemotherapy, radiotherapy, or combination of any of these. Overall median survival for the EC patients was 6 months. Patients treated with concurrent chemoradiation had better survival. Conclusion: EC is a serious malignancy with a dismal prognosis due to the advanced stage at presentation. Larger clinical trials using new therapeutic strategies are the need of the hour.

S2379 Squamous Cell Carcinoma of the Gastroesophageal Junction as an Unusual Underlying Cause of Pseudoachalasia

Introduction: Achalasia is a rare esophageal motility disorder characterized by progressive dysphagia to solids and eventually liquids[1-2]. Pseudoachalasia refers to an achalasia secondary to an underlying etiology, such as masses, post-operative complications, or paraneoplastic syndromes[1-2]. The most common cause of pseudoachalasia is adenocarcinoma of the cardia or esophagus [1] however, we discuss a rare case that deviates from the typical etiology of esophageal cancer. Case Description/Methods: This is a 71-year-old male presenting with intermittent dysphagia for years with rapid progression for a month including intolerance of oral intake and 6-pound weight loss. On examination he was hemodynamically stable with a soft, nontender abdomen. His initial barium esophagram revealed decreased esophageal peristalsis, esophageal distention, and narrowing at the gastroesophageal junction (GEJ) with “bird beak” appearance consistent with possible achalasia. Further imaging studies were performed with computed tomography (CT), esophagogastroduodenoscopy (EGD) with dilation, and endoscopic ultrasound with biopsies revealing an invasive squamous cell carcinoma of the GEJ with submucosal involvement extending into the gastric cardia (Figure). We present our patient as the first reported case of pseudoachalasia due to SCC of the GEJ. The patient underwent esophageal stenting and mediport placement with plans for neoadjuvant chemotherapy with concurrent radiotherapy followed by definitive resection. Discussion: Pseudoachalasia is often misdiagnosed for primary achalasia because of its rarity, indistinguishable symptomatology, and normal findings on CT, EGD, and biopsy[1-2]. Nearly 75% of pseudoachalasia cases are due to adenocarcinoma of the gastric cardia[1]. Only one case of pseudoachalasia has been known to be caused by SCC in the distal esophagus[3]. SCC of the GEJ is an extremely rare esophageal malignancy and has never previously been reported as an underlying cause of pseudoachalasia.Figure 1.: Esophagogastroduodenoscopy revealed severe stricture at the GEJ with a 4 cm submucosal mass at the GEJ with extension to the gastric cardia.REFERENCES 1. Campo SM, Zullo A, Scandavini CM, Frezza B, Cerro P, Balducci G. Pseudoachalasia: A peculiar case report and review of the literature. World J Gastrointest Endosc. 2013;5(9):450-454. 2. Roushan N, Zolfaghari A, Asadi M, Taslimi R. Pseudoachalasia: a diagnostic challenge. Med J Islam Repub Iran. 2014;28:54. 3. Kahrilas, P., Kishk, S., Helm, J., Dodds, W., Harig, J. and Hogan, W., 1987. Comparison of pseudoachalasia and achalasia. The American Journal of Medicine. 1987;82(3):439-446.

S2408 A Case of Advanced Esophageal Carcinosarcoma

Introduction: The majority of esophageal cancers are classified histologically as squamous cell carcinomas or adenocarcinomas. We present a case of a 69-year-old man, presented with progressive dysphagia, found to have an esophageal carcinosarcoma, a rare etiology of esophageal cancer. Case Description/Methods: A 69-year-old man, an everyday smoker with a history of ongoing alcohol use, presented for the evaluation of unintentional weight loss and progressive dysphagia of 2 months duration. Upper endoscopy revealed a large, 6 cm in diameter, partially obstructing ulcerating mass in the mid esophagus. PET/CT revealed intense FDG uptake in the esophageal mass, mediastinal lymph nodes, T6 and T10 ribs suggestive of metastatic disease. Surgical pathology of the tumor was consistent with a high grade squamous cell carcinoma mixed with a high grade spindle cell sarcoma (carcinosarcoma). The patient was started on chemoradiation including Paclitaxel, Carboplatin. Improvement of symptoms and CT findings was documented with treatment (Figure). Discussion: Esophageal cancer ranks seventh in incidence and sixth in cancer-related mortality. The majority of esophageal cancers are classified histologically as squamous cell carcinomas or adenocarcinomas. When 2 distinct malignant components, both carcinomatous and sarcomatous are present histologically, the tumor is classified as esophageal carcinosarcoma (ECS). The pathogenesis is debatable, with some arguing that it is an initial carcinoma, facilitating a simultaneous secondary development of sarcoma, while others hypothesize a single cell origin. Carcinosarcomas were documented in tumors of the uterus, breast, thyroid, lung and gastrointestinal tract. ECSs have a rare incidence, accounting for approximately 1.5% of all esophageal tumors. It has been noted that ECS tumors have different clinical behaviors when compared to squamous cell carcinomas or adenocarcinomas. ECS tumors were noted to have a calculated doubling time of 2.2 months, with predominantly exogenous polypoid growth, perhaps explaining the earlier symptom of dysphagia, earlier diagnosis and more favorable 5 year survival rate. Given their rarity, no standard protocol has been developed to treat ECS tumors. Resection, regional lymph node dissection, radiotherapy and chemotherapy have all been utilized. Our case presentation further enriches the literature regarding rare, advanced esophageal adenocarcinoma tumors responding to systemic therapy.Figure 1.: A, B - Endoscopic findings. A large protruding, 6 cm in diameter partially obstructing ulcerating mass in the mid esophagus. C - Intense FDG uptake by the esophageal tumor in the esophagus (green arrow) and intense FDG uptake in the posterior/lateral aspect of the right T6 rib (yellow circle). D - Intensely avid subcarinal lymph node (yellow circle).

3D Organoids: An Untapped Platform for Studying Host-Microbiome Interactions in Esophageal Cancers.

The microbiome is an emerging key co-factor in the development of esophageal cancer, the sixth leading cause of cancer death worldwide. However, there is a paucity of data delineating how the microbiome contributes to the pathobiology of the two histological subtypes of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma. This critical knowledge gap is partially due to inadequate modeling of host–microbiome interactions in the etiology of esophageal cancers. Recent advances have enabled progress in this field. Three dimensional (3D) organoids faithfully recapitulate the structure and function of the normal, preneoplastic, and neoplastic epithelia of the esophagus ex vivo and serve as a platform translatable for applications in precision medicine. Elsewhere in the gastrointestinal (GI) tract, the co-culture of 3D organoids with the bacterial microbiome has fostered insight into the pathogenic role of the microbiome in other GI cancers. Herein, we will summarize our current understanding of the relationship between the microbiome and esophageal cancer, discuss 3D organoid models of esophageal homeostasis, review analogous models of host–microbiome interactions in other GI cancers, and advocate for the application of these models to esophageal cancers. Together, we present a promising, novel approach with the potential to ameliorate the burden of esophageal cancer-related morbidity and mortality via improved prevention and therapeutic interventions.

Microbiome and Cancers of the Esophagus: A Review.

Esophageal cancer (EC) is an aggressive malignant disease ranking amongst the leading causes of cancer deaths in the world. The two main histologic subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), have distinct geographic and temporal patterns and risk factor profiles. Despite decades of research, the factors underlying these geo-temporal patterns are still not fully understood. The human microbiome has recently been implicated in various health conditions and disease, and it is possible that the microbiome may play an important role in the etiology of EC. Although studies of the microbiome and EC are still in their early stages, we review our current understanding of the potential links between ESCC, EAC, and bacterial communities in the oral cavity and esophagus. We also provide a summary of the epidemiology of EC and highlight some key challenges and future directions.

Infection with Human Papillomavirus 18 Promotes Alkylating Agent-Induced Malignant Transformation in a Human Esophageal Cell Line.

The relationship between human papillomavirus (HPV) and esophageal cancer (EC) has been controversial, which may be caused by the difference in geographic regions of sample origin. Thus, we conducted a case-control study to find that HPV increased the risk of esophageal cancer, and the HPV18 detection rate is the highest (24.2%) among patients with EC, suggesting that HPV18 could be the most risk subtype of HPV infected. We then identified high-risk HPV18 and N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) to establish a model on the viral etiology cooperating with environmental carcinogens. Het-1A cells containing HPV18 were continuously exposed to MNNG or not; then the morphological phenotype and function assays were performed in 25th passage cells. MNNG promoted the proliferation and invasion abilities and inhibited apoptosis both in Het-1A-HPV18 and control group. However, the Het-1A-HPV18 had a stronger change in phenotypic features and formed more transformed foci in soft agar. Further, Western blot found p53 and p21 were down-regulated, and expression of c-Myc, MMP-2, and MMP-9 and Bcl-2/Bax ratio were up-regulated. Our results revealed that MNNG was easier to induce malignant transformation of Het-1A cells transfected with HPV18. It is good evidence for the close relationship between HPV and the etiology of EC, providing foundation for further study in molecular mechanism and specific intervention targets.

Analyzing the Expression Level and Associated Clinical Characteristics of miRNA-138 in Esophageal Squamous Cell Carcinoma in Iranian Patients

Background: Esophageal Squamous Cell Carcinoma (ESCC) is the seventh most common and lethal malignancy worldwide with a high incidence in Iran. Esophageal cancer has a poor prognosis and low 5-years survival rate. Despite several studies on esophageal cancer, its underlying mechanism remains unclear. Therefore, it is significant to analyze the molecular factors involved in disease for introducing effective diagnosis and therapeutic approaches. Accordingly, the aberrant expression of miRNA was demonstrated in the etiology of esophageal cancer, and applying them as detecting biomarkers was further considered by researchers. This study aimed to evaluate the expression level of miRNA-138 in the tumor tissues of ESCC and normal adjacent tissues. Objective: In total, 35 samples of tumor and normal tissues of the esophagus were collected from ESCC patients. Methods: Then, RNA extraction was conducted and the expression level of miRNA-138 was assessed in the collected tissue samples, applying real-time RT-PCR. Moreover, the relationship between the miRNA-138 expression level and the patient’s clinical characteristics was assessed. Results: According to the obtained results, the expression of miR-138 was significantly downregulated in the tumor tissues of ESCC, compared to normal adjacent tissues (P<0.05). Additionally, the level of miRNA-138 downregulation was significantly correlated with tumor differentiation degree and metastasis status (P<0.05). Conclusion: The significant downregulation of miRNA-138 in the tumor samples of ESCC indicated the role of this epigenetic alteration in esophageal carcinogenesis. Therefore, applying the miRNA-138 could be considered as a potential molecular biomarker for ESCC diagnosis and screening.

Risk factors for precancerous lesions of esophageal squamous cell carcinoma in high-risk areas of rural China: A population-based screening study.

Although many studies in China have found that environmental or lifestyle factors are major contributors to the etiology of esophageal cancer, most of the patients in the above studies are in the middle and late stages, the early-stage patients account for a small proportion. To clarify the risk/protective factors contributing to early lesions, we conducted the present cross-sectional study.A total of 2925 healthy controls and 402 patients with esophageal precancerous lesions were included in our study by endoscopic examination. Information on risk/protective factors was collected by personal interview, and unconditional logistic regression was used to determine adjusted odds ratios (AORs) by the maximum-likelihood method.Smoking >20 pack-years (AOR = 1.48), duration of drinking >30 years (AOR = 1.40), alcohol consumption >100 mL/d (AOR = 1.44), gastroesophageal reflux disease (AOR = 1.75), esophagitis (AOR = 1.25), a family history of esophageal cancer (AOR = 1.92), or stomach cancer (AOR = 1.92) were significant risk factors for esophageal precancerous lesions. There was a negative correlation between abdominal obesity and early esophageal cancer and precancerous lesions (AOR = 0.75). In addition, we found that there was a synergistic effect between a family history of esophageal cancer and drinking (AOR = 3.00) and smoking (AOR = 2.90).Lifestyle risk factors, genetic factors, and upper gastrointestinal diseases are associated with the development of esophageal precancerous lesions. These results highlight the need for primary prevention to reduce the future burden of cancer and other chronic diseases in high-risk areas of rural China.

Abstract A24: Exploration of esophageal cancer etiology using comprehensive DNA adduct analysis (DNA adductome analysis)

Abstract Objective: China has among the highest incidence and mortality rates of esophageal cancer in the world. Cixian, one of the high-incidence areas, demonstrates a much higher incidence when compared with other rural or urban areas in China. To address the etiology of esophageal cancer in Cixian, we carried out a comprehensive DNA adduct analysis (DNA adductome) using surgical specimens that were collected from esophageal cancer patients living in Cixian and Shijiazhuang (low-incidence area for esophageal cancer). Methods: Both tumorous and nontumorous tissues were collected from patients who underwent surgical procedures at Cixian Cancer Hospital and the Fourth Hospital of Hebei Medical University. A peripheral blood sample was also collected in each hospital. DNA adductome analysis was performed with LC-QTOF mass spectrometer by using DNA derived from surgical specimen. Whole-exome sequencing analysis was also conducted using esophageal tumor/peripheral blood paired samples. Mutation analyses of candidate chemical substance, which was predicted by DNA adductome analysis, were performed with Ames assay and gpt delta transgenic rats. Results: Multiple DNA adducts were detected in samples from both areas in the DNA adductome analysis. The 2D-PCA scores plot of the DNA adducts showed a clear clustering of the high- and low-incidence areas, and the associated loadings plot demonstrated that several DNA adducts made a greater contribution to the high-incidence area. By referring to an in-house DNA adduct database, N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)deoxyguanosine (THP-dG), which was derived from N-nitrosopiperidine (NPIP), emerged as a major DNA adduct. In order to confirm the DNA adduct that was highly correlated to the high-incidence area, we synthesized authentic 15N5-THP-dG and analyzed it by quantitative LC-MS/MS apparatus. An elution peak, which appeared at the same position of authentic 15N5-THP-dG, was observed in the surgical specimens collected from the high-incidence area. Examination of THP-dG adduct in peripheral blood samples demonstrated that the adduct levels were significantly higher in the high-incidence area than in the low-incidence area. Moreover, NPIP exhibited a strong mutagenic activity under metabolic activation in the Ames test and a significant dose-dependent increase in mutation frequency during in vivo mutagenicity tests with gpt delta rats. The NPIP-induced mutation was dominated by A:T to C:G transversions, followed by G:C to A:T and A:T to G:C transitions, in both liver and esophagus of animal samples. Similar mutational patterns were observed in the mutational signatures of esophageal cancer patients, which demonstrated weak correlation with THP-dG levels. Conclusion: This is the first study that used DNA adductome analysis to reveal the etiology of esophageal cancer in Cixian. These findings suggested that NPIP exposure is partly involved in the development of esophageal cancer in Cixian residents. Citation Format: Hitoshi Nakagama, Yukari Totsuka, Yingsong Lin, Yutong He, Haruna Sato, Tomonari Matsuda, Yoshitaka Matsushima, Mamoru Kato, Asmaa Elzawahry, Yasushi Totoki, Tatsuhiro Shibata, Baoen Shan. Exploration of esophageal cancer etiology using comprehensive DNA adduct analysis (DNA adductome analysis) [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A24.

Ways and tradition of Japan in esophageal surgery for cancer.

This report presents the essence in practice of Japanese methods and tradition in surgery for esophageal cancer. The etiology of esophageal cancer and the concepts of lymphadenectomy in esophagectomy, in neoadjuvant treatments, and in stage classifications are compared between Western countries and Japan. With respect to the type and relative incidence of esophageal cancer, in Western countries, adenocarcinoma in the lower thoracic esophagus and in the cardia is common, and among esophageal surgeons, there remains some controversy over the extent of lymphadenectomy. On the other hand, in Japan, squamous cell carcinoma in the middle thoracic esophagus is common, and concerning lymphadenectomy, Japanese esophageal surgeons consider that three-field lymphadenectomy is superior to other types of lymphadenectomy. In Japan, surgeons believe that most patients with esophageal cancer even those having lymph node metastasis can be best treated using esophagectomy and lymphadenectomy. In Japan, the tradition in esophageal surgery places great significance on lymphadenectomy. The ways and procedures for esophageal cancer surgery, the neoadjuvant and adjuvant treatments, the Japanese Classification of Esophageal Cancer, the Esophageal Cancer Practice Guidelines, and other scientific reports are all based on a close combination of esophagectomy with lymphadenectomy.

Strontium and antimony serum levels in healthy individuals living in high- and low-risk areas of esophageal cancer.

BackgroundIt has been shown there is an upward trend for strontium (Sr) and antimony (Sb) levels from low‐risk (LR) to high‐risk (HR) areas of etiology of esophageal cancer in water, soil, and grains grown in Golestan province. In the present study, the serum levels of Sr and Sb were determined in healthy individuals living in these areas.MethodsThis cross‐sectional study was performed on fasting blood serum of adult healthy individuals collected by cluster sampling. Subjects were divided into two groups, those living in either HR or LR areas. Strontium and antimony serum levels were measured using a graphite furnace atomic absorption spectroscopy.ResultsA total of 200 volunteers were enrolled from which 96 persons (48%) and 104 persons (52%) were from either HR or LR areas, respectively. The sex distribution was 40.9% male and 59.1% female, and the average age of enrolled people was 50.9 years. The average strontium levels were 30.44 ± 4.05 and 30.29 ± 3.74 μg/L in LR and HR, respectively. It also has been shown the average antimony levels were 15.21 ± 3.40, 14.81 ± 3.17, 15.13 ± 3.62, and 15.07 ± 3.62 μg/L in LR, HR, urban, and rural populations, respectively.ConclusionThe serum levels of strontium and antimony were not significantly different in healthy adults living in high‐ and low‐risk areas of esophageal cancer. However, the average antimony serum levels in Golestan Province were above the reference interval in different countries.

Prevalence of the integration status for human papillomavirus 16 in esophageal carcinoma samples.

To investigate the etiology of esophageal cancer (EC) related with human papillomavirus (HPV) infection. Fresh surgically resected tissue samples and clinical information were obtained from 189 patients. Genomic DNA was extracted, and HPV was detected using polymerase chain reaction (PCR) with HPV L1 gene primers of MY09/11; HPV16 was detected using HPV16 E6 type-specific primer sets. Copies of HPV16 E2, E6, and the human housekeeping gene β-actin were tested using quantitative PCR to analyze the relationship between HPV16 integration and esophageal squamous cell carcinoma and the relationship between the HPV16 integration status and clinical information of patients. Of the 189 samples, 168 HPV-positive samples were detected, of which 76 were HPV16 positive. Among the HPV16 positive samples, 2 cases (E2/E6 ratio>1) were 2.6% (2/76) purely episomal, 65 (E2/E6 ratio between 0 and 1) were 85.6% (65/76) mixture of integrated and episomal, and 9 (E2/E6 ratio=0) were 11.8% (9/76) purely integrated. The results indicate that integration of HPV16 was more common in the host genome than in the episome genome. The prevalence rate of HPV16 integration is increasing with the pathological stage progression of esophageal carcinoma (EC). A high prevalence of HPV16 suggested that HPV16 has an etiological effect on the progress of EC. Integration of HPV16 is more common than episome genome in the host cells, indicating that continuous HPV infection is the key to esophageal epithelial cell malignant conversion and canceration.

The Prevalence and Association of Human Papillomavirus with Esophageal Cancer in West Azerbaijan, Iran

Background: Esophageal cancer (EC) is a common cancer worldwide. Despite epidemiological studies, the etiology of EC is undetected. It was recommended that tobacco, alcohol, food carcinogens, and infectious agents may be involved in the pathogenesis of EC. Accumulating evidence suggests the role of human papillomavirus (HPV) on EC. Objectives: The aim of this study was to evaluate the prevalence and association of HPV with EC. Methods: In this case-control study, 86 samples of formalin-fixed and paraffin-embedded esophageal tissues were gathered from the pathology laboratory, Imam Khomeini Hospital, Urmia, West Azerbaijan, Iran. A total of 43 samples were esophageal cancers (cases) and 43 samples were esophageal non-cancerous tissues (controls). The tissues were sectioned and deparaffinized, and deoxyribonucleic acid was extracted. The polymerase chain reaction test was conducted to detect HPV, using general (GP5+/GP6+) and type-specific (E6/E7) primers. HPV types were confirmed by sequencing. The data were analyzed by the SPSS software. Results: Out of 86 samples, 23 (26.74%) were positive for HPV (15 cases, and 8 controls). By type-specific primers, high-risk HPVs were detected in the cases (3 HPV-16, 10 HPV-18, 1 HPV-31, and 1 HPV-33) and the controls (6 HPV-18, 1 HPV-31, and 1 HPV-33). No significant association was observed between HPV and EC (P = 0.078). Conclusions: Although no significant association was observed between HPV and EC, high-risk HPV genotypes were found in esophageal cancers more than non-cancerous esophageal tissues. To confirm this result, more studies should be carried out in other populations.

Aetiology of Oesophageal Cancer in Africa - A Review of Historical and Current Evidence

There is no current agreement on the cause of squamous cancer of the oesophagus in Africa, a major cause of morbidity and mortality in East and Southern Africa. The remarkable history is reviewed together with all recent evidence using a literature search.
 
 There are consistent and continuing associations with maize and with tobacco. Changes of type of maize, patterns of consumption and processing occurred around 1930, and a rapid rise of oesophageal cancer dated from that time. 
 
 Tobacco has a worldwide association with cancer of the oesophagus, but there is a substantial minority of non-users in high incidence areas. Other carcinogens have come under suspicion, but there is evidence against any of these acting as the principal carcinogenic influence in Africa. Recent studies in Japan and in South Africa have shown an association between non-acid gastro-oesophageal reflux and squamous cancer of the oesophagus.
 
 There is no credible candidate for principal oesophageal carcinogen in Africa. There is good reason to look again at milled maize: its deficiencies, contaminations, and degenerative processes. Associations between diet, non-acid reflux and squamous cancer of the oesophagus merit further study.

Abstract A34: The genetic etiology of esophageal cancer in South African Black populations

Abstract Esophageal squamous cell carcinoma (ESCC) is common in Black populations of the sub-Saharan Africa, with high incidence regions in East and South Africa. Clinical presentation in Africa is late, and treatment is mainly palliative with a very poor prognosis. Various environmental risk factors have been identified, but the possible contribution of genetics to disease risk is an important question, which is unresolved. The aim of this project is to test the hypothesis that genetic variation in the South African Black population contributes significantly to the risk of ESCC. We have begun by testing genetic risk factors for ESCC which were identified by genome-wide association scans in other populations for association with ESCC in the South African Black population. Cases with a histologically confirmed diagnosis of ESCC and population controls were recruited, with informed consent and institutional ethical approval. All individuals were from the Black population of the Western Cape, with 98.2% being from the Xhosa ethnic group. A total of 513 ESCC cases and 820 controls were genotyped for 15 single nucleotide polymorphisms (SNPs) by validated TaqMan assays on a 7900HT (Applied Biosystems). SNPs were tested for association using an allelic chi-square test; odds ratios (OR) and 95% confidence intervals (CI) used the common allele as reference. A significance threshold of p=0.0033 was applied, from a Bonferroni multiple testing correction for 15 SNPs. No significant evidence of association was observed for the index SNPs at the previously reported loci ATP1B2, CASP8, c20orf54, HEATR3, PDE4D, PLCE1, PTPN2, RUNX1, SMG6, ST6GAL1, TMEM173 and UNC5L loci. However, the SNP rs2239815 at XBP1 on chromosome 22q12 was associated with ESCC (OR =1.41, P = 0.00087), as were 2 SNPs in CHEK2, rs4822983 (OR = 1.31, P = 0.0013) and rs1033667 (OR = 1.29, P = 0.0025). These 3 SNPs are within 70kb of each other and are in partial linkage disequilibrium in African populations. Fine-mapping of this locus will be required to determine the causal gene and variant/s driving this association. The lack of association with ESCC in the Black South African population at most of the loci previously associated in Asian GWAS suggests that at least some of these may not contribute to susceptibility to ESCC in the South African population. However, expansion of samples sizes and thus statistical power is required for more definitive exclusions, and the lower level of linkage disequilibrium (LD) across African genomes may produce a negative result if the SNP which is tagging the causal variant in Asian or European populations is in weak LD with the causal SNP in African populations. In order to address these issues we are now expanding the power and density of this study by genotyping 36 SNPs from loci of interest in 1000 South African ESCC cases and 940 controls from the Johannesburg Cancer Study by mass spectrometry using the MassArray genotyping system (Agena Bioscience). Citation Format: Wenlong Carl Chen, Hannah Bye, Marco Matejcic, Robyn Kerr, Elvira Singh, Natalie J. Prescott, Cathryn M. Lewis, Chantal Babb de Villers, Iqbal Parker, Christopher G. Mathew. The genetic etiology of esophageal cancer in South African Black populations [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A34.

Abstract 4961: The oral microbiome and prospective risk for esophageal cancer: A population-based nested case-control study

Abstract Background: The two most common types of esophageal cancer, esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC), are highly fatal. The human microbiota have been suggested to play a role in esophageal cancer etiology, although the evidence is limited to small, cross-sectional studies. We hypothesized that the oral microbiota, which shape the esophageal microbiota, may be causative agents in esophageal carcinogenesis. Methods: We conducted a prospective study nested in two large U.S. cohorts: ACS CPS-II and NCI-PLCO. Oral bacteria were assessed in pre-diagnostic mouth-wash samples collected from cases and controls (n=81/160 EAC and n=25/50 ESCC cases/matched controls), using 16S rRNA gene sequencing. We compared overall microbial composition between cases and controls using permutational multivariate analysis of variance (PERMANOVA) of UniFrac distances, and we examined associations between centered log-ratio transformed taxon abundances and cancer risk using conditional logistic regression. Metagenome functional content was predicted from taxonomic composition using PiCRUST. Results: Overall microbial composition did not differ between EAC cases and matched controls or ESCC cases and matched controls, adjusting for matching factors (age, sex, race, cohort, time to diagnosis/selection), BMI, smoking, and alcohol intake (all p>0.40). The periodontal pathogens Tannerella forsythia and Porphyromonas gingivalis were nominally associated with increased risk for EAC (OR [95% CI] = 1.21 [1.01, 1.46], p=0.04) and ESCC (OR [95% CI] = 1.3 [0.96, 1.77], p=0.09), respectively. Conversely, genus Neisseria, previously shown to be depleted by cigarette smoking, was associated with protection against EAC (OR [95% CI] = 0.88 [0.8, 0.97], p=0.01). Other species associated with EAC risk (p<0.05) included Corynebacterium durum, Prevotella nanceiensis, and Streptococcus pneumoniae (inversely associated with EAC), and Actinomyces cardiffensis, Selenomonas oral taxon 134, and Veillonella oral taxon 917 (positively associated with EAC). Other species associated with ESCC risk (p<0.05) included Aggregatibacter paraphrophilus (inversely associated with ESCC) and Prevotella nanceiensis, Bergeyella oral taxon 322, and Neisseria weaveri (positively associated with ESCC). Analysis of inferred metagenomes revealed that bacterial carotenoid biosynthesis was associated with protection against EAC (OR [95% CI] = 0.84 [0.7, 1.0], p=0.05). Conclusions: Our findings from this prospective study suggest that specific bacterial pathogens may play a causal role in esophageal cancer, while members of the healthy oral microbiota may protect against carcinogenesis. Unique microbial profiles may contribute to each of the distinct esophageal cancer types, EAC and ESCC. Oral microbiota manipulation may be a future strategy for preventing this highly fatal disease. Citation Format: Brandilyn A. Peters, Jing Wu, Zhiheng Pei, Liying Yang, Mark P. Purdue, Neal D. Freedman, Eric J. Jacobs, Susan M. Gapstur, Richard B. Hayes, Jiyoung Ahn. The oral microbiome and prospective risk for esophageal cancer: A population-based nested case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4961. doi:10.1158/1538-7445.AM2017-4961

The distribution of cancer cases in Somalia

The aim of this study was to investigate the frequency and distribution of cancer cases in a defined time period in Somalia. A total of 403 cancer cases were diagnosed between January 01, 2016 and March 01, 2017 in the Department of Pathology at the Somalia Mogadishu-Turkey Education and Research Hospital or the Department of Oncology at Uniso Hospital, Somalia University. Data on cancer type, patient age, and gender were obtained from pathology reports and hospital records. Female patients totaled 49.6% (n = 200) and 50.4% of patients were male (n = 203). The youngest patient was 18 years of age, the oldest was 97, and the average age was 53.4 years. The 10 most common types of cancer were esophageal (n = 130, 32.3%), non-Hodgkin lymphoma (n = 35, 8.7%), liver (n = 26, 6.5%), breast (n = 24, 6.0%), skin (n = 17, 4.2%), thyroid (n = 13, 3.2%), brain (n = 12, 3.0%), bone (n = 11, 2.7%), colorectal (n = 11, 2.7%), and soft tissue (n = 11, 2.7%). The most common site of cancer in both males and females was the esophagus. These results show a high incidence of esophageal cancer in Somalia, and strongly suggest that environmental risk factors and nutritional habits have a strong impact in this population. Serious and extensive research on the etiology of esophageal cancer is required.

Oesophageal Stem Cells and Cancer.

Oesophageal cancer remains one of the least explored malignancies. However, in recent years its increasing incidence and poor prognosis have stimulated interest from the cancer community to understand the pathways to the initiation and progression of the disease.Critical understanding of the molecular processes controlling changes in stem cell fate and the cross-talk with their adjacent stromal neighbours will provide essential knowledge on the mechanisms that go awry in oesophageal carcinogenesis. Advances in lineage tracing techniques have represented a powerful tool to start understanding changes in oesophageal cell behaviour in response to mutations and mutagens that favour tumour development.Environmental cues constitute an important factor in the aetiology of oesophageal cancer. The oesophageal epithelium is a tissue exposed to harsh conditions that not only damage the DNA of epithelial cells but also result in an active stromal reaction, promoting tumour progression. Ultimately, cancer represents a complex interplay between malignant cells and their microenvironment. Indeed, increasing evidence suggests that the accumulation of somatic mutations is not the sole cause of cancer. Instead, non-cell autonomous components, coming from the stroma, can significantly contribute from the earliest stages of tumour formation.The realisation that stromal cells play an important role in cancer has transformed this cellular compartment into an attractive and emerging field of research. It is becoming increasingly clear that the tumour microenvironment provides unique opportunities to identify early diagnostic and prognostic markers, as well as potential therapeutic strategies that may synergise with those targeting tumour cells.This chapter compiles recent observations on oesophageal epithelial stem cell biology, and how environmental and micro-environmental changes may lead to oesophageal disease and cancer.

A Case-Control Study to Evaluate the Etiology of Esophageal Cancer in Tanzania

Abstract 75 Objective: East Africa has been previously reported as a geographic area with a disproportionately high incidence of squamous cell esophageal cancer (EC). In the setting of an apparent geographic cluster, we sought to identify specific etiologic factors contributing to the high incidence of EC in Tanzania (TZ). Methods: We performed a case-control study to examine possible associations between EC and selected environmental, dietary, and lifestyle factors. Newly diagnosed EC cases were recruited at Muhimbili National Hospital and Ocean Road Cancer Institute during 2014-2015. Hospital controls were identified from patients with non-malignant conditions and matched 1:1 for gender and age ±10 years. The study team conducted in-person interviews. A matched case-control analysis used McNemar’s test with a Mantel-Haenszel estimate for odds ratios (OR). Results: 375 cases and 375 controls were enrolled. 71% of cases and controls were male. Median age was 58 years (range 30-91) for cases and 55 years (range 31-88) for controls. Among cases with a confirmed pathologic diagnosis, squamous cell carcinoma was the most common histology (85%). Liquor consumption (OR 1.84, 95% CI: 1.05-3.22, p=0.04), burning firewood (OR 2.66, 95% CI: 1.88-3.76, p<0.001), use of kerosene (OR 3.29, 95% CI: 2.36-4.59, p<0.001), and use of surface water as a primary source of drinking water (OR 2.3, 95% CI: 1.41-3.76, p=0.001) were associated with increased risk of EC. Running water, gas, and electric utilities in the household were protective. Conclusion: Alcohol consumption, firewood and kerosene use as fuel, and surface water consumption merit further investigation as potential etiologic factors contributing to high EC incidence in TZ. Future research will include conducting multivariate analysis with these and other potential risk factors and a genome-wide analysis study using DNA extracted from saliva specimens obtained from cases and controls. Funding: Research support provided by the National Cancer Institute, National Institutes of Health Contract No. HH5N261200800001E. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Elia Mmbaga No relationship to disclose Katrina Deardorff No relationship to disclose Beatrice Mushi No relationship to disclose Li Zhang No relationship to disclose William Mgisha No relationship to disclose Aparna Parikh Employment: Genentech Stock or Other Ownership: Genentech Travel, Accommodations, Expenses: Genentech Robert A. Hiatt No relationship to disclose Julius Mwaiselage No relationship to disclose Katherine Van Loon Consulting or Advisory Role: Bayer Company: OncoPlex Diagnostics