Understanding The Molecular Diversity of Esophageal Cancer

...is key for effective targeted therapies.

by Rosa Moreno-Hanson, PhD

The incidence of esophageal cancer in the USA is markedly demarcated by gender and race. The incidence is greater in men, and the predominance of specific esophageal cancer subtypes differs among Caucasians and African Americans. Two main subtypes of esophageal cancer are recognized based on tissue analysis: esophageal squamous cell carcinoma (ESCC, more common in African Americans), and esophageal adenocarcinoma (EAC, more common in Caucasians). The upper and mid-esophagus are predominantly affected by ESCC1. Consumption of alcohol and use of tobacco are considered major risk factors for developing ESCC. Combined use of alcohol and tobacco is known to further augment the risk for developing ESCC. This is due to the compounding effect of alcohol as an irritant of the esophageal tissue and tobacco as the source of carcinogens2. Currently, EAC represents the predominant subtype in the USA; 80% of all cases of esophageal cancer diagnosed fall within this subtype2. EAC primarily affects the lower esophagus and is associated with gastroesophageal reflux disease and obesity 1, 2, 3.

Esophageal cancer is a very aggressive disease. Spreading of the tumor cells to the liver, lung, and bones is common before diagnosis2. Therefore, esophageal tumor staging is critical for selecting a therapeutic approach. For staging, physicians rely on various imaging approaches such as: computed tomography or CT scan, endoscopic ultrasound, and positron emission tomography (also know as PET scan)4. These approaches allow physicians to determine the extent of tumor invasion. Depending on the stage, patients may be treated with chemotherapy and radiotherapy. Additionally, surgery for the purpose of tumor removal may also be performed2.

Patient survival under current treatments remains poor, with a 5-year survival rate of about 15-20%1. Investigators believe that targeted approaches for the treatment of esophageal cancer may improve patient outcomes. Nevertheless, knowledge of the specific genes and proteins affected in this disease is lacking. Therefore, two recent independent studies undertook the difficult task of unraveling the genetic abnormalities that underscore esophageal cancer1, 5.

The first study was conducted by a group of researchers as part of The Cancer Genome Atlas (TCGA) Research Network, which stemmed from a collaborative initiative between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI)1. The main goal of this initiative is to provide insight on the genomic changes that contribute to various types of cancer. In this study a total of 164 esophageal tumor samples from patients around the world were used to analyze the genetic changes underscoring esophageal cancer. Advanced genetic sequencing techniques allowed investigators to demonstrate that the two subtypes of esophageal cancer, ESCC and EAC, may be distinguished by the expression levels of specific proteins. These differences in protein expression occur as the result of mutations in particular genes. The particular genes mutated, and the type of genetic mutations found in tumors from patients diagnosed with ESCC or EAC were very different. In fact, based on the genetic signatures, ESCC more closely resembles head and neck squamous cell carcinomas, while EAC tumors are similar molecularly to gastric adenocarcinomas. These findings led investigators to conclude that different molecular changes drive the development of these two main subtypes of esophageal cancer.

Additionally, investigators found that tumors from patients diagnosed with ESCC could further be classified into three main sub-groups: ESCC-1, -2 and -3, based on the particular mutations and molecular processes affected. Interestingly, tumors sub-classified as ESCC1 were predominantly found in patients from Asia, while tumors classified as ESCC3 were exclusively found in American and Canadian patients. These findings may suggest that different risk factors drive the development of esophageal cancer around the world.

In the second study, investigators used whole-genome sequencing approaches to analyze 129 samples from patients with EAC, as part of the International Cancer Genome Consortium project5. Overall, investigators found that the genetic changes underscoring EAC are highly variable, and predominantly involve large-scale mutations or changes that affect large portions of the genome. However, extensive analysis of the identified mutations allowed investigators to recognize that EAC cases could be classified within three major sub-groups. Investigators classified EAC cases based on genome instability as: C>A/T dominant (with fewer large-scale genetic mutations), DNA damage repair (DDR) impaired (deficient in mechanisms to repair mutations), and Mutagenic (with the highest incidence of large-scale genetic mutations). Investigators believe that understanding these "mutational signatures" will facilitate the design of more effective targeted therapies5.

Thus, these studies shed light onto the complexities of esophageal cancer classification. The two previously recognized subtypes of esophageal cancer, ESSC and EAC, may be more clearly distinguished by the tumor’s molecular characteristics. Mutational signatures may be very different between patients and thus present a challenge for clinical trials. Investigators believe that ESCC and EAC require different therapeutic approaches that take into account the specific molecular changes present in these tumors.