Abstract
The upper aerodigestive tract (UADT) is highly susceptible to multiple primary cancers originated from squamous epithelia and constitutes a field of cancerization. Patients with head and neck cancer (head and neck squamous cell carcinoma, HNSCC) are at high risk of developing multiple cancers in the esophagus (esophageal squamous cell carcinoma, ESCC). Conversely, esophageal cancer patients are prone to develop multiple primary tumors in the head and neck region. The East Asian-specific dysfunctional ALDH2*2 missense mutation is a genetic risk factor for UADT cancer. It is not only associated with increased incidences of UADT cancer, but is also implicated in faster cancer progression and poorer prognosis. Alcohol use is a major lifestyle risk factor which causes UADT cancer among ALDH2*2 carriers. The accumulation of the immediate metabolite of alcohol, acetaldehyde, is likely the genotoxic agents that is involved in the process of tumorigenesis. This review summarizes recent publications on the risk and association of ALDH2*2 mutation, alcohol consumption in synchronous, metachronous UADT cancer. Possible molecular mechanisms involved in cancer initiation, progress and prognosis are discussed. The review also highlights a need for precision medicine-based preventive and therapeutic strategies by integrating lifestyle and genetic risk factors, such as alcohol consumption, genotypes of the alcohol metabolizing genes, ADH1B and ALDH2, into a risk assessment model for better screening, surveillance and treatment outcome.
Highlights
The upper aerodigestive tract (UADT) region, which includes the oral cavity, pharynx, larynx and esophagus, is highly susceptible to multiple primary cancers originated from squamous epithelia
The East Asian-specific aldehyde dehydrogenase 2 (ALDH2)*2 missense mutation is a genetic risk factor for UADT cancer. It is an example of interaction between strong genetic risk factors and multiple behavioral risk factors that synergistically leads to initiation and malignant transformation to cancer
Epidemiological studies have clearly indicated that ALDH2*2 is associated with increased the susceptibility of synchronous and metachronous UADT cancers and is highly represented in the majority of these cancer patients
Summary
The upper aerodigestive tract (UADT) region, which includes the oral cavity, pharynx, larynx and esophagus, is highly susceptible to multiple primary cancers originated from squamous epithelia. The low-activity ALDH2*2 missense mutation originated in East Asia approximately 2000–3000 years ago [16] It has become a predominant genetic variant in the region affecting an estimated 8% (or 540 million) of the current world population [15]. ESCC, which most frequently occurs in the upper and middle third of the esophagus, is the predominant esophageal cancer in East Asia countries and highly associated with alcohol and tobacco use. East Asia has the highest population-attributable fraction of cancer caused by alcohol use, especially upper esophageal cancer (ESCC) [19] This is partly due to the high prevalence of the ALDH2*2 variant and a rapid increase in alcohol consumption in this region in the past three decades [26]. This review will focus on studies that have indicated or implicated differences in clinical diagnosis, progression, prognosis and outcome in East Asian UADT cancer patients with regard to the ALDH2 genetic status
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