Covering the Cover

Abstract

In a prospective study of a national colorectal cancer screening program, increasing the adenoma detection rate of endoscopists was associated with a reduced risk of interval colorectal cancer and colorectal cancer death. The adenoma detection rate (ADR) has been endorsed as a quality measure for colonoscopy-based colorectal cancer screening programs. Although previous studies have shown that the ADR is associated inversely with interval colorectal cancer and colorectal cancer death, data regarding whether improving ADRs impacts outcomes are lacking. In this issue of Gastroenterology, Kaminski et al investigated the association of increasing the ADR of individual endoscopists with risk of interval colorectal cancer and subsequent death within the Polish national colorectal cancer screening program. Between 2004 and 2008, 294 endoscopists who performed 146,860 colonoscopies were enrolled in a program of annual feedback based on benchmarking with quality indicators. An increase in ADR, defined as an increase of ≥1 quintile category or the maintenance of the highest category was achieved by 75% of endoscopists. Increased ADR was associated with a decreased hazard ratio for interval colorectal cancer of 0.63 (95% CI, 0.45–0.88) and cancer death of 0.50 (95% CI, 0.27–0.95). The greatest decrease in interval cancer risk was observed among endoscopists who achieved or maintained an ADR above 25% (Figure 1). These results support current efforts to improve ADRs to enhance the clinical impact of colonoscopy screening programs. However, additional research is needed regarding the downstream consequences of higher adenoma detection, such as the intensification of colonoscopic surveillance and its attendant complications. See page 98; editorial on page 8. In a cohort of individuals with >10 polyps, patients with multiple serrated polyps who did not meet formal criteria for serrated polyposis had a similar increase in risk of colorectal cancer as patients who did meet formal criteria for serrated polyposis. Current guidelines recommend that individuals with serrated polyposis syndrome undergo intensive colonoscopic surveillance owing to their increased risk for colorectal cancer. Because the genetic basis of serrated polyposis syndrome is unknown, the diagnosis is currently based on strict yet somewhat arbitrary clinical criteria. However, the risk of colorectal cancer among individuals with multiple serrated polyps who do not meet these criteria is unclear. In this issue of Gastroenterology, Egoavil et al report their analysis of data from a cohort of 567 patients with >10 colonic polyps recruited from 24 hospitals in Spain between 2008 and 2009. Within this cohort, 53 patients met World Health Organization criteria for serrated polyposis syndrome and 145 patients did not meet these criteria but had >10 polyps throughout the colon, of which >50% were serrated. Compared with patients with serrated polyposis syndrome, patients with multiple serrated polyps who did not meet criteria for serrated polyposis had a similar prevalence of colorectal cancer (odds ratio, 1.35; 95% CI, 0.64-2.82). Both groups had comparable standardized incidence ratios for colorectal cancer. The incidence of cancer among first-degree relatives of patients with serrated polyposis and the first-degree relatives of patients with multiple serrated polyps also did not differ significantly. These results suggest the need to potentially loosen the criteria for the diagnosis of serrated polyposis and recommend more intensive colorectal cancer surveillance among patients with multiple serrated polyps and their first-degree relatives. See page 106. The mutational spectrum of esophageal squamous adenocarcinoma development is described, and common mutational events define progression from epithelial hyperplasia to intraepithelial neoplasia and ultimately adenocarcinoma. Esophageal squamous adenocarcinoma (ESCC) is the most common type of esophageal malignancy, and genomics analysis has informed our understanding of the molecular alterations occurring in these cancers. Genomic alterations in precancerous intraepithelial neoplasia are less well-known, and an appreciation for molecular events preceding frank carcinoma may yield diagnostic and therapeutic targets allowing earlier detection and management. In this issue of Gastroenterology, Liu et al performed whole genome, whole exome, and targeted sequencing on a panel of nondysplastic, but hyperplastic epithelium, intraepithelial neoplasia (IEN), and ESCC. This was done to catalog genomic changes in the spectrum of ESCC development. Relatively few somatic mutations were identified in hyperplastic samples; however, chronic inflammation and DNA damage were correlated positively with cellular atypia in nontumor samples. The mutational landscape of both IEN and ESCC were remarkably similar, with a progressive increase in DNA damage and genomic instability with augmented mutational frequency and chromosomal number alterations. Analysis of genes common to IEN and ESCC identified driver or “trunk” events that could be divided into DNA repair and apoptosis, proliferation genes and oncogenes, and variations in cell adhesion and junction genes (Figure 2). Of note, early loss of TP53 and CDKN2A and gain of CCND1/SOX2/NFE2L2 drive progression through IEN to ESCC. However, it remains unclear what genetic events ultimately trigger this progression. It will be important to see if this mutational spectrum is replicated in other patient populations. This landmark study defines the mutational landscape and sets the map for progression from esophageal hyperplasia to infiltrating adenocarcinoma. See page 166. Occult aflatoxin exposure contributes to a subset of incident hepatocellular carcinomas. This subset has a unique mutational spectrum and is noteworthy for expression of PD-L1 and thus may be responsive to checkpoint inhibitor therapy. Aflatoxin, produced by the fungi Aspergillus flavus and A parasiticus, is a potent hepatocarcinogen, and given that many millions of people are exposed to this agent yearly, a significant portion of hepatocellular carcinoma (HCC) cases are likely due to its action. Aflatoxin is also present in improperly processed cooking oil; therefore, many more could be susceptible without exposure to traditional fungally derived sources, and thus be at risk for developing aflatoxin-induced HCC (AF-HCC). Cancers arising from mutagen exposure can have characteristic mutational spectra. For example, aflatoxin-associated HCC frequently exhibits R249S mutations in tumor protein p53 (TP53). However, the genome-wide effects of aflatoxin in HCC development are unknown as mutational profiling studies in AF-HCC have yet to be performed. Whether this cancer arises via mutational targeting of canonical HCC targets or by novel oncogenic mutational events is unknown. In this issue of Gastroenterology, Qu et al performed whole exome sequencing on 49 AF-HCC cases in the high-risk AF-HCC community of Qidong, China. They defined the mutational signature in AF-HCC, noting increased C>A transversions, in particular in the context of GCN trinucleotide sequences. In addition to confirming the known TP53 hotspot mutation, they also identified novel mutations in ADGRB1, a protein belonging to an orphan G-protein–coupled receptor subfamily comprising three brain-specific angiogenesis inhibitory genes. Mutations in noncoding regions affecting transcription factor CCCTC-binding factor/cohesin-binding sites were also discovered. Sequencing of a nonknown aflatoxin-exposed HCC cohorts from multiple countries, identified a subset of patients with AF-HCC associated mutations, suggesting unrecognized environmental exposure to aflatoxin is driving HCC development (Figure 3). Last, they observed that HCC tumors produced high levels of mutation-associated neoantigens and infiltrating lymphocytes and tumor cells both with PD-L1 expression. In summary, environmental exposure to aflatoxin is more common than previously thought. AF-HCC carries unique mutational spectra and may represent a subset of HCC that would be responsive to checkpoint inhibitor therapy. See page 249. Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to CarcinomaGastroenterologyVol. 153Issue 1PreviewEsophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer. Little is known about the genetic changes that occur in esophageal cells during the development of ESCC. We performed next-generation sequence analyses of esophageal nontumor, intraepithelial neoplasia (IEN), and ESCC tissues from the same patients to track genetic changes during tumor development. Full-Text PDF Increased Rate of Adenoma Detection Associates With Reduced Risk of Colorectal Cancer and DeathGastroenterologyVol. 153Issue 1PreviewThe quality of endoscopists' colonoscopy performance is measured by adenoma detection rate (ADR). Although ADR is associated inversely with interval colorectal cancer and colorectal cancer death, the effects of an increasing ADR have not been shown. We investigated whether increasing ADRs from individual endoscopists is associated with reduced risks of interval colorectal cancer and subsequent death. Full-Text PDF Defeating Cancer by Boosting the Adenoma Detection Rate: The Circle of LifeGastroenterologyVol. 153Issue 1PreviewPrimary colonoscopy screening is highly effective in reducing incidence and mortality of colorectal cancer (CRC), a major cause of cancer-related morbidity and mortality.1 Irrespective of patient factors, endoscopist skill seems to affect screening efficacy dramatically. A proxy of endoscopist quality of mucosal inspection, namely, the adenoma detection rate (ADR),2–4 has been inversely associated with the risk of interval cancer and its death, with high detectors being able to reduce such risk by 50%-90%. Full-Text PDF Increased Risk of Colorectal Cancer in Patients With Multiple Serrated Polyps and Their First-Degree RelativesGastroenterologyVol. 153Issue 1PreviewWe investigated whether patients with multiple serrated polyps, but not meeting the World Health Organization criteria for serrated polyposis syndrome, and their relatives have similar risks for colorectal cancer (CRC) as those diagnosed with serrated polyposis. Full-Text PDF Genetic Features of Aflatoxin-Associated Hepatocellular CarcinomaGastroenterologyVol. 153Issue 1PreviewDietary exposure to aflatoxin is an important risk factor for hepatocellular carcinoma (HCC). However, little is known about the genomic features and mutations of aflatoxin-associated HCCs compared with HCCs not associated with aflatoxin exposure. We investigated the genetic features of aflatoxin-associated HCC that can be used to differentiate them from HCCs not associated with this carcinogen. Full-Text PDF