Hereditary Gastrointestinal Cancer Syndromes and Early-Onset Gastrointestinal Cancers

Abstract

Gastroenterologists are frequently at the forefront of patient care for patients with hereditary gastrointestinal (GI) cancer syndromes. Familiarity to the main hereditary colorectal cancer (HCRC) syndromes such as Lynch syndrome (LS) and familial adenomatous polyposis (FAP) and understanding the genotype/phenotype relationship are paramount for recommending personalized management and surveillance. Furthermore, it would be considered good practice to refer patients and family members to dedicated cancer genetic services for genetic counseling, address specific concerns associated with each genetic susceptibility, and for cascade testing if appropriate [1].

In recent issues of the Journal of Gastroenterology and Hepatology, several studies have been published that shed further light on hereditary GI cancer syndromes. First, lifestyle and environmental risk factors still play an important role in disease burden for this patient group. A Korean study found that apart from high baseline polyp burden of > 100 polyps and specific genetic mutations, exposure to smoking independently predicted a high risk of increased polyp burden in patients with suspected polyposis syndrome. A similar finding was found for patients with LS where patients who smoked had CRC at a younger age, and heavy drinkers had a high risk of CRC and any cancer [2]. This suggests that lifestyle modification such as smoking cessation and alcohol abstinence not only reduces the risk of sporadic CRC but may also play a prominent role in reducing the risk of HCRC. Second, there are some differences in the cancer surveillance guidelines for LS that may cause confusion and difficulty for clinicians. This includes the age to begin CRC screening, recommendations on gynecological surveillance and modalities, urological surveillance, recommendations for surgery, and chemoprophylaxis strategies [3]. Third, the prevalence and incidence of Peutz–Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) in Japan were determined for the first time. In 2021, the prevalence of PJS and JPS were 0.6/100000 and 0.15/100000, respectively, and the incidence of PJS and JPS were 0.07/100000 and 0.02/100000, respectively [4]. In Korean polyposis patients (≥ 10 biopsy-proven cumulative polyps) but without germline mutations for known HCRC syndromes, genome-wide association studies revealed 71 novel risk single-nucleotide polymorphisms (SNPs). Two novel genes (CNTN4 and CNTNAP3B) were identified, and three SNPs (rs149368557, rs12438834, and rs9707935) were associated with a higher risk of polyposis recurrence [5]. This implies that ethnic and regional variations may exist and emphasizes the importance of identifying the polygenic risk profile of these low to medium penetrant genes and their cumulative effects on the risk of CRC.

Moving on to sporadic GI cancers, there has been a plethora of studies that show an increase in early-onset GI cancers (usually defined as younger than 50 years of age). For example, in CRC, there are worrying trends that younger individuals are having more cancer, especially in high human development index countries and regions. These trends are also observed in Southeast Asia (SEA), which has seen rapid economic growth and industrialization in recent years. Notable increases were observed among males in the Western Pacific and females in SEA. Mortality rates increased by 10.6% and DALYs due to CRC also increased significantly in SEA, with a greater rise among females. This also presents itself as a window of opportunity where effective interventions may be able to stem the tide. A comprehensive approach consisting of controlled risk reduction, health promotion, and implementation of effective screening strategies executed timely may mitigate the burden of early-onset CRC in the region [6]. However, there is conflicting data for other types of GI cancers. In a study examining early-onset esophageal and gastric cancer, it was noted that there was a decrease in the incidence, death and disability-adjusted life-years (DALYs) globally. In contrast, the incidence rates increased in both early-onset esophageal cancer and gastric cancer in the Eastern Mediterranean region [7]. To date, we cannot say for certain what the drivers for these epidemiological trends are. However, implicated factors include sedentary lifestyle, westernized diet, sugar and sugar sweetened beverages, obesity, inflammation, gut microbiome, ethnic disparities, and genetics [8]. In particular, the obesity pandemic has had a profound impact on the burden of cancer. One study showed that from 2010 to 2019, there was more than a one-third increase in deaths and DALYs from cancers due to high body mass index (BMI), with liver cancer being the fastest growing cause of cancer mortality in this patient group [9]. Despite the major role that lifestyle and environmental risk factors play in the development of early-onset GI cancers, genetic risk factors and their role in gene–environment interactions also cannot be overlooked. In a prospective study of 450 patients with early-onset CRC, 16% were found to have genetic mutations [10]. A study in the Journal looked at a one-stop, tumor-based, next generation sequencing approach in predicting germline variants and found high sensitivity for both LS and FAP, with positive predictive values of 94.1% and 71.4%, respectively [11].

Based on these recent findings, whether the age to start screening for CRC should be brought forward in population-based screening programs is still widely debated. Since 2018, the American Cancer Society has recommended to start screening at age 45 years for average risk individuals as a qualified recommendation [12]. However, this decision was based largely on modeling analyses which may not be generally applicable outside of the United States. Contrary to popular belief, they were not the first major organization to suggest an earlier age to start screening in the general population. Population-based CRC screening in Japan (2-day fecal immunochemical test [FIT] annually) starts at age 40 since the inception of their program in 1992. Elsewhere in the Asia-Pacific, Australia and Taiwan will be lowering the starting age for CRC screening to 45 in 2024 and 2025, respectively. In the latest rendition of the Asia-Pacific consensus recommendations on CRC screening and postpolypectomy surveillance, it was specifically mentioned that although a rising trend of early-onset CRC in Asia was observed, there is a paucity of data supporting the cost-effectiveness of lowering the age to start screening in this region [13]. There are genuine difficulties to implement universal CRC screening even at the age of 50 given the huge population of the region, an aging population with more individuals reaching screening age, low public awareness for CRC, suboptimal uptake rates even for existing screening programs, implications on healthcare resource utilization, and a shortage of endoscopists, to name a few. Thus, a risk-stratified approach for average risk individuals utilizing a FIT as the primary screening tool with subsequent colonoscopy for positive cases is still considered the most reasonable approach in this part of the world [14]. The surveillance schedule for hereditary GI cancer syndromes is a different subject altogether, but it can be broadly summarized that surveillance starts at an earlier age, with more shorter intervals between subsequent endoscopies, and the potential need for additional investigations such as cross sectional imaging, when compared with sporadic cancers. The performance of FIT in cancer surveillance for patients with LS remains unclear. Currently, guidelines recommend colonoscopy as the preferred screening and surveillance tool in this high-risk population, though this was largely established during the era of guaiac-based fecal occult blood test which is known to have very low sensitivity for detecting precancerous advanced adenomas.

Given the advances in sequencing technology with costs coming down rapidly, genetic testing has become more widely available. Though predominantly driven by the environment and lifestyle, genuinely sporadic early-onset GI cancers may also have a component arising from genetic risk factors. The role of gene–environment interaction, and how they influence the microbiome will be a fertile field for research in the coming years. For hereditary GI cancer syndromes, gastroenterologists already play a prominent role in the diagnosis, pattern recognition, counseling, surveillance, and long-term follow-up of these patients. This will become even more pertinent in the near future, as earlier screening for CRC implies a higher likelihood of diagnosing hereditary cancer syndromes. In such cases, the awareness and knowledge of HCRC by gastroenterologists will become increasingly crucial. Previous analyses have shown that the number of family members of HCRC probands being screened [15], as well as the age at which screening is offered [16], play pivotal roles in maintaining the cost-effectiveness of universal screening for LS. Cost, funding, and reimbursement policies for genetic testing are also important considerations.

Thus, the mainstreaming of genomic medicine in gastroenterology is both essential and inevitable as the field moves rapidly forward. However, there are existing gaps in the education, training and overall medical curriculum in this regard. A survey of gastroenterology trainees in the United Kingdom found that less than 10% of respondents believed that their training programs adequately prepared them for integrating genomic medicine in their future clinical practice. The top two barriers identified include the lack of education, and inadequate clinical guidance on how to act on the results of genomic testing [17]. Novel approaches to enhance genomic literacy such as distance learning may be a way forward to build capacity in the health workforce [18].

To conclude, in gastroenterology, and in particular for hereditary GI cancer syndromes and early-onset GI cancers, we need to adequately equip and integrate genomic medicine education and training for healthcare professionals to adapt to these developments. This will ensure they have the knowledge, skill set, and genomic literacy to provide personalized patient care in this post-genomic era.