Early-Onset Cancer in the Gastrointestinal Tract Is on the Rise—Evidence and Implications

While growing evidence indicates a significant increase in the incidence of early-onset colorectal cancer (EOCRC), a deeper exploration in recent epidemiologic studies reveals a bothersome trend reflecting a general rise in the incidence of early-onset cancer diagnosis also in other locations of the gastrointestinal (GI) tract. Sung and colleagues have analyzed datasets from 25 state registries covering two thirds of the U.S. population between 1995 and 2014. This extensive pooled analysis revealed a dramatic surge in cancer incidence among younger adults (aged 25–49 years) diagnosed with GI tract cancers, including colorectal, gallbladder, and pancreatic cancers (1). Moreover, a recent study demonstrated an increase not only in the incidence of pancreatic cancer but also in cholangiocarcinoma below the age of 50 years (2). Analysis of long-term trends in cancer incidence from the U.S. Surveillance, Epidemiology, and End Results (SEER) database and other worldwide registries demonstrates a significant rise in the incidence of EOCRC, gastric cancer, and pancreatic cancer (3).

Traditionally, cancer has been considered a disease of the elderly population. In addition, this dramatic increase in young adults during the past two decades remains to be elucidated, while the overall incidence of colorectal cancer is declining (4, 5). Recent SEER data on incidence of different GI cancers in individuals younger than 50 years reveal a differential pattern upon gender. Whereas colorectal cancer is on the rise in both men and women, gastric cancer is increasing mainly among women, while pancreatic cancer is increasing in both sexes, with a steeper increase in women, as depicted in Fig. 1 (https://seer.cancer.gov/statfacts/index.html, accessed August 2022).

While in several other cancer types, rising incidence among young populations may be attributed to early detection due to the increasing adoption of screening, this trend may not explain the rise in GI tract cancers (6, 7).

A shift in cancer incidence toward younger age may reflect several potential causes, such as genetic factors, but more notably environmental factors and host-related mechanisms. Because these trends were first noted in colorectal cancer before it became evident in other GI tract cancers, the bulk of evidence related to possible causes derives from studies in colorectal cancer. Worldwide, among EOCRC, 75% to 80% of the cases are sporadic and harbor no hereditary etiology (8), indicating that the increasing incidence of colorectal cancer may predominantly be attributed to behavioral and environmental factors. Obesity, physical inactivity, and Western pattern diet (ref. 9; rich in red meat, dairy products, processed and artificially sweetened foods, and salt, with minimal intake of fruits, vegetables, fish, legumes, and whole grains) are all risk factors associated with an increased risk for colorectal cancer. Moreover, there are undoubtedly complex epigenetic interactions resulting from obesity, sedentary behavior, and unhealthy diet (10–13). Evolving research suggests that particular dietary elements, like high glycemic load carbohydrates, may trigger a cascade of detrimental health effects beyond caloric content (14). The gut microbiome was shown to play an essential role in the pathogenesis of colorectal cancer by complex mechanisms of interaction with the host immune system and molecular signaling pathways that have also been attributed to the pathogenesis of EOCRC (15, 16) Although still speculative, we suspect that some of the mechanisms underlying the carcinogenesis, risk factors, and treatment-related long-term effects are most probably shared between EOCRC and cancers arising from other parts of the GI tract, such as gastric and pancreatic cancers, in young adults (Fig. 2). Current evidence reveals that young patients with GI cancer are usually diagnosed at later stages compared with average-onset patients. However, data are lacking to indicate which part of the younger population should undergo screening for GI cancers, with an exception for patients with a positive family history of colorectal cancer (17–19).

Although early-onset cancer appears to be on the rise also in other parts of the GI tract, such as biliary tract and liver cancers, data are mounting mainly on gastric, colorectal, and pancreatic cancers. Therefore, we will comprehensively explore the common perspectives on these young-onset GI cancers.

Gastric cancer is a relatively rare disease with a worldwide estimated age-standardized incidence rate of 11.1 per 100,000 population in 2020, with the highest incidences in Asia and the west coast of South America (20). In younger patients, gastric cancer is even rarer, and up to the age of 40 gastric cancer is not included in the top 10 incidence of cancers worldwide.

However, although worldwide gastric cancer incidence is projected to fall, in the population below 50 years of age, increased incidence is seen and the incidence is increasing in successively younger generations (1, 21). In terms of mortality, in the age group up to 40, gastric cancer ranks seventh in both males and females. Together, these data underscore that gastric cancer in adolescents and young adults is a matter of urgent concern.

Epidemiologic studies performed in the United States indicate that early-onset gastric cancer represents a demographically distinct population with varying characteristics and treatment outcomes dependent upon demographic location and cancer center volume (22).

The large majority of gastric cancers are sporadic, and only 1% to 3% of gastric cancer cases are truly hereditary (23). Young age (<50 years) at onset of the disease, family history, and diffuse-type histology are the specific characteristics of hereditary gastric cancer and should guide genetic testing. Hereditary gastric cancers can be classified into three distinct entities: hereditary diffuse GC (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC; ref. 24). HDGC is caused by mutations in the E-cadherin gene (CDH1), which was first identified by analysis of early-onset, histologically poorly differentiated, high-grade diffuse gastric cancers in a large kindred from New Zealand (25). Pathogenic variants in the Catenin-α1 gene (CTNNA1) occur in a minority of families with HDGC (26). GAPPS is defined by autosomal-dominant transmission of fundic gland polyposis restricted to the proximal stomach with a significantly increased risk of gastric cancer (27). Finally, FIGC is characterized by the intestinal histologic subtype diagnosed in an autosomal-dominant inheritance pattern in families, with a young age of onset (28). In addition, gastric cancer may occur in the context of hereditary cancer syndromes, such as Lynch syndrome (caused by mutations in one of the mismatch repair genes MLH1, MSH2, MSH6, PMS1, PMS2, or EPCAM), Li–Fraumeni syndrome (TP53 mutations), familial adenomatous polyposis [FAP; adenomatous polyposis coli (APC germline mutations)], Peutz–Jeghers syndrome (PJS; STK11 mutations), juvenile polyposis syndrome (SMAD4 or BMPR1A mutations), and hereditary breast or ovarian cancer syndrome (germline BRCA1 or BRCA2 mutations; refs. 29, 30–41; Table 1).

Unhealthy lifestyle factors such as smoking and alcohol drinking, Helicobacter pylori infection, and (poly)genetic predisposition all contribute to the development of sporadic gastric cancer. The overall decrease in incidence in the development of gastric cancer has been related to improved sanitation, increased consumption of fruit and vegetables, less consumption of salt, and, most importantly, the eradication of H. pylori infections (42). Importantly, it has been shown that individuals at a high genetic risk could still substantially reduce their risk of incident gastric cancer by adopting a healthy lifestyle (43). Intriguingly, the increase in gastric cancer in the younger age group has been observed in countries with a low incidence of H. pylori infections (44), suggesting that other factors play a more important role. Obesity is one of the well-known risk factors for gastric cancer (45). The prevalence of overweight and (severe) obesity has increased dramatically, not only in (young) adults but even in children (43, 45). In addition, atrophic gastritis, resulting from auto-immune gastritis, is increasing, which is a known risk factor for gastric cancer. In a population-based study from Sweden, the prevalence of atrophic corpus gastritis increased from 22 to 64 per 1,000 in young individuals of 35 to 44 years of age between 1990 and 2009 (46). The increased incidence of autoimmune gastritis has been linked to changes in the gut microbiome due to increased use of antibiotics, which in itself may also have a direct carcinogenic effect (47). In an analysis of the National Cancer Database, it was shown that the observed increased incidence of early-onset gastric cancer between 2004 and 2015 disproportionally affected the Hispanic and Black populations as compared to white citizens (48). The reason for this disproportionate burden remains currently unknown.

Although epidemiologic studies consider gastric cancer as one disease, four different molecular subgroups of gastric cancer can be distinguished according to The Cancer Genome Atlas (TCGA) classification: (i) microsatellite instable (MSI) tumors with increased mutation rates; (ii) Epstein–Barr virus (EBV)–positive tumors, characterized by PIK3CA mutations, DNA hypermethylation, and amplification of JAK2, CD274, and PDCD1LG2; (iii) genomically stable tumors with predominantly diffuse histology and mutations in RHOA; and (iv) a chromosomal instable (CIN) subgroup with amplification of receptor tyrosine kinases and mostly intestinal histology (49). The frequency of these subgroups differs for different regions in the stomach (49). The CIN subtype forms the large majority of gastric cancers located in the cardia, and the incidence decreases toward the more distal parts of the stomach, although even there almost half of the cancers belong to the CIN subtype. MSI tumors most frequently occur in the noncardia part of the stomach, while EBV tumors most frequently occur in the fundus or body of the stomach. Genomically stable tumors are more or less equally distributed throughout the stomach. Although knowledge about age-specific molecular characteristics of the four TCGA subgroups is still limited, in an analysis of 39 patients with young-onset gastric cancer compared with 35 patients with average-onset gastric cancer, the EBV subtype was significantly more prevalent in the young-onset (33%) compared with the average-onset (11%; ref. 50) group.

Somatic genomic alterations in the diffuse subtype show age-dependent differences. In a Korean study, a cohort of 109 diffuse gastric cancer samples from patients ≤ 45 years— excluding patients with pathogenic germline mutations in CDH1, TP53, and ATM—revealed a higher proportion of somatic mutations in CDH1 or TGFBR1 compared with 115 diffuse gastric cancers from patients who were 46 years or older (51). Conversely, in this study, a smaller proportion of somatic mutations in RHOA was found in early-onset gastric cancer compared with late-onset diffuse gastric cancer. In another study, genomic analysis of gastric cancer from 81 patients who were 50 years or younger showed a twice as high rate of CDH1 mutations compared with later-onset gastric cancers (52). The diffuse/mixed types correlated with the TCGA genomically stable subtype, and the remaining Lauren types correlated with the TCGA chromosomal instability type (52). Proteogenomic analysis of diffuse gastric cancers in young populations may further distinguish between different good and poor prognosis subtypes (53).

Colorectal cancer is a highly prevalent disease with more than 1.9 million new cases estimated in 2020; it ranks third in incidence and second in mortality worldwide, and it is considered a landmark of socioeconomic development (54, 55). A 9-fold variation across world regions exists, with highest rates in Europe, Australia/New Zealand, and North America (54). Multiple changes in lifestyle factors and diets affect incidence trends across ages: Animal-sourced food and sedentary lifestyle leading to excess body weight, alcohol consumption and cigarette smoking, and red and processed meat intake result in an increased colorectal cancer risk; consumption of calcium, whole grain, and fiber likely reduces the risk (54). Changes toward a healthier lifestyle behavior and uptake in screening programs, with removal of precursor lesions, contributed to the decline in incidence in some high-income countries. However, these trends are mainly based on screening a population above the age of 50 to 55 years, with limited data available in young patients. Although the absolute risk of colorectal cancer in young adults remains significantly lower compared with the older population [age-standardized incidence rate between 2008 and 2012 in the United States: 10 (95% confidence interval (CI), 9.8–10.3) per 100,000 in ages 20–49 vs. 109.6 (95% CI, 108.6–110.6) in age >50], the increasing incidence trends in young patients are worrisome and forecast the future disease burden (56).

A relevant proportion of young patients are diagnosed with colorectal cancer with an already metastatic disease (57). This is possibly due to delays in investigating the presence of cancer even when classic symptoms like hematochezia, abdominal pain, change in bowel habits, weight loss, and iron-deficient anemia are apparent; delays can last from 7 weeks to up to 2 years (58).

A rising incidence of 1% to 4% per year in certain high-income countries led the American Cancer Society to lower the age for screening initiation from 50 to 45 years in 2018, with an expected moderate net benefit described by the U.S. Preventive Services Task Force (59). For individuals with a positive family history of colorectal cancer, screening is recommended to start 10 years before the age of diagnosis of the youngest colorectal cancer patient in the family. This recommendation is still based on modeling rather than evidence-based studies (60, 61). Between 2004 and 2016, colorectal cancer incidence increased on average by 7.9%, 4.9%, and 1.6% per year in individuals ages 20 to 29, 30 to 39, and 40 to 49, respectively, across 20 European countries, with heterogeneous data between countries (11). With only 14% of European Union citizens between 50 and 74 years of age having the opportunity to participate in organized screening programs (ranging from >65% in Slovenia down to 0%–19% in Spain, Portugal, and Ireland), lowering the age for screening while expecting an effective uptake rate may pose a significant challenge in some parts of Europe (62). These data highlight the urgent need to understand the causes of EOCRC to prevent further increase in rates and how to possibly reverse these trends.

Controversial data related to sex have been reported, with female sex previously recorded as more frequent in EOCRC, while recent literature shows the male/female ratio similar in EOCRC compared with the older population (58, 63). Left colon and rectal cancers appear more prevalent in young patients, while associated precursor adenomatous lesions are less frequent (63, 64). Aggressive phenotypes including poor differentiation and signet ring cell histology as well as lymphovascular and perineural infiltration have been described (7). Higher rates of relapse, despite higher treatment intensity, have been observed in younger patients compared with older patients (65). The dominant histotype of EOCRC is adenocarcinoma. Although a small rise in neuroendocrine cancers in EOCRC has also been reported, this histology represents only a tenth of the colorectal cancer cases and a similar incidence rise has been reported in older patients, making trend assessment difficult to interpret (66). In the United States, southern and rural states showed a higher incidence of EOCRC (57, 67). Although incidence rates in ethnic minorities and non-Hispanic Blacks have been reported as nearly double compared with whites, cases in non-Hispanic whites have rapidly increased in western states in more recent years (63). Less granular data in EOCRC are available outside the United States, in part due to lack of registries in Asian, African, or Caribbean countries, and opposite trends are seen in different European countries (11, 68).

Most colorectal cancer cases (around 75%) are sporadic. Of the remaining 25%, up to 20% are considered familial in view of a positive family history of colorectal cancer, while only 5% are strictly hereditary and linked to highly penetrant germline mutations (69). Already in 1895, Dr. Aldred Scott Warthin from the University of Michigan described a suspected colorectal cancer family, the “Family G,” which was followed by Lynch and Krush in 1971 reporting what later became the well-known Lynch syndrome (70, 71). In 1930, mutations in the APC gene were linked to the FAP hereditary syndrome and subsequently associated with the initial step of molecular carcinogenesis as described by Fearon and Vogelstein (72). Lynch syndrome, FAP and attenuated FAP, MYH-associated polyposis (MAP), and rare hamartomatous polyposis syndromes confer a significantly high lifetime risk for the development of multiple cancers, including colorectal cancer especially in young age (Table 1; ref. 31). The mean age of colorectal cancer in patients with Lynch syndrome is around 45 years. The hundreds of thousands of colonic adenomas in FAP result in nearly 100% chance of colorectal cancer by the age of 40, while patients with MAP frequently present with multiple adenomatous polyps between the age of 40 and 60. Other rare syndromes like PJS, juvenile polyposis, and Cowden syndrome are associated with intestinal hamartomatous polyps and typical clinical features like mucocutaneous pigmentation in PJS, childhood GI bleeding and pain in juvenile polyposis, and benign skin and buccal lesions and macrocephaly in Cowden syndrome (31, 73, 74). Although a proportion of these cases are probably undiagnosed due to variable phenotype in nondominant disorders and different gene penetrance, there is no current evidence suggesting increased incidence of hereditary cases.

As previously discussed for sporadic gastric cancer, contemporary lifestyle patterns significantly contribute to the development of sporadic colorectal cancer, while the adoption of healthier habits has possibly contributed to the recent decreased incidence of colorectal cancer in high-income countries (54). No clear differences in risk factors associated with young patients with colorectal cancer compared with older patients are known so far; a multifactorial risk profile including a combination of germline genetic features and early exposure to specific lifestyle factors seems more plausible. Of note, up to 30% of patients with EOCRC have at least one first-degree relative with a history of colorectal cancer (75)—whether this is due to genetic background, similar environmental exposures, or a combination of both remains to be elucidated. Beyond diet and sedentary habits with their direct consequences typically associated with conventional colorectal cancer, exposure to antibiotics and modification of the gut microbiome may play a relevant role in young adults (76). Increasing obesity and chronic bowel inflammation in children because of a Western-style diet is a known phenomenon potentially causing gut dysbiosis and ultimately inducing carcinogenesis (76). Insulin-like growth factors, adipocytokines, sex hormones, and alteration in circadian rhythms have been proposed as biological links between obesity and colorectal cancer (77). Whether any of these factors can possibly accelerate the expected 10-year-long adenoma–carcinoma sequence is unknown. Importantly, exposure to risk factors like unhealthy lifestyle, consumption of processed food, and environmental pollution have possibly affected a large proportion of the population in high-income countries in the last few decades; whether the effectiveness of different screening programs is masking a similarly increasing incidence in all age groups is unknown.

Several studies have attempted to identify molecular drivers of sporadic colorectal cancer in young adults. In doing this, data were adjusted for germline genetics and clinical features with different modalities and age cutoffs, making findings from different institutional studies or case series difficult to reconcile. Moreover, these studies are possibly subject to several selection biases linked to the demographic characteristics of the populations included, access to genomic profiling, and germline testing or research programs. So far, minimal genomic differences in cancer-related genes between young colorectal cancer and average-onset colorectal cancer cases have been identified. A retrospective study from Memorial Sloan Kettering Cancer Center included 759 patients with young-onset colorectal cancer and 687 patients with average-onset colorectal cancer and evaluated genomic profiles of microsatellite-stable tumors in three different age groups: 35 years and younger, 36 to 49 years, and 50 years and older (78). No differences in frequency of oncogenic drivers were identified except for TP53 alterations enriched in the intermediate age group. Extreme age cohorts (≤35 and ≥70) were compared with no differences found. When assessing germline variants independently of microsatellite instability status, young patients were more frequently found to carry pathogenic or likely pathogenic mutations compared with older patients (23% vs. 14%), with enrichment for high-penetrance gene alterations and biallelic inactivation, suggesting these as carcinogenic drivers.

In another study, from MD Anderson Cancer Center, four datasets including >36,000 patients with colorectal cancer from retrospective institutional cohorts and publicly available sources were analyzed according to six different age groups: 18 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, and older than 70 years of age (79). Younger patients were more likely to show microsatellite instability [microsatellite instability–high (MSI-H)], distal tumor location, fewer BRAF^V600E and APC oncogenic mutations, and enrichment for CTNNB1 mutations. Although germline status was not analyzed, these findings are in line with the known higher incidence of Lynch syndrome in young patients, thus not entirely clarifying the biological nature of sporadic cases. Similarly, when assessing gene expression profiles, enrichment for Consensus Molecular Subtype-1 (CMS1; ref. 80), which is associated with MSI-H status, was observed in young patients. While macroscopic differences in cancer-related pathogenic variants are not so obvious, several common genetic variants associated with colorectal cancer susceptibility have been identified in genome-wide association studies. A 95 variant–based polygenic risk score developed from previously identified common genetic risk variants for colorectal cancer demonstrated strong association with young-onset colorectal cancer in a large population study including 12,197 patients with young-onset colorectal cancer and 95,865 patients with colorectal cancer who were older than 50 years (81). Recently, a genome-wide DNA methylation profiling study demonstrated unique methylation changes in patients with young-onset colorectal cancer when compared with patients with intermediate-age colorectal cancer (50–69 years), patients with late-onset colorectal cancer (>70 years), and normal mucosa samples from individuals without colorectal cancer (82). Only nonhereditary, mismatch repair–proficient tumors were included to avoid the confounding effect of hypermethylated MSI-H cancers. Interestingly, age acceleration changes were identified in normal mucosa of young patients compared with older patients and healthy individuals, supporting the hypothesis of environmental exposure inducing an accelerated aging process (methylomic drift) with shorter time to carcinogenesis.

Pancreatic cancer is the fourth leading cause of cancer-related death, with a 5-year survival rate of about 11.5% [SEER Program Populations (1969–2017; www.seer.cancer.gov/popdata); 2018]. According to GLOBOCAN, 495,773 new cases and 466,003 cancer-related deaths were observed in 2020, with a preponderance in males (54). From 2000 to 2019, the incidence increased among both genders; however, a significantly greater relative increase was observed in females, with an annual percentage change of 2.4% compared with 1.2% in males. In addition, epidemiologic models estimate that total deaths due to pancreatic cancer are projected to increase and become the second most frequent cause of cancer-related death by 2030 (83). The median age of patients with pancreatic cancer is about 70 years. According to the SEER registry, young patients represent a small group, accounting for <2% of pancreatic cancer diagnoses in the United States. Nevertheless, U.S. analysis of a population-based cancer registry showed that between 1995 and 2014, the pancreatic cancer incidence increased in younger adults (25–49 years), with a steeper increase with younger age. The average annual percentage change in pancreatic cancer incidence in the age group of 45 to 49 years resulted in a 0.77% (95% CI, 0.57–0.98) increase compared with the age group of 25 to 29 years in which it reached 4.34% (95% CI, 3.19–5.50; ref. 54). In terms of gender differences, the average annual percentage increase among women ages 35 to 54 years was 1.56% compared with 0.65% in men in the same age group. The rate of change was also substantially different in women ages 15 to 34 years versus men (7.68% vs. 4.20%; ref. 84).

A recent study evaluated the incidence of pancreatobiliary cancer (pancreatic cancer and cholangiocarcinoma diagnosed between 2004 and 2017) from the U.S. National Cancer Database and indicated that early-onset pancreatobiliary cancer was associated with better survival compared with the average-onset population. Furthermore, it was shown that socioeconomic disparities significantly impact clinical outcomes (2).

There are significant differences in the prevalence of pancreatic cancer depending on ethnicity. In general, in U.S. data, the prevalence of pancreatic cancer in Caucasians increases similarly of both sexes. However, a difference was observed in the African-American population, with a predominance in females (85).

In addition, young patients are more likely to be diagnosed with stage IV pancreatic cancer and with a more aggressive phenotype characterized by poor differentiation and perineural invasion (86, 87).

Late presentation in more advanced stages is related to the absence of symptoms in early stages and also to the absence of any population-based screening. Routine screening for pancreatic cancer is generally not recommended in asymptomatic individuals. However, several screening concepts have been suggested for high-risk individuals (88, 89).

Familial aggregation accounts for around 5% to 10% of all ductal pancreatic adenocarcinoma (90). The most prevalent germline mutations observed in pancreatic cancer are the hereditary breast–ovarian cancer genes BRCA1 and BRCA2, CDKN2A linked to familial atypical mole and melanoma syndrome, mutations in DNA mismatch repair genes associated with Lynch syndrome, and mutations in ATM, PALB2, STK11, and TP53 genes (91). According to the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium the BRCA1, BRCA2, and CDKN2A genes were identified in 7.4% of patients with familial pancreatic cancer (92). Similar to gastric cancer, both somatic and germline mutations in STK11 are characteristic for PJS (93), and particular mutations in Fanconi anemia/BRCA pathway genes, including PALB2, FANCC, and FANCG (30), are also linked to pancreatic cancer. There is currently no identified specific age for early-onset pancreatic cancer (94). Data from the U.S. National Familial Pancreas Tumor Registry indicate that early onset (≤50 years) was not different between relatives of familial pancreatic cancer and sporadic pancreatic cancer. The only increase was noticed among members of familial pancreatic cancer relatives with a young-onset case in the kindred (standardized incidence ratio = 9.31; 95% CI, 3.42–20.28; P < 0.001). The recent publication by Verghese and colleagues analyzed a single institutional dataset of 450 patients with early-onset pancreatic cancer (95). Of them, 138 patients (30.7% of the cohort) underwent germline testing. In total, 44 of 138 (31.9%) displayed a pathogenic germline variant, and 27.5% harbored alterations in cancer susceptibility genes. The most frequent pathogenic germline variants were found in BRCA1, BRCA2, PALB2, and CHEK2 genes. The authors performed an analysis of patients diagnosed between 2015 and 2018 to explore the overall outcomes in the particular cohort treated according to contemporary treatment guidelines. They showed reduced all-cause mortality compared with patients without a pathogenic germline variant. These findings highlight recent recommendations for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma to tailor the treatment approach.

The Global Burden of Diseases, Injuries, and Risk Factors Study identified the leading risk factors for risk-attributable pancreatic cancer–related deaths. In general, smoking, alcohol use, and high body mass index (BMI) were the most significant factors for both sexes (96). Obesity cancer linkage to young adults was recognized as a variable of early-onset pancreatic cancer among 12 other factors based on an epidemiologic review reported by the International Agency for Research on Cancer (43, 97). A case–control study of 841 patients with pancreatic adenocarcinoma and 754 healthy individuals matched by age, race, and sex was conducted in the United States from 2004 to 2008. It showed that BMI of 25 to 29.9 from the age of 14 to 39 years or BMI ≥30 from the age of 20 to 49 years was associated with increased risk of pancreatic cancer independent of diabetes status. The association was stronger in men and smokers. Pancreatic cancer had an earlier onset by 2 to 6 years in persons who were overweight and obese: Median age of onset was 64 years for patients with normal weight, 61 years for patients who were overweight (P = 0.02), and 59 years for patients who were obese (P < 0.001; ref. 98).

From other known risk factors such as cigarette smoking, exposure to chemicals and heavy metals, pancreatitis, heavy alcohol consumption, periodontal disease, and impaired fasting glucose, only alcohol consumption seems to be associated with early-onset pancreatic cancer (99, 100), while heavy drinkers who consume ≥3 drinks daily are at higher risk of pancreatic cancer (101).

According to older studies, the clinicopathologic features in young patients with pancreatic cancer were generally similar to those in older patients (102, 103). However, limited data exist about the genomic landscape of early-onset pancreatic cancer. A lower rate of KRAS mutations in early-onset pancreatic cancer seems to be important (42% compared with 90%–95% in older patients; ref. 104) In a recent study that analyzed the genomic landscape of 90 early-onset pancreatic cancer compared with 203 average-onset pancreatic cancer cases, the most prevalent alteration was KRAS mutations in both cohorts, followed by TP53 and CDKN2A. Similar to the abovementioned study, KRAS mutations were less frequent in the early-onset pancreatic cancer cohort (83% vs. 96%; P = 0.016). In both studies, mutations in the SMAD4 gene were significantly more prevalent in early-onset pancreatic cancer. In terms of gene expression, different patterns between early-onset pancreatic cancer and average onset were reported with upregulated Hedgehog, TGFβ, hypoxia, and PI3K pathways in the early-onset pancreatic cancer cohort. In a later study (95), a larger cohort of early-onset pancreatic cancer was characterized, indicating again that early-onset pancreatic cancer had more RAS wild-type compared with the classical rate in pancreatic cancer.

Surgery in patients with early-onset GI cancers follows the same oncologic and reconstructive principles as the surgery performed for patients in general. However, there are some aspects that need special attention in younger patients. First, a large proportion of young patients are still in a phase of life where body image, finding a partner, and building a family are essential priorities. This emphasizes a more urgent need to avoid surgical interventions that severely affect patients’ body image or carries a risk of impairing their sexual and reproductive functions. Second, a consequence of the long life expectancy in young patients cured from their cancers is that the surgical reconstructions need to last and be fully functional for many decades to come. This adds an additional aspect that needs to be considered in the choice of surgical reconstruction for young patients compared with the large majority of middle-aged or elderly patients with cancer.

Most published data addressing the effect of surgery on patients with early-onset GI pertain to colorectal cancer. Surgery for colorectal cancer often has a strong negative impact on patients’ body image. A particular issue is the use of bowel stomas postoperatively. Several studies show that this may strongly impact body image, especially in young patients (105, 106). Interestingly, even temporary use of defunctioning stomas for a limited time after surgery has been described to sometimes affect the body image negatively in the long-term (105, 106). Other issues relevant to body image and partnership, especially after rectal cancer surgery, are bowel function with urgency, high stool frequency and incontinence, as well as urogenital function including dyspareunia and erectile dysfunction (106). In a recent international, multicenter observational study addressing long-term outcomes reported after surgery by 1,428 patients who had been operated for rectal cancer at ages 18 to 49, 17% had significant bowel symptoms, 7% had urinary symptoms such as urgency or even need of self-catheterization, and 6% experienced sexual dysfunction at follow-up 3 years after surgery (106). Only 1% reported an evident negative effect on fertility (106).

Some recently published observational data suggest that certain genomic profiles may be associated with a differential effect on survival comparing patients with early- to average-onset colorectal cancer undergoing resection for liver metastases. In a cohort study by Jacome and colleagues, early-onset patients with RAS mutations undergoing resection for liver metastases had a significantly poorer overall survival than later-onset patients with the same mutation, although a similar study by Narayan and colleagues did not reveal any association between genomic profiles, time of onset, and outcome (107, 108).

Data on patients with noncolorectal early-onset GI cancer are scarce. Patients undergoing surgery for upper gastrointestinal or hepato-pancreato-biliary cancers have a different pattern of long-term symptoms and functional detriments compared to patients with colorectal cancer (109–111). After surgery for gastroesophageal cancers, many quality-of-life detriments are related to nutritional problems with severe weight loss and underweight issues as well as gastroesophageal reflux, particularly after esophagectomy and diarrhea (110, 111). These symptoms are likely to affect body image, self-confidence, and partnership in early-onset patients.

The durability of function of the surgical reconstruction can be a particularly critical issue after esophagectomy. Patients with gastric tube reconstructions often suffer from severe and lifelong gastroesophageal reflux (110, 111). This may affect young patients in particular, as they face lifelong high-dose proton pump inhibitor treatment and permanent lifestyle modifications. In addition, there is a significant risk of developing Barrett's esophagus with dysplasia and ultimately a new cancer. Young patients reconstructed with a colon interposition often over the many years of remaining life suffer from elongation of the colonic conduit, leading to redundancy with the formation of sigmoid loops, with impeded bolus transit, regurgitation, and increasing difficulties in managing their nutritional requirements orally (112, 113). In addition to the negative effects on quality of life that this leads to, it often requires repeated reinterventions, both endoscopic and surgical (112, 113).

In summary, surgery for gastrointestinal cancers in early-onset patients may have severe effects on body image, partnership, and long-term quality of life. Prior to surgery, it is important to carefully consider an optimal function-preserving surgical approach with long-term durability. However, as many of the negative effects of these types of surgery are unmodifiable, it is of equal importance to very carefully inform and counsel patients before deciding on the exact type of surgery.

Treatment modalities in GI cancers include chemotherapy, molecular targeted therapies, immunotherapy, radiation, and surgery. The potential negative impact of these modalities on reproductive and sexual function is largely unknown. Fluoropyrimidines represent the backbone of chemotherapeutic protocols in many GI cancers, while their gonadotoxic effect appears to be very mild, as assessed in a cohort of patients with breast cancer. The addition of oxaliplatin induces usually a transient gonadotoxic effect, especially in female patients above the age of 40 years (114, 115). While there is robust evidence for the use of gonadotropin-releasing hormone analogues (GnRHa) in patients with breast cancer to preserve future ovarian function following cytotoxic treatment with cyclophosphamide (116–118), there is currently no evidence for GnRHa in the setting of other cancer types in which non-cyclophosphamide–based protocols are used, as in the setting of oxaliplatin-based protocols. The effects of pelvic radiation on fertility and sexual dysfunction in females has been previously described and hence ovarian transposition, known as oophoropexy, out of the radiation field is recommended prior to irradiation in patients with rectal cancer (119, 120). Studies performed in childhood cancer survivors demonstrated that pelvic irradiation induced an elevated risk for pregnancy-related complications (121–124). The increasing incidence of rectal cancer at younger ages introduces a major challenge to consult with patients regarding the effect of rectal radiation because there is lack of data regarding the uterine effect of newer radiation modalities, such as intensity-modulated radiotherapy.

Cardiovascular toxicity represents a key concern, although the impact among young GI cancer survivors remains unclear. A large study performed among colorectal cancer survivors aged >65 years who were compared with a matched cohort without cancer indicated the 10-year cumulative incidence of new-onset cardiovascular disease and chronic heart failure to be 57.4% and 54.5% compared with 22% and 18% for control, respectively (P < 0.001; ref. 125). With the implementation of oxaliplatin into commonly used adjuvant protocols in GI cancers, the long-term effect on bone marrow became a significant issue. A population-based cohort study using SEER and Medicare risk analyses had shown that risks for myelodysplastic syndrome and acute myeloid leukemia were significantly elevated after chemotherapy (relative risk ranged from 1.5 to 10 and excess absolute risks from 1.4 to 15 cases per 10,000 person-years compared with the general population). Of note, according to the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, has increased substantially since 2000, most notably for GI tract cancers (10% from 2000–2001 to 81% from 2012–2013; ref. 126).

Young patients with cancer often face unique psychosocial challenges as well as interruption of education, academic, and professional activities and responsibilities for young children and families (126, 127). Decreased energy and sexual drive and the associated strains on relationships have been identified as substantial stressors in mixed-age survivors (128). Among adolescent and young adult survivors with mixed cancers, the results portrayed a unique spectrum of psychosocial symptoms and subsequent burden. A recent study compared young adults with breast cancer to those with colorectal cancer and demonstrated a differential pattern of symptom burden and symptom severity. Of note, patients with colorectal cancer experienced worse symptoms (129). Prior evidence regarding the unique traits of young patients with cancer emphasized breast or hematologic cancers, while there is paucity of data regarding young patients with GI cancers. The combination of rising rates of patients with GI cancer of reproductive age, improving cancer survival rates, and the trend toward delayed childbearing has made the issue of the impact of treatments on fertility and sexual function of high significance. Current evidence for long-term side effects of anticancer treatments relevant to young GI cancer survivors is depicted in Fig. 3.

The documented increase in the incidence of cancer in the GI tract among the young population in the past decade raises several implications for future research. The relatively low proportion of hereditary cases among the early-onset GI cancer population indicates a potential key role for environmental and behavioral factors in pathogenesis. Genetic de novo alterations, environmental factors, lifestyle changes including obesity, diet high in red or processed meat, and lack of physical activity are possible causes of the shift in burden of disease in the younger population. Ethnicity and genetic predisposition to specific iatrogenic environmental substances may also play a role in the differential pattern of disease incidence.

Because of the relatively minor differences in the genomic landscape of early-onset GI cancer compared with late-onset GI cancer, future research should emphasize potential epigenetic changes that may reveal the pathogenic impact of extrinsic factors (Fig. 4).

Host mechanisms represent a second plausible research direction. The microbiome is becoming a major research focus in many ongoing studies. Because of geographic diversity in the incidence of early-onset GI cancer, the microbiome along dietary and ethnical predispositions may underlie differences in disease rate in different parts of the world. Utilizing state-of-the-art technologies would allow for integration of genomic, epigenetic, and host traits of young patients with GI cancer. Obesity was found to be correlated with early-onset GI cancer. Therefore, a major part of future research should aid health care policy makers in developing risk reduction strategies to minimize childhood and adolescent intake of processed and high-sugar food and consider early detection measures among high-risk populations.

There is paucity of data regarding late-term treatment-related toxicities that are unique for the population of young GI cancer survivors. Future research should aim to study toxicity mechanisms to develop preventive measures and early detection of long-term morbidity. The psychosocial unmet needs should be addressed in the portfolio of disease- and treatment-related adverse effects. Societal and financial perspectives should be considered as well with regard to patients with early-onset GI cancer, whose life expectancy is good on the one hand, but the disease meets them in the most productive time in their life, sometimes leaving them with significant economic ramifications. We should further advance our understanding of the molecular landscape of early-onset GI cancers, with the aim of designing future prevention, screening, and treatment strategies to optimize outcomes for this novel patient population. The ultimate goal would be to develop accessible platforms able to integrate individual genetic predisposition and environmental risk models to identify individuals at risk who could potentially benefit from preventative measures.

H.W.M. van Laarhoven reports other support from Ampera, AstraZeneca, BeiGene, Daiichi Sankyo, Dragonfly, Eli Lilly, MSD, Astellas, and Novartis; grants, nonfinancial support, and other support from Nordic Pharma, Servier, and Bristol Myers Squibb; grants and nonfinancial support from Bayer, Celgene, Janssen, Incyte, Philips, and Roche; and grants from Eli Lilly and MSD outside the submitted work. E. Fontana reports personal fees from CARIS Life Science, Seagen, Sapience Pharma; grants from Repair Therapeutics, Bicycle Therapeutics, Artios Pharma, Seagen, Amgen, Nurix Therapeutics, BioNTech, Relay Therapeutics, Taiho Pharmaceutical, Pfizer, Roche, Daiichi Sankyo, Gilead Sciences, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, HUTCHMED, Merus, Crescendo Biologics, GSK, BeiGene, Turning Point Therapeutics, and Sapience Pharma outside the submitted work, as well as a leadership role in the European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Tract Group (group secretary). R. Obermannova reports grants and nonfinancial support from Roche; other support from Servier and Merck; and nonfinancial support and other support from Bristol Myers Squibb outside the submitted work. F. Lordick reports personal fees from Amgen, Astellas, AstraZeneca, Art Tempi, Bayer, BeiGene, BioNTech, Daiichi Sankyo, Eli Lilly, Elsevier, Iomedico, Incyte, Imedex, Medscape, MedUpdate, Merck Serono, MSD, Novartis, Roche, Servier, Springer Nature, StreamedUp!, and Servier; grants and personal fees from Bristol Myers Squibb; and grants from Gilead outside the submitted work. No disclosures were reported by the other authors.