# Early-Onset colorectal Cancer: From the laboratory to the clinic

Annalice Gandini, Julien Taieb, Hélène Blons, Jeanne Netter, Pierre

Laurent-Puig, Claire Gallois

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Annalice Gandini, Julien Taieb, Hélène Blons, Jeanne Netter, Pierre Laurent-Puig, et al. Early-Onset colorectal Cancer: From the laboratory to the clinic. Cancer Treatment Reviews, 2024, 130, 10.1016/j.ctrv.2024.102821. hal-04955624

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# Early-Onset colorectal Cancer: From the laboratory to the clinic

Annalice Gandini<sup>a,b,c</sup>, Julien Taieb<sup>b,c</sup>, Hélène Blons<sup>b,d,e</sup>, Jeanne Netter<sup>c</sup>, Pierre Laurent-Puig<sup>b,f</sup>, Claire Gallois<sup>b,c,*</sup>

## ARTICLE INFO

### Keywords:

Early-onset colorectal cancer

EOCRC

Clinical characteristics

Molecular profiling

Transcriptomic

## ABSTRACT

Colorectal cancer that occurs before age of 50 is defined as Early-Onset Colorectal Cancer (EOCRC). Its incidence has worryingly increased since the late 90 s and is expected to keep rising in the next future, despite Late-Onset CRC (LOCRC) is decreasing worldwide. Because of this, there is an urgent need to better understand this subset of patients in order to give them the best treatment possible. However, most of the literature is retrospective and often discordant. In this review, we aim to provide a general overview of the issue, endeavoring to highlight the current available knowledge. We decided to move from the beginning, investigating risk factors and inheritance, passing through diagnosis and clinical aspects, and to conclude with the translational part, focusing on the biology of the tumor. However, lot of questions remain open, including screening age and prognosis. Indeed, young patients tend to be treated more aggressively, even if a survival benefit has not been proven yet. Every clinician should be aware of the best practice for young people, and more translational studies are awaited in order to clarify is EOCRC represents a distinct biological entity.

## Introduction

The recent evidence on the alarming increasing trend of colorectal cancer (CRC) incidence in young patients led to the definition of Early-Onset CRC (EOCRC), a distinct entity defined by the occurrence of CRC before the age of 50. The age cut-off was decided based on general recommendations for CRC screening, which was usually indicated between 50 and 75 years old. Even if some countries are lowering screening age at 45 (NCCN guidelines colorectal cancer screening Version 1.2023 — May 17, 2023), at the moment this is not standard worldwide and more data are required to better define the best screening strategy [1], considering that cases are increasing also in people under 45 years of age, often associated with a positive family history. One study showed, indeed, that about one-quarter of cases between 40 and 49 years met the already existent criteria for early screening based on family history: among these, almost all could have been screened at an age younger than the observed age of diagnosis [2].

Reasons for this increasing trend are still not clear and hereditary cases are not the only explanation. Moreover, it is important to better understand if EOCRCs are clinically and molecularly distinct entities than Late-Onset CRC (LOCRC) since literature remains ambiguous. In this review, we would like to pass through the main differences nowadays known, trying to give a complete overview from the diagnosis to the translational analyses. Since these data are alarming, last year specific guidelines (Delphi Initiative for Early-Onset Colorectal Cancer - DIRECT) have been drafted with the consensus of 69 major opinion leaders in this field [3], in order to guide clinicians through the management of this subset of patients. However, lot of aspects still need to be clarified, and more studies on this population are required.

## Incidence and epidemiology

CRC is still one of the leading causes of cancer-related death, even if its incidence is decreasing by about 2 % per year in people over 50 years

<footnote><sup>a</sup> Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy</footnote>

<footnote><sup>b</sup> Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France</footnote>

<footnote><sup>c</sup> Institut du Cancer Paris CARPEM, AP-HP Centre, Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris, France</footnote>

<footnote><sup>d</sup> Assistance Publique-Hôpitaux de Paris, Department of Biochemistry, Pharmacogenetics and Molecular Oncology, European Georges Pompidou Hospital, Paris Cancer Institute CARPEM, 20 Rue Leblanc, 75015, Paris, France</footnote>

<footnote><sup>e</sup> Department of Genetics and Molecular Medicine, Georges Pompidou European Hospital, APHP Centre, Paris, France</footnote>

<footnote><sup>f</sup> Institut du Cancer Paris CARPEM, APHP. Centre, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France</footnote>

<footnote>* Corresponding author at: 20 Rue Leblanc, 75015 Paris, France.</footnote>

<footnote>E-mail address: claire.gallois2412@gmail.com (C. Gallois).</footnote>
old because of screening programs. On the contrary, the incidence of EOCRC has dramatically increased since the early 90 s of about 1.5 % per year [4] in both men and women, (Fig. 1A), becoming the first leading cause of cancer-related death in young men and the second in young women after breast cancer [4].

The increasing incidence in the very last few years (2016–2020) seems to be guided by rectal cancer, since colon cancer incidence has stabilized at 5.5/100.000/y (SEER Explorer). Based on the APR-predictive model, a 131.1 % increase in the incidence rate of EOCRC is expected by the year 2030 [5] with 11 % of colon cancers and 23 % of rectal cancers estimated to occur in people under 50 years of age [6]. Fig. 1B shows the estimated number of cases in the next future.

Incidence is not equal across the world. When compared with non-Hispanic whites, non-Hispanic blacks seem to exhibit a higher prevalence of EOCRC than LOCRC (16 % vs 9 %) [7] and a worse survival [8]. Among geographic distribution, EOCRC's prevalence seems to correlate with Socio-demographic Index (SDI), since in high-SDI countries prevalence is almost 10 times higher than low-SDI countries (44 cases/100.000 vs 5.4/100.000 inhabitants in 2019) [9] (Fig. 1C), possibly related to early-life risk factors' exposure. Moreover, incidence and mortality seemed to be higher among young people living in rural areas, which were more often Caucasian and uninsured [8].

However, the trend is reported worldwide and only three countries (Italy, Austria, Lithuania) have registered a decreasing trend in people of age 40–49, possibly due to an early access to screening program [10].

## Risk factors

### Sporadic EOCRC

The vast majority of EOCRC is sporadic and the identification of the main risk factors is crucial to limit the exposure and reduce cancer incidence. Lifestyle risk factors seem to have the greater impact on EOCRC, and the principal ones are illustrated in Fig. 2.

First of all, dietary habits seem to represent one of the major determinant of the increase in EOCRC incidence [11] and recommendations do not differ from the general CRC population, particularly in terms of limiting processed meat and fried food. Alcohol has a strong correlation with EOCRC, and the risk is directly proportional to its abuse [12]. An interesting insight suggests a possible association with a diet low in milk, although stronger evidence is needed to confirm this point in the early-onset subpopulation [13]. Obesity is widely recognized as a risk factor for various cancers, including those of the gastrointestinal tract, uterine, and breast, and is linked to doubling the risk of CRC in women [14]. Persistent obesity, especially if abdominal, is even more relevant in determining the occurrence of EOCRC and some data suggest that obesity is particularly impactful in this subgroup of patients if it occurs very early-age (<24 years old) [15]. Persistent metabolic syndrome was associated with an odd ratio (OR) of 1.16 of CRC among 20–39-year-olds and even of 1.22 among 40–49-year-olds, with a particular association with rectal cancer [16]. A sedentary life is a well-known risk factor for CRC, but evidence related to EOCRC is not conclusive. On the one hand, it was demonstrated to be directly proportional to the risk of EOCRC, particularly of the rectum [17]. On the other hand, several studies were not conclusive on this point [12,18]. In addition, there is potentially a confounding bias as sedentary behavior is directly associated with

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Epidemiology of EOCRC. A: SEER trends of CRCs diagnosis rate per 100.000 people in United States. SEER\*Explorer: An interactive website for SEER cancer statistics [Internet]. Surveillance Research Program, National Cancer Institute. B: Estimated number of new cases from 2022 to 2050, males and females < 50 years old. C: Age-standardized Rate (World) of CRC<50 years old per 100.000 in both sexes in 2022. Figure B and C created with Global Cancer Observatory (https://gco.iarc.who.it/tomorrow/en/).</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Main risk factors for sporadic EOCRCs. Picture created with **BioRended.com** and **Freepik**.</figcaption></figure>

obesity, a well-established risk factor for EOCRC. Finally, a meta-analysis in EOCRC confirmed that smoking is associated with an OR of 1.44, even if a high heterogeneity was reported [19].

A rapidly emerging field of interest in Oncology is the gut microbiome analysis and its potential critical role in the development and progression of various cancers, as well as its secondary impact on modulating responses to treatments and prognosis [20]. For example, higher bacterial diversity was associated to major pathologic response after neoadjuvant treatment in EO rectal cancer, while this was not confirmed for LO rectal cancer [21]. The potential relevance of gut microbiome is also confirmed by the correlation between gastrointestinal cancers and inflammatory bowel diseases (IBD), in which dysbiosis-related inflammation increases CRC risk of 10–15 % [22]. Metagenomic or metataxonomic approaches highlighted imbalanced bacterial hierarchy in patients with CRC. Hence, some bacterial species are considered pro-oncogenic (e.g. *Bacteroides*, *Escherichia*, *Fusobacterium*, and *Porphyromonas*) and others potentially protective (e.g. *Roseburia*) [23]. Consequently, everything that has an impact on the intestinal bacterial balance should be considered as a potential risk factor. Gut microbiome seems to have an even more impactful effect on the development of CRC in young patients since enhanced microbial-host interactions were observed at the tumor site in EOCRC, indicating a direct involvement of microbes in tumorigenesis through their interaction with cancer-related pathways in young patients [24]. Strictly referring to EOCRC, differences in microbiota composition were observed in EOCRC when compared to LOCRC; however, data are still limited and not always consistent among each other. For example, in one study, EOCRC was associated with the upregulation of Fusobacteria, while LOCRC was associated with the upregulation of Bacteroidetes, but another study comparing the two cohorts of patients identified enrichment in *Fusobacterium nucleatum* in LOCRC while *Flavonifractor plastic* was enriched in EOCRC [25]. A high prevalence of *Escherichia Coli* also seems to be associated with EOCRC [21]. This underlines the difficulty of studying microbiome due to methods and the influence of diet and lifestyles. Nevertheless, the microbiome is known to vary throughout life. A deeper understanding of gut microbiota profiles in EOCRC patients may facilitate the identification of diagnostic and potentially predictive biomarkers for the efficacy of treatments. Prolonged use of antibiotics, that can induce dysbiosis of the microbiota, seems to

increase the risk of gastrointestinal tumors; however, its precise impact on EOCRC is still unknown [26]. Few data suggest that birth by cesarian delivery could represent a risk factor, possibly due to the consequent modulation of gut microbiota, especially in females [27]. Lastly, breastfeeding appears to modify bacterial species, but its clinical impact is not yet well defined. Thus, breastfeeding seems to be protective in some studies [28], while others saw an increase in the risk of EOCRC directly related to the duration of breastfeeding, especially if ≥ 9 months, and also of high-risk adenomas under 50 years of age [29]. Additional research is required to elucidate the underlying biological mechanisms and to establish a cause-and-effect relationship for this association.

## Hereditary EOCRC

Almost one-third of all EOCRC patients have a first-degree family history of CRC [30], and this percentage rises up to 50 % in those affected by a genetic syndrome [31]. As illustrated in Fig. 3, even if sporadic cases represent almost 80 % of EOCRC, the prevalence of germline pathogenic variants (PV) is higher (16–25 %) than in LOCRC (10–15 %). In the population of less than 35 years, the incidence of inheritance-related cases seems to be even higher, reaching almost 35 % [32]. However, the incidence of inherited variants is not increasing among the general population, suggesting that the rising incidence of EOCRC is probably due to sporadic cases. Nevertheless, it is possible that some young patients without pathogenic variants could have a genetic susceptibility on which sporadic risk factors can act. In particular, this genetic susceptibility appears to be related to non-coding signals enriched in epigenetic markers expressed on the epithelial cells of the intestinal tract, including insulin signaling and genes with immune functions [33].

More than half of inherited EOCRC are related to Lynch Syndrome (LS) [31,34], which is a dominantly inherited predisposition caused by germline PV in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or in EPCAM gene [35]. In EOCRC, the most frequent germline PV are found in MLH1 and MSH2, similar to LOCRC. LS is associated with an increased incidence of cancer, especially, but not only, colorectal and endometrial; the lifetime risk of developing CRC is up to 80 %, with variable percentages among the PV [36]. In EOCRC, LS
<figure><img src="image_6.png" /><figcaption>Fig. 3. Prevalence of pathogenic variants in the etiology of CRC according to age. Picture created with BioRender.com.</figcaption></figure>

should be suspected in all the dMMR/MSI patients, and the identification of this phenotype is nowadays mandatory for two different reasons. Firstly, it allows the diagnosis of LS, which leads to a reduction in mortality of approximately 60% in patients and their relatives, thanks to the enrollment in surveillance programs [37]. Secondly, it allows the identification of patients who could benefit from immunotherapy, both in localized and metastatic settings, which has revolutionized their prognosis [38].

The second most common inherited CRC syndrome is the Familial Adenomatous Polyposis Syndrome (FAP), a dominantly inherited disease which has a prevalence of 2 cases per million inhabitants [39] and is associated with a 100% risk of developing CRC before the age of 40. FAP is caused by germline PV in the gene APC, which acts on the WNT pathway and causes the development of a huge number of colonic adenomas that inevitably degenerate into invasive disease at a median age of 39, if not treated [40]. Less common is MUTYH-associated polyposis, an autosomal recessive inheritance disease linked to the presence of biallelic MUTYH PV, which has a clinical presentation similar to attenuated FAP (less than a hundred polyps) and a risk of CRC development about 43% by the age of 60 [41]. Other less frequent syndromes could occur, such as polymerase proofreading-associated polyposis (caused by missense variants in the DNA polymerases POLE and POLD1), Peutz-Jeghers syndrome, Cowden syndrome, juvenile polyposis and Li-Fraumeni syndrome [40].

Therefore, the National Comprehensive Cancer Network (NCCN) and DIRECt recommend genetic risk counseling and evaluation for all persons with CRC before the age of 50. The genetic panel should include, at minimum, APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, POLD1, POLE, PMS2, PTEN, SMAD4, STK11, and TP53 [3].

## Clinical aspects

### Diagnosis

Due to the absence in most countries of screening programs in patients under 50 years old, diagnosis is usually prompted by symptoms [42]. In the pooled analysis of the ACCENT trial, among stage III CRC, no differences were highlighted between EO and LOCRC in terms of sex, race, tumor grade, and risk group [43].

In contrast with the available literature, there was no difference in

tumor sidedness, possibly related to the absence of rectal cancers, which are the mostly uprising in the last years. Moreover, EOCRC had similar T and N stage to LOCRC, even though it is known that fewer than half of the EOCRC patients have stage I or II disease [44–46]. This correlation may be attributed to the considerably longer average time to receive a diagnosis in younger patients. A retrospective study conducted at Stanford registered a difference of 50 days between the two sub-populations (128 vs 79 days), a little bit reduced for patients with severe symptoms that led them to the emergency department [47]. However, the longer time to diagnosis is not necessarily the sole explanation for the higher proportion of advanced diseases among younger patients. Still, it may also be due to more aggressive diseases, with the need to explore molecular and biological factors [47]. Indeed, CRCs in young people usually have more aggressive histopathological characteristics, such as high grade, mucinous and/or signet ring cell differentiation, and perineural and vascular invasion [48]. The most frequent onset signs and symptoms and their incidence are described in Table 1. Is it possible that the minor frequency of anemia in young patients could be related to tumor location and more routine blood testing in older patients [49]. One or more of these symptoms are reported by approximately 20%

<caption>**Table 1**</caption>

Main clinical [86], pathological, and molecular differences among LOCRC and EOCRC, irrespective of stage.

<table><thead><tr><th></th><th>LOCRC</th><th>EOCRC</th></tr></thead><tbody><tr><td>Male / female ratio</td><td>1.45</td><td>1.2</td></tr><tr><td>Time to diagnosis</td><td>80 days</td><td>130 days</td></tr><tr><td>First manifestation</td><td></td><td></td></tr><tr><td>Hematochezia</td><td>27 %</td><td>41 %</td></tr><tr><td>Abdominal pain/bloating</td><td>28 %</td><td>35 %</td></tr><tr><td>Change in bowel habits</td><td>28 %</td><td>20 %</td></tr><tr><td>Iron deficiency anemia</td><td>16 %</td><td>3 %</td></tr><tr><td>Sidedness</td><td></td><td></td></tr><tr><td>Right</td><td>32 %</td><td>15 %</td></tr><tr><td>Left</td><td>39 %</td><td>46 %</td></tr><tr><td>Rectum</td><td>23 %</td><td>34 %</td></tr><tr><td>Synchronous metastases</td><td>20 %</td><td>30 %</td></tr><tr><td>Unfavorable histology</td><td>12 %</td><td>20 %</td></tr><tr><td>CMS subtype</td><td>CMS 2–3-4</td><td>CMS 1–2</td></tr><tr><td>MSI/dMMR</td><td>10 %</td><td>20 %</td></tr><tr><td>BRAF mutant</td><td>13 % in &gt; 70y</td><td>3 % in &lt; 30y</td></tr><tr><td>RAS mutant</td><td>50 % in &gt; 50y</td><td>38 % in &lt; 30y</td></tr></tbody></table>
of patients, with their onset occurring between 3 months to 2 years before the diagnosis. The time required for diagnosis is directly related to both the number and the severity of the symptoms [50]. Moreover, young people report higher severity of symptoms compared to LOCRC, emphasizing the significance of accurate clinical management [51]. Because of the increasing incidence and the late diagnosis in young patients, several guidelines are changing, favoring early access to screening programs. The age cut-off is debated since a lot of studies have proven its cost-effectiveness ratio when started at the age of 40 [52,53]. The American guidelines NCCN have already updated recommendations to lower screening programs' starting age to 45 in people with an average risk of CRC, consistent with a US Preventive Services Task Force recommendation in May 2021. However, in several countries (Canada, France) CRC screening, in the average risk population, still starts at 50 years old, and a worldwide strategy must be better defined. In people with at least one first-degree relative with a history of CRC, the recommendation for screening colonoscopy is confirmed at 40 years old or 10 years before the earliest diagnosis in the family in most European, US and Asian guidelines.

## EOCRC and pregnancy

Alarming data are emerging on CRC during pregnancy and postpartum period due to both the rising incidence of EOCRC and delayed childbearing. In a *meta*-analysis on 79 studies, the risk of CRC during pregnancy was calculated to be 0.002 %, with a median age of 32 years old [54]. Diagnosis of CRC-p is often delayed due to the attribution to the pregnancy of symptoms like abdominal pain, rectal bleeding, and constipation, resulting in more advanced disease [55]. Moreover, pregnancy can limit the use of standard diagnostic and therapeutic tools, further delaying the diagnosis [56]. Endoscopy is recommended if a tumor is suspected, and it should preferably be performed after the first trimester [57]. In a recent analysis of the International Network on Cancer, Infertility and Pregnancy (INCIP) database, CRC during pregnancy appeared to be more likely left-sided or rectal, and more than 70 % of the patients had stage III or IV disease [58]. A case series reported advanced disease up to 93 %, with really poor outcomes (mPFS and mOS of 5.2 and 17 months, respectively) [59]. Though not formally recommended due to the consequences of pre-term newborns, iatrogenic preterm delivery and cesarian surgery seem to be more frequent [58]. In the specific case of locally advanced rectal cancer, the impossibility of administering radiotherapy remains a challenge [60]. On the opposite, chemotherapy seems safe, particularly after the first trimester [61]. Moreover, few data suggest that also a history of EOCRC could be associated with complications during the following pregnancy, such as pre-eclampsia and emergency delivery by C-section; congenital malformations were not significantly more prevalent than in the general population [62]. To conclude, since the alarming rising incidence of EOCRC and the more often delayed pregnancy, CRC during gestation or postpartum is a critical issue that requires attention. However, since the limited number of cases, no specific guidelines exist, and managing these patients remains challenging. A universal reporting system is needed, and clinicians should be aware of giving attention to persistent gastrointestinal symptoms during pregnancy and the postpartum period.

## Prognosis

Considering the prognostic impact of early age, there are conflicting results in the literature.

Some evidence suggest that EOCRC could have a better short-term and long-term outcomes when compared to LOCRC, even if the diagnosis is often delayed [63]. Similar conclusions were reached by a huge retrospective study on more than 500,000 CRC patients, where younger patients had a better cancer-specific survival despite the presence of clinical-pathological aspects of aggressiveness [stage IV, poor differentiation, mucinous) [64]. Some potential explanations could include

fewer co-morbidities, a better dose-intensity of the treatments and a higher rate of MSI-high status, a positive prognostic factor in early disease and a predictive factor of efficacy of immune checkpoint inhibitors.

Opposite results were obtained in other studies. A pooled analysis of 24 clinical studies enrolling CRC patients treated in first line identified a correlation between very young and very old age with a worse prognosis. Thus, compared to patients between 57–61 years (best prognosis), patients aged nearly 18 and 90 had a higher overall risk of death (19 % for the youngest and 42 % for the oldest), even more pronounced during the first year of follow-up (28 % for the youngest and 71 % for the oldest), with the limit of competing risk of death in older patients [65]. At the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium 2024, an Italian group presented a study evaluating the prognosis of metastatic EOCRC in almost 600 patients from 4 different centers. This study found that young people had a generally worse prognosis when compared to LOCRC, irrespective of the RAS/BRAF mutation status [66].

Finally, other evidence suggests that the age itself does not determine the prognosis [67]. In a subgroup analysis of EOCRC patients from the IDEA database, young patients were found to have a similar risk of cancer-specific mortality as older patients, despite more aggressive treatments and a better treatment adherence. However, young age seemed to be a poor prognostic factor in high-risk stage III CRC, possibly due to the more aggressive biology of their tumors, even if further translational studies are needed to confirm this [68]. Indeed, the pooled analysis from the ACCENT database showed in stage III EOCRC better disease-free survival (DFS), OS, and survival after recurrence (SAR) compared to LOCRC, but this prognostic value was lost when the outcomes were adjusted for molecular markers (RAS/BRAF mutation status and MSI status) [43].

However, although all these data derived from retrospective analyses, they are concordant in finding poor prognostic histopathological features in EOCRCs. Moreover, young people typically have fewer competing causes of death, thus, an equivalent prognosis may suggest a more aggressive disease. However, due to the absence of clear evidence of worse outcome, guidelines do not support the use of more aggressive treatment choices based only on younger age, but treatment choices should be guided by clinical and molecular factors [3]. Altogether, more prospective studies are needed to better define the prognosis of EOCRC (Fig. 4).

## Treatment and long-term consequences

Despite recommendations, in clinical practice, young patients are often more likely to be treated intensively, both in the adjuvant setting with doublet chemotherapy [45,69,70] and in the metastatic setting with anti-EGFR and triplets, even if no longer survival has been proven yet [71,72]. Moreover, local and surgical treatments are more frequent, which might play a relevant role in improving prognosis.

In the early stages, young people usually have a greater number of lymph nodes removed, which could lead to a better staging of the patients [43] and a higher percentage of stage III. However, we still do not know if the prognosis would be the same between young and old patients receiving the same intensity of treatment. A subgroup analysis of EOCRC patients from the IDEA database (about 10 % of all the patients) showed that adherence to treatment was higher, especially if the planned adjuvant treatment duration was 6 months. As expected, the dose intensity of chemotherapy was significantly higher but with similar toxicity rates [68].

Finally, it is important to notice that these patients usually are at a crucial point in their lives, in terms of family and career. Patients should always receive oncofertility counseling and should be carefully informed about long-term consequences, including bowel alterations, sexual dysfunction, psychological disorders, and also financial damages [73–75].
<figure><img src="image_7.png" /><figcaption>Fig. 4. Good and bad prognostic factors in EOCRC. Picture created with BioRender.com.</figcaption></figure>

## Histological and molecular profile

It seems that EOCRC differs from LOCRC from a histological point of view. Especially very young patients (<30 years old) seem to have a higher prevalence of signet ring cell tumors [76] and poorly differentiated histology [77,78]. EOCRC developed on IBD were seen to be more likely to have mucinous histology [76]. It is interesting to notice that among microsatellite-stable tumors, no differences were found between EOCRC and LOCRC in terms of histopathological characteristics and thus that most of these differences were linked to dMMR/MSI tumors [49].

Regarding genomic profiling, several studies have been conducted to

evaluate if EOCRC molecular profile significantly differs from LOCRC (see Table 1). Irrespective of stage, MMR deficiency is more frequent in EOCRC [77,79] and it is more frequently associated with hereditary syndromes and good prognosis [80]. Consistently with this information, the most frequent Consensus Molecular Subtypes (CMS) in young patients are CMS1 and CMS2 [76,81]. Indeed, CMS1 is associated with hypermutated tumor DNA and often immune JAK-STAT activation and microsatellite instability; CMS2 is associated with Wnt/MYC activation, and its prevalence is constant among ages [82]. In a retrospective analysis among 36,000 CRC patients, EOCRC showed higher frequency of CTNNB1 mutations, while BRAF V600E, KRAS, MAPK and APC mutations were less frequent than in LOCRC [76]. Moreover, EOCRCs are

<figure><img src="image_8.png" /><figcaption>Fig. 5. Genomic profile of colorectal cancers, according to age and sidedness. * In right-sided EO: MSH6 = 11.1%; MSH2 = 10.5%; MLH1 = 10.5%. In left-sided EO: MSH6 = 2.3%; MSH2 = 1.2%; MLH1 = 2.3%. Ref: [83,84,87]. Picture created with BioRender.com.</figcaption></figure>
associated with lower levels of Long Interspersed Nucleotide Elements-1 (LINE-1) methylation, which could partly explain the worse prognosis in these patients [79].

Different results came from MD Anderson's group, which limited the analysis to MSS tumors in more than 700 patients. The most common molecular alterations in EOCRC were APC (79 %), TP53 (82 %), KRAS (42 %), SMAD4 (15 %) and PIK3CA mutations. However, none was significantly different compared to old patients after adjustment for primary tumor sidedness [49]. Limiting analysis to left-sided primary tumors, EOCRC seem to be more frequently TMB-high, MSI, and mutated in genes associated with cancer-predisposing syndromes (POLE, CDH1) and histone modification [83]. Lower rates of BRAF, KRAS, PIK3CA, RNF43 mutations were reported [84]. Fig. 5 presents genomic differences among CRC, according to age and sidedness.

Interestingly, the pattern of somatic mutations seems to vary also among ethnicities. Excluding hypermutated cases, APC mutations were found to be more frequent in non-Hispanic white patients (75 %) than Asian (59 %) patients. Statistically significant differences in prevalence in young patients across races were also highlighted in other mutations, like FBXW7, FLT4, RNF43, LRP1B, PIK3CA, and ATRX. This evidence could explain the variations of incidence among races, and further studies are needed to confirm this since confounding factors could have impacted these results [85].

Transcriptomic signature and whole exome sequencing data

Not only DNA but also RNA could provide important insights to better understand cancer. With the progress in knowledge and technology, transcriptomics is proving to be crucial in highlighting cancer-related alterations in signaling pathways that could explain neoplastic cell behaviors. This technique has also been used to study EOCRC; however, literature on this is still scarce, and more studies are highly awaited. Here, we will highlight the most studied transcriptome signature in this field.

The proto-oncogene MYC regulates the activation and repression of many genes involved in cell cycle progression, and it is also implied in the regulation of transcript abundance [88]. Due to its key role in cell proliferation, MYC is usually aberrant or deregulated in carcinogenesis, including that of CRC [89]. The Pennsylvania State University conducted a comparative RNA-seq analysis in flash-frozen tumors of 24 EOCRC and adjacent segments of normal tissue as controls. Focusing on MYC expression, they observed that patients could be divided into two groups: the “high-MYC” and the “low-MYC” expressors, with different characteristics. High-MYC tumors patients had PVT1 co-amplification, downregulation of immune response gene signatures and tended to be older and overweighted. Indeed, obesity may increase intestinal MYC expression through the Wnt/β-catenin pathway or through the enrichment of Unfolded Protein Response (UPR) due to higher endoplasmatic reticulum stress. Therefore, MYC level of expression could identify different subset of patients whose pathogenesis and eventually treatment could be different [90]. c-Myc expression was also associated with lymphatic invasion in 40 EOCRC [91].

Among 88 MSS EOCRC, it was observed an activation of the Wnt signaling pathway and mTOR, that could represent poor prognostic factors and be predictive of sensibility to specific inhibitors. Moreover, compared to LOCRC and controls, EOCRC had higher WASF1 expression, a WNT signaling potentiator, and lower TNFRSF14 expression. Their prognostic role in literature is debated, but, knowing that TNFRSF14 was associated with better OS, low expression was associated to poorer prognosis of the younger patients [81]. However, not all the studies confirmed a higher frequency of WNT alterations in EOCRC, while a correlation was found with rectal cancer [92].

Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) and are usually characterized by the expression of fibroblast activation protein (FAP) and actin alpha 2 (ACTA2). They are involved in the deposit and the remodeling of the extracellular matrix,

and hence they could take part in the carcinogenesis and in the metastatic spreading [93]. The gene FAP appeared to be upregulated in younger patients, so as the FAP mRNA levels, and a significant upregulation of the WNT signaling pathway was observed in EOCRC. High levels of mRNA FAP appeared to have a poor prognostic value in 13 EOCRC after the exclusion of patients with hereditary syndromes and IBD, and the major transcriptomic differences between EOCRC and LOCRC were observed at the tumor margin [94]. Further studies need to be addressed to confirm the different intrinsic transcriptomic profile of CAFs in EOCRC and to better define if the differences in the tumor margin could have clinical implications, due to the interaction with epithelial cells.

Organoids are culture systems generated from stem cells that are able to reproduce the characteristics of the corresponding organs, allowing to studying cell processes [95]. Hence, bio-banks of organoid lines of different tumors, including CRC, were built to analyze genomic profiling on preclinical models [96]. In an EOCRC-enriched cohort, whole exome sequencing analysis was performed, and different profiles were outlined. Using RNA-seq, multiple fusion transcripts involving R-spondin family members RSPO2 and RSPO3 were identified. These fusions had already been described in colon cancer: they seem to be mutually exclusive with APC mutations and to have a role in tumorigenesis through the Wnt signaling pathway [97].

Altogether, the amount of knowledge on different transcriptomic pattern is very scarce and limited to small number of patients, therefore at the moment it could not be considered standard and more studies on a larger scale are awaited.

Conclusions

Incidence of EOCRC has increased in the last decades and it is expected that by 2030 almost one quarter of rectal cancers will occur in people under 50 years of age [6]. This dramatic trend urgently requires improving our knowledge about this population in order to screen and treat them optimally. Inheritance is more frequent than in LOCRC, being responsible for almost 25 % of the cases [30] and 33 % in very early onset CRC [32], but it is not explaining the full picture. Lifestyle and environmental risk factors seem to be crucial aspects that need to be better classified and eventually modified. Prevention is probably the key to reduce morbidity and mortality, but there are still a lot of unanswered questions on how to best perform an efficient prevention [1], screening strategy, and a prompt diagnosis. It is well established that EOCRC have more frequently left-sided and rectal tumors, and are usually diagnosed in more advanced stages [45]. They usually present poor prognostic histological features (mucinous or signet ring cell, poor differentiation), but largely due to the enrichment in MSI tumors. They are also more often BRAF wild-type and mutated in other genes involved in hereditary syndromes. However, there is an urgent need to understand if they represent a distinct biological entity, and if their prognosis is defined only by age and not also by the known clinical-molecular features, since in clinical practice they usually tend to be overtreated even if a survival benefit has not been proven yet [70]. Finally, due to the young age, it is important to have a complete patient care, since treatments can have short and long-term consequences on physical, psychological and socioeconomic spheres [73,75].

Disclosure

AG, HB, JN, declares no conflict of interest. JT reports personal fees from Amgen, Astellas, AstraZeneca, BristolMyersSquib, Merck, MSD, PierreFabre, Servier, and Novartis outside the submitted work. PLP reports personal fees from Biocartis, Amgen, Pierre Fabre, and Servier, and other support from MethysDX outside the submitted work. CG reports personal fees from Servier, Pierre Fabre, and Merck outside the submitted work.
CRediT authorship contribution statement

**Annalice Gandini:** Conceptualization, Methodology, Data curation, Writing – original draft, Writing – review & editing, Supervision, **Julien Taieb:** Conceptualization, Methodology, Data curation, Writing – original draft, Writing – review & editing, Supervision, **Hélène Blons:** Writing – review & editing, Supervision, **Jeanne Netter:** Writing – review & editing, Supervision, **Pierre Laurent-Puig:** Conceptualization, Methodology, Data curation, Writing – original draft, Writing – review & editing, Supervision, **Claire Gallois:** Conceptualization, Methodology, Data curation, Writing – original draft, Writing – review & editing, Supervision.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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