Colorectal Cancer in Australian Young Adults

Purpose of Review: Although the overall incidence and mortality rates of colorectal cancer (CRC) have been decreasing in Australia over the last 20 years, there has been a significant increase in the incidence of early-onset CRC (EOCRC) without a clear explanation. In this review, we have outlined the epidemiology, suggested risk factors, clinicopathological and molecular features, survival and prognosis, and treatment approach for Australian young adults with CRC. Recent findings: There has been a shift in the epidemiology of bowel cancer incidence and mortality across different age groups, and there are clinicopathological and molecular feature differences between EOCRC and late onset CRC (LOCRC). EOCRC is more common in the distal colon and rectum. Young patients are diagnosed at more advanced stages of the disease with increased prevalence of aggressive pathologic features and tend to receive more aggressive chemotherapies. EOCRC patients present with a predominance of symptoms in the left side of the colon, and importantly, cases do not have clinically known risk factors. The microbiota may play a significant role in the CRC pathogenesis through an impact on host metabolism and through the transmission of metabolic and even CRC risk in non-Mendelian familial aggregation. Summary: The increase in the incidence and mortality rates of young adults with CRC has been significant. Thus, more collaborative research is needed to explain the reasons behind the increase in CRC incidence, and to identify young adults in the population at an increased risk of developing CRC at an early age.


INTRODUCTION
In Australia, colorectal cancer (CRC) was estimated to be the most frequently diagnosed digestive-tract cancer in 2018 and was Australia's most frequent digestive-tract cancer killer [1].CRC is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide [2].The age distribution, however, has altered with an increase in incidence of early-onset CRC (EOCRC) being reported in Australia, the USA and many other developed countries [3][4][5][6][7][8][9].
There is a difference in the literature regarding the exact definition of early onset as different researchers have used various age groups including individuals under analysis of CRC temporal trends shows a decrease in incidence and mortality rates of this disease in all ages combined over time in Australia.In contrast, the incidence and mortality rates of EOCRC have been increasing, when the analysis is stratified into specific age groups, over the last two decades in Australia, the USA, and other countries with similar overall trends of this disease (Figure 1) [32,38].The incidence of CRC has increased 186% in individuals between the ages of 15-24 years in the last three decades [27] and it is considered to be the most common cancer-related cause of death for those aged 25-29 [15].In addition, Feletto et al., recently analysed over 375,000 cases of colon and rectal cancers from 1982 to 2014 in Australia.This study confirms that the incidence rates of colon cancer has increased in young adults under the age of 50 years since the mid-2000s, with the increase in the annual percentage changes (APCs) ranging from 1.7% to 9.3% per annum depending on specific age group.The incidence rates of rectal cancer has also increased among the same group of ages from the 1990s, with the increase in the APCs ranging from 0.9% -7.1% per annum [32].The data shows that early-onset CRC is a current public health concern in the USA, Australia [23,27,39] and in other countries [3][4][5][6][7][8][9] (Table 1).The prevalence of CRC is not uniform across all racial and ethnic groups, though there is an increase in the prevalence of this disease across the entire population.This variation in proportion of CRC occuring at an earlier age may reflect the expected lifespan of these sub-group in particular countries, as well as genetic background and a greater sensitivity to Western lifestyle risk factors (Table 1).For example, in the USA, incidence rates were reported to be higher among African Americans aged between 20-40 years than non-Hispanic  concentration of bile salts and the microbial enviroment [67].

Hereditary and Family High-Risk of CRC Cases
It is reported that up to 30% of bowel cancer patients have a strong family history of the disease, and 5% of those are due to a demonstrable inherited genetic abnormality [68].Compared to individuals without a family history of CRC, people with a firstdegree family history of CRC have two to four times the risk of developing this cancer [69].In Australia, 16% of CRC patients have at least one first-degree relative with bowel cancer [70].
However, this figure is lower in Sweden and Finland as ~11% to 13% of all CRC cases have at least one first-degree relative with CRC [70][71][72].Hereditary and family history risk factors can induce the development of EOCRC and form a group of people with higher risk relative to the general population who should be under closer cancer surveillance [73].However, given that hereditary CRC is under closer surveillance in current times, it is unlikely that this group of patients are responsible for the increase in incidence in EOCRC.
Lynch syndrome (LS) is the most frequently diagnosed of the EOCRC inherited syndromes, accounting for up to 17% of all CRC cases [74] (Tables 1 and 2).2).SPS accounts for a currently unknown proportion of EOCRC.

Risk Factors and Microbiota
Different lifestyle-related risk factors including obesity and diabetes have been associated with the significant increase in the prevalence of EOCRC (Table 3).In Australia, the prevalence of obesity and overweight have increased [101], and from 1985-2012, childhood obesity has also grown among Australian's children [102].

Inflammatory bowel diseases (IBDs)
People with IBDs have a two to threefold higher risk of developing CRC. [107]

Physical Inactivity
Least active individuals are by 27% at higher risk of susceptibility to CRC. [110]

Obesity
Obese or overweight women have double the risk of developing bowel cancer under age 50 years compared to healthy body weight women. [111]

Meat Consumption
Red meat and processed meat increase the risk of CRC by 30% and 20%, respectively. [112]

Fibre
Swedish women with a high intake of vegetables and fruits had 32% risk reduction for bowel cancer.[113] Calcium T risk of CRC was about 70% lower in people with the highest consumption of Ca+2 compared to people with the lowest calcium intake. [

114]
Vitamin D There was a considerably lower risk of developing CRC in people with a high blood level of vitamin D (1,25(OH)2D3) and high lymphocyte accounts. [115]

Alcohol
A modest increased risk of colon tumour (45%) and rectal tumour (49%) with regular high intake of alcohol (>45 g/day) in both genders combined in relative non-drinkers. [116]

Smoking
Smokers were 2-fold at higher risk of advanced neoplasia than non-smokers, similar to or higher than those patients that have the first-degree relative with this disease.[117,118] DOI: https://doi.org/10.30654/MJCS.10018 adults have increased in parallel to the increase in EOCRC, and an independent relationship is yet to be clearly demonstrated.

Nguyen et al., has recently reported a significant association
between increased risk of EOCRC and sedentary TV watching time after adjusting the persumed risk factors such as lack of exercise and obesity [105].Additionally, there is a consistent relationship between type 2 diabetes and CRC, and this is likely to be more pronounced in young adults under 55 years [106].In summary, lifestyle factors involving activity level and metabolism issues are the most liekly contenders for the increase in the incidence of EOCRC.
The microbiota may play a role through impacting on host metabolism, and through the transmission of metabolic and even CRC risk factors in non-Mendelian familial aggregation, as has been shown in co-housed preclinical animal models [119].Obesity and diabetes, and CRC itself have been linked to changes in the gingival and gut microbiota in humans.Though there have been multiple findings suggesting causation in animal models, a number of confounding factors such as genetic background, and stress may have played a role.It is currently not definitively known whether these observations are readily translated into human settings and whether human studies suggest direct causation or setting-associated colonisation in a predisposed host.For example, findings in humans of insulin sensitivity being improved in obese subjects after faecal transplantation into the small intestine from lean donors [120], indicate that microbiota in the obese do not necessarily cause obesity, but that a certain element of the microbiota from lean individuals lacking in the obese can modify insulin sensitivity.Similarly, obese patients who experienced weight loss had improved response to periodontal therapy over those who remained obese with persisting gum disease [121,122], could be interpreted as setting-associated.
The composition of bacteria chronologically alters as people age, as well as depending on location within the bowel [123,124].
Some species of bacteria have been recognized to have a role in investigating bowel cancer pathogenesis such as Bacteroides fragilis, Fusobacterium nucleatum, Streptococcus bovis, and some strains of Escherichia coli.Findings of studies in older CRC patients showed a significant role of F. nucleatum in the pathogenesis of CRC, particularly in the right-side cancers [124].Other studies found that F. nucleatum travels as bowel cancer metastasizes in mice, and murine cancers with this bacterium respond to the metronidazole antibiotic [125].
However, while it can be postulated that microbiota might be involved, there is not yet much convincing evidence in an area which is difficult to research.Also, it is currently not known whether the microbiota has a role in EOCRC.

Survival rate, Prognosis and Clinical Features of EOCRC
The overall 5-year survival rate of CRC for all stages combined from diagnosis is approximately 69% in Australia [126]

Molecular Characteristics of Sporadic EOCRC
Approximately 65% of CRC is sporadic with no apparent hereditary genetic predispositions or family history [154,155].Though EOCRC raises the likelihood of a hereditary predisposition, only the minority of CRC cases in young adults (15% to 20%) are due to the hereditary syndromes [60,156], which is slightly higher than all CRC cases (2% to 8%) [157].Among EOCRCs and in the general population, the adenoma-carcinoma pathway contributes to the development of approximately 85% of all CRCs.In contrast, evidence has shown that about 15% to 30% of CRCs exhibit the features of an alternative serrated neoplasia pathway [158][159][160].There are three underlying molecular mechanisms which have been described in the development of CRC: chromosomal instability (CIN), microsatellite instability (MSI) and CpG methylator phenotype (CIMP) [161].These three mechanisms are not mutually exclusive and may overlap in some subsets of CRC [158][159][160][161][162].
Studies have consistently shown that the prevalence of KRAS/ RAS and BRAF mutations, as well as MSI, is higher in rightside colon tumours than left-side [191][192][193][194].This is clinically relevant given survival benefits with selective anti-EGFR inhibitors are higher in patients with left-side RAS wild-type colon tumours compared to the individuals with proximal colon tumours.The differing prevalence of primary site may lead to survival implications based on age.For female EOCRC estrogen may play a role as some studies have suggested that estrogen might be a protective factor for the development of CRC in the proximal colon.As its level decreases with age, this may result in the increasing prevalence of proximal colon tumours in female adults above the age of 50 years [195].
Evidence for this hypothesis comes from reports that women with higher estrogen exposure were more protected against high-MSI cancers which are very often found in the proximal colon [196].However, a tumour mutational burden (TMB) is more frequent in young adults with left-sided colon tumour than their older counterparts (9.7% vs 2.8%, P<0.001).TMB may have relevance to immunotherapy options for this group of patients [197].For example, although RAS WT is higher in leftsided cancer, there is a higher rate of HER2 amplification and NF1muattions in young adults with left-sided colon tumour than older individuals [197] which may have clinical relevance.
Therefore, though there is a difference in the proportion of mutations between EOCRC and LOCRC, this may reflect, at least in part, the different site distrubution of CRC between the two age groups.

Treatment
CRC patients are generally treated in a standardized way based on current guidelines [198,199].Sporadic CRC in individuals younger than 50 years may have a different molecular profile, and treatment may differ based on this [136,197,200,201], but ultimately the therapeutic strategy will be guided by the exact profile rather than age.There are subtle but real differences that may reflect age.For example, guidelines allow choice of first-line systemic chemotherapy schedules, which may vary from single-agent fluoropyrimidine to triplet therapy (FOLFOXIRI), although in general doublet chemotherapy is recommended [202].However, data from registries do suggest that young adults with CRC tend to receive more aggressive chemotherapies compared to older patients with this disease.
This is probably because these patients can tolerate more aggressive regimens and the misconception that EOCRC patients have worse treatment outcomes.EOCRC patients more commonly receive adjuvant therapy more often with multiagent adjuvant regimens.Despite this trend, there is little evidence this improves outcome significantly.For example, Kneuertz et al., showed no survival gain in their analysis for patients diagnosed with stage II CRC (RR, 0.90; 95% CI, 0.69-1.17).A minor survival benefit may exist for those diagnosed at stages III-IV (RR, 0.89; 95CI, 0.81-0.97)[136].However, further evidence is required to which subgroups may benefit most [150].Surgical intervention does appear to differ by age, with resection of primary cancer more commonly performed in young adults with metastatic CRC (mCRC) compared to older mCRC patients (70.8% versus 66.6%; P < 0.001) [14, [203][204][205].Resection of primary may impact on the outcome by preventing future complications [204][205][206] and may impact on survival [145,204,205,[207][208][209][210].
EOCRC patients are also more likely to undergo radiation therapy in the setting of metastatic rectal cancer than

Figure 1 :
Figure 1: Age-adjusted SEER incidence rates of CRC from 1990 to 2015 among people under and above 50 years of ages in the USA.Graph (A) shows the incidence of CRC in people under the age of 50 years.Graph (B) shows the incidence of CRC in people above the age of 50 years.(https:// seer.cancer.gov/faststats/selections.php?#Output).

Whites [ 57
].In New Zealand, even though the death rates of young-onset CRC were similar among Pacific, non-Mâori non-Pacific and Mâori people by 1996-99, the death rates had accelerated up to 10-fold among Pacific people, by 50% among Mâori and decreased by 10% to 20% among non-Mâori non-Pacific people during 1981 to 1995 [58].

SMAD4
and DCC genes, is more common in LOCRCs than EOCRCs[182][183][184].In contrast, EOCRCs lose the chromosomal regions which code for CRC markers (TJP2)[185][186][187] and FOX transcriptional factors[188], and gain regions coding for AMPkinase regulatory subunit and BMPR1A[185].Puccini et al., reported that mutations in genes such as KDM5C, KMT2A, KMT2D and SETD2 which are involved in the modification of histones are higher in EOCRCs than LOCRC.MSI-H, which represents ~21% of the EOCRC, is characterized by the inability of the MMR system to maintain the DNA structure or to correct errors during the process of DNA replication as well as by accumulation of point mutations and changes in the repetitive microsatellite nucleotide sequences[146,147,173,175].MSI-H cancers in EOCRC are mostly linked to LS, with some cases having epigenetic inactivation of MLH1 and wild-type BRAF which are categorized as epimutation-type LS.CIMP has been shown to contribute to approximately 40% of all CRCs and is involved in the alternative serrated neoplasia pathway[155,189].This pathway is categorized by high methylation of CpG islands and early BRAF mutations.Hypermethylation of the MMR gene MLH1 is also frequently reported in this pathway, and can result in diploid CRCs that are MSI.Tumours which are CIMP-high are usually found in the right-side colon, have high-MSI, a higher rate of BRAF mutations and are poorly differentiated.CRC with CIMP and BRAF that are MSI-H are mostly observed in LOCRC.Tumours which are

Table 1 .
The prevalence of early-onset CRC in different countries.

Table 2 :
Summary of the main hereditary and familiarly high risk CRC syndromes.

Syndrome Inheritance Gene The average age of CRC diagnosis CRC lifetime risk factor Incidence in EOCRC Clinicopathological features
[97]her syndrome of CRC predisposition is serrated polyposis syndrome (SPS).SPS is under recognized and is characterized by the presence of many serrated polyps in the colon and rectum[97].Boparaiet al., found CRC in 35% of individuals with SPS, with the majority of cases (94.5%) being diagnosed with CRC at the time of SPS diagnosis.However, 6.5% of patients [99,100]h syndrome, FAP; Familial Adenomatous Syndrome, MAP: MUTYH-Associated Polyposis, SPS: Serrated Polyposis Syndrome.MUTYH-Associated Polyposis (MAP) is another subtype of polyposis which has an autosomal recessive transmission,and is related to bi-allelic germline mutations in the mutY DNA glycosylase (MUTYH) gene[93].MAP patients have a lifetime risk of developing CRC of 43% to 100%, at an average age of 48 years, with about 50% of cases presenting with cancer at the time of diagnosis[94,95].The phenotypes of AFAP and MAP syndromes are often indistinguishable.There are currently, no exact phenotypes of the MAP condition.Some reports show one single CRC and no or less than ten polyps, or cases presenting with mostly hyperplastic/serrated polyps[96], while proximal adenomas are also commonly seen.Moreover, the cancers related to MAP syndrome are more likely to be found in the proximal side of the colon in comparison to the AFAP related tumours[95].Germline mutations in the MUTYH have also been reported in patients with LLS (Table2).wereundersurveillanceforSPSwhile diagnosed with CRC[98].Currently, 40% to 60% of SPS patients demonstrate a family history of bowel cancer rather than of polyposis.Nevertheless, it is worth noting that the exact patterns of inheritance of this syndrome are still not clear, and autosomal recessive alleles and autosomal dominant alleles are suggested[99,100](Table

Table 3 :
Some factors associated with the risk of colorectal cancer (CRC).
older counterparts[14].Radiation therapy for the rectal primary in metastatic disease is used to control the local recurrence rate.There are few studies regarding the recurrence rate of rectal cancer in young adults compared to their older counterparts after radiation therapy.However, You et al., reported that the recurrence incidence of the tumour was higher in young adults with rectal cancer, especially distant Comparing colorectal cancer treatment and survival for Aboriginal and non-Aboriginal people in New South Wales.Med J Aust. 204(4): 156.60.Siegel RL, Jemal A and Ward EM. (2009).Increase in incidence of colorectal cancer among young men and women in the United States.Cancer Epidemiol Biomarkers Prev.18(6): 1695-1698.61.Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, et al. (2017).Lee SY, Song WH, Oh SC, Min BW, et al. (2018).Anatomical distribution and detection rate of colorectal neoplasms according to age in the colonoscopic screening of a Korean population.Ann Surg Treat Res.94(1): 36-43.64.Andrea B-H, John DP, Jessica C, Douglas C, et al. (2018).surgery among elderly patients with stage IV colorectal cancer.J Clin Oncol.22(17): 3475-3484.207.Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, et al. (2011).Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature.Ann Surg Oncol.18(12): 3252-3260.208.Karoui M, Roudot-Thoraval F, Mesli F, Mitry E, et al. (2011).Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study.Dis Colon Rectum.54(8): 930-938.209.Ferrand F, Malka D, Bourredjem A, Allonier C, et al. (2013).Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicenter, randomised trial Federation Francophone de Cancerologie Digestive 9601.Eur J Cancer.49(1): 90-97.210.Stillwell AP, Buettner PG and Ho YH. (2010).Meta-analysis of survival of patients with stage IV colorectal cancer managed with surgical resection versus chemotherapy alone.World J Surg. 34(4): 797-807.211.You YN, Dozois EJ, Boardman LA, Aakre J, et al. (2011).Young-onset rectal cancer: presentation, pattern of care and long-term oncologic outcomes compared to a matched older-onset cohort.Ann Surg Oncol.18(9): 2469-2476.212.Fossum CC, Alabbad JY, Romak LB, Hallemeier CL, et al. (2017).The role of neoadjuvant radiotherapy for locallyadvanced rectal cancer with resectable synchronous metastasis.J Gastrointest Oncol.8(4): 650-658.Mikaeel RR, et al. © 2019.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.