Prognostic Biomarkers in Colorectal Cancer: Comparison
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Please note this is a comparison between Version 2 by Bruce Ren and Version 1 by Christine Koulis.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects.

  • biomarkers
  • colorectal cancer
  • predictive
  • prognostic
  • organoid
  • consensus molecular subtypes

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1. Introduction

Colorectal cancer (CRC) represents the third most common cancer in developed countries and is a leading cause of cancer deaths worldwide [1], highlighting the need to study predictive markers for response to available and emerging therapies. Treatment for CRC is largely determined by the pathologically based tumor/node/metastasis (TNM) staging system. The evolving understanding of the genetic heterogeneity of CRC suggests however, that a purely pathologic classification is insufficient to determine optimal therapy. The model of progressive stepwise accumulation of genetic and epigenetic events leading to adenoma and carcinoma formation is well described [2]. This includes ‘driver’ alterations in tumor suppressor genes and oncogenes, leading to the currently utilized predictive and prognostic clinical biomarkers such as microsatellite instability (MSI) due to deficient mismatch repair (dMMR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF) and mutational status of various single genes (e.g., KRAS and BRAF).
In this review, we discuss current prognostic and predictive clinical biomarkers, including those that guide therapy and those associated with familial cancers (summarized in Table 1). The advent of new technologies characterizing the molecular mechanisms underlying tumorigenesis has resulted in the emergence of many potential new biomarkers, including consensus molecular subtypes (CMS), stem cell markers, circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), genetic alterations, immune- and apoptosis-related biomarkers, which will be outlined in this review (summarized in Table 2).
Table 1. Current clinical biomarkers and their clinical utility.
Clinical Biomarkers Role Clinical Utility References
Table 2. Potential emerging biomarkers and their clinical utility.
Emerging Biomarkers Potential Role Potential Clinical Utility References
dMMR Diagnosis/Therapy choice Widespread use. Testing for loss of DNA MMR proteins (MLH1, MSH2, MSH6, PMS2) is typical of Lynch Syndrome/HPNCC. Used to indicate contraindication for the use of fluoropyrimidine chemotherapy. [3,4,5,6,7,8,9][3][
CMS Therapy Choice4][5][6][7][8][9]
CMS4 tumors may predict whether a patient responds to irinotecan.

CMS2 and possibly CMS3, tumors benefit from addition of bevacizumab to first line capecitabine-based chemotherapy in mCRC. [35,36][35][36] MSI Diagnosis/Prognosis/Therapy choice Widespread use. MSI tumors have a better prognosis. May suggest possible resistance to fluoropyrimidine chemotherapy. MSI-H tumors are highly responsive to immunotherapy. [10,11][10][11]
KRAS Prognosis/Therapy choice
CIMP Prognosis Tumors with hypermethylation in the promoter regions of tumor suppressing genes with MSI and BRAF mutations have a good prognosis. Tumors that are CIMP positive, MSI negative and BRAF mutated have poor prognosis. [37,38,39,40,41,42,43][37][38][39][40][41][42][43] KRAS mutations indicate unresponsiveness to EGFR-ab therapies. [12
DNA aneuploidy Prognosis,21,22][1213,][1314,][14 DNA aneuploidy is linked to poor prognosis in Stage II-III CRC.15,][1516,][1617,]18,17][18]19,[20,[19][20][21][22]
[44,45,46,47,48][44][45][46][47][48] BRAF Prognosis BRAF
Stem cell markers mutations indicate a decreased survival rate. Prognosis[23,24][23] ‘Stem cell signature’ on cancer cells is associated with more aggressive tumors and predicts disease relapse.[24]
[49,50,51,50][52,51][53,52][54,53][55,54][56,55][57,58][49][56][57][58] CEA Diagnosis/Prognosis Widespread use. A rising CEA post-surgery often correlates with relapse. [25,
ctDNA and cfDNA26,27,28][25][26][27][28]
Prognosis ctDNA in blood tests could be used to predict whether a patient would relapse following surgical resection. cfDNA in blood tests could predict shorter overall survival and inferior recurrence free survival. [59,60,61,[61]62,[62]63,[63]64,[64]65,66,67][59][60][65][66][67] UGT1A1*28 Therapy choice UGT1A1*28 polymorphism is associated with irinotecan toxicity.
RAS Prognosis/Therapy choice Testing for RAS in patient blood may predict whether a patient will be resistant to EGFR-ab therapies.[29]
[68,69,70][68][69][70] DPD Therapy choice DPD deficiency may lead to life threatening toxicity of fluoropyrimidine chemotherapy. [30]
PIK3CA mutations Prognosis/Therapy choice Mutations in PIK3CA may be predictive for the effectiveness of adjuvant aspirin therapies. [71,72,73,74,75,,81][76,71][77,7278,79,][73][74][75][76][77][78][79]80[80][81] APC Diagnosis PrognosisAPC mutations are common in the autosomal dominant FAP syndrome, with confirmation of FAP by colonoscopy. Loss of PTEN in tumors is associated with shorter progression free survival.[31,32,33][31][32][33]
PTEN [82,83,84,85,86][82][83][84][85][86] SMAD4, BMPR1A Diagnosis 40% of Juvenile polyposis syndrome (JPS) cases have SMAD4 and BMPR1A gene mutations. [34]
TYMS, EGFR
and
p21
Prognosis/Therapy choice
Low expression of TYMS and EGFR is associated with increased tumor regression rates. Low p21 expression may be associated with improved survival in rectal cancer.
[87,88,[89,88][90,89][91,92][87]90][91][92]
18q loss of heterozygosity (LOH) Prognosis 18q LOH predicts lower overall survival in CRC. [93,94,95,][93]96,[94]97,[98,99,95][96][97][98][99]100[100]
TIL Prognosis High density of TILs is correlated with better survival. [101,102,103,104,105][101][102][103][104][105]
Bcl-2 Prognosis Loss of Bcl-2 expression is correlated with tumor recurrence. [106,107,108,109,110,111,112][106][107][108][109][110][111][112]

2. An Overview of CRC Classification and Molecular Pathways

CRC is a heterogeneous disease that can be currently classified according to its global genomic status in terms of MSI and chromosomal instability (CIN) and epigenomic status as expressed by CpG island methylator phenotype (CIMP). These molecular genetic and epigenetic changes act to dysregulate conserved signaling pathways resulting in the transformation of normal colonic epithelium to an intermediate adenoma and ultimately to an adenocarcinoma.
The CIN pathway is responsible for approximately 65–70% of sporadic CRC [113] and is characterized by an imbalance in chromosome number (aneuploidy), chromosomal genomic amplifications and a high frequency of loss of heterozygosity (LOH), commonly occurring through mutations in APC and KRAS [114]. A small proportion of CIN tumors are inherited and arise secondary to germline mutations in the APC gene as seen in familial adenomatous polyposis (FAP) or the MUTYH gene (as seen in MUTYH-associated polyposis) [115].
The MSI pathway occurs in 15% of CRC and can be sporadic. This pathway is characterized by dMMR proteins resulting in insertion and deletion mutations in stretches of short tandem DNA repeats (microsatellites) as well as nucleotide substitutions throughout the genome. The detection of instability is identified via a PCR-based assay categorizing tumors as either MSI-high (MSI-H), MSI-low (MSI-L) or microsatellite stable (MSS), based on the number of microsatellite markers demonstrating instability [116].
The CIMP pathway is characterized by epigenetic alterations, resulting in changes in gene expression or function without changing the DNA sequence of that particular gene. These epigenetic changes are usually caused by DNA methylation or histone modifications. DNA methylation occurs commonly at the 5′-CG-3′ (CpG) dinucleotide. Methylation of gene promoter region results in gene silencing, thus providing an alternative mechanism for loss of function of tumor suppressor genes. Genes involved in CRC that are silenced by DNA hypermethylation include APC and MLH1 [113]. Testing for CIMP is performed via PCR for hypermethylation in CACNA1G, MLH1, NEUROG1, RUNX3 and SOCS1 [37].
The classification of CRC consensus molecular subtypes (CMS) was formed in an effort to understand the heterogeneous clinical and drug outcomes observed in CRC patients, even when controlled for similar pre-operative prognostic features, tumor stage and clinicopathological characteristics [117,118,119,120,121,122][117][118][119][120][121][122]. Each CMS has distinguishing expression data and pathways and are designated CMS1 (microsatellite instability immune), CMS2 (canonical), CMS3 (metabolic), CMS4 (mesenchymal) and a mixed features phenotype representing transitional or intratumoral heterogeneity [123]. CMS can be determined through gene expression analysis, however, recently five immunohistochemistry-based classifiers, CDX2, FRMD6, HTR2B, ZEB1 and KER have been identified that demonstrate 87% concordance with traditional transcriptome-based classification [124]. The recent classification of four CMS may form the basis for future clinical stratification of CRC with subtype-based targeted interventions.

3. An Overview of Current CRC Therapeutics

The current medical treatment for CRC involves a mix of surgery, chemotherapy protocols and the inclusion of monoclonal antibody therapy [125]. Selected treatment options are now dependent on a range of factors including stage, patients’ health status, initial treatment intent (curative vs. palliative), clinical features such as tumor location and molecular factors (e.g., RAS, BRAF mutational status). These factors play important prognostic roles and may also predict a patient’s response to treatment.
Fluorouracil (5-FU; an anti-metabolite fluoropyrimidine agent) continues to be the most widely used agent for CRC and provides modest improvements in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS) and response rate (RR) both in the adjuvant setting and in metastatic CRC (mCRC) [126]. Oxaliplatin and irinotecan (anti-neoplastic agents) and antibodies targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), have provided incremental gains in RR, PFS and OS in advanced disease, with only oxaliplatin enhancing fluoropyrimidine-based adjuvant chemotherapy.

4. Current Prognostic and Predictive Biomarkers

Clinical biomarkers can be prognostic, predictive or both. Prognostic biomarkers are an independent measure of the course of a disease in an untreated population. The presence or absence of a biomarker is associated with a patient’s overall clinical outcome (i.e., risk of recurrence and mortality). Prognostic biomarkers in CRC provide treatment-independent prognostic information on patient outcomes and include dMMR/MSI, KRAS, BRAF and CEA. Conversely, predictive biomarkers help to assess whether a biomarker-positive individual will respond beneficially to a specific therapeutic intervention. In CRC, predictive biomarkers for toxicity to irinotecan and 5-FU include, UGT1A1 and dihydropyrimidine dehydrogenase (DPD) deficiency, respectively. Lastly, a biomarker that confers both prognostic and predictive qualities in CRC is primary tumor location; right-sided CRC is associated with a poorer prognosis than left-sided CRC [127] and left-sided CRC predicts response to EGFR-targeted therapies [12]. Current prognostic and predictive biomarkers are discussed in this section and summarized in Table 1.

4.1. Biomarkers that Guide Therapy

4.1.1. Mismatch Repair Deficiency (dMMR)

DNA damage repair proteins exist to facilitate the replication of normal cellular DNA [3]. The MSI phenotype results when this protective mechanism is lost through dMMR. Critical mismatch repair (MMR) proteins involved in proofreading and correction of insertion-deletion loops include MLH1, MSH2, MSH6 and PMS2. Deficiencies in MMR can occur through either a germline mutation in an MMR gene (MLH1, MSH2, MSH6 and PMS2), resulting in Hereditary Nonpolyposis Colorectal Cancer (HNPCC) also known as Lynch syndrome, however, this condition occurs more commonly through sporadic epigenetic inactivation of MLH1 [3]. The latter is generally associated with hypermethylation of promoter regions of cancer-specific genes known as the CIMP-H.
Currently, the routine use of adjuvant chemotherapy is not recommended in stage II CRC patients. Exceptions to this include those at higher risk of recurrence, for example tumors with adverse features such as poor differentiation, lymphovascular or perineural invasion and younger age patients. dMMR provides a molecular, tailored approach to stratifying patients based on their potential response to chemotherapy. Sargent and colleagues described dMMR as a predictive biomarker for poor response to FU-based adjuvant therapy in stage II and stage III colon cancer [4]. This is highlighted in their study of 457 colon cancer patients who were randomly assigned to either FU-based therapy or no post-surgical treatment. Patients with dMMR tumors receiving FU-based therapy had no improvements in DFS (hazard ratio [HR], 1.10; 95% CI, 0.42 to 2.91; p = 0.85), when compared to those assigned to surgery alone. In contrast, patients with microsatellite-stable or proficient MMR (pMMR) tumors, receiving adjuvant therapy, demonstrated significantly improved DFS (HR, 0.67; 95% CI, 0.48 to 0.93; p = 0.02) [4]. Similarly, in an Australian cohort study, patients with dMMR, despite not being given adjuvant chemotherapy, still had excellent outcomes [5]. These studies support the concept that adjuvant chemotherapy in stage II colon cancer patients with high dMMR results in minimal OS benefit (2–3%) and as such it is not routinely recommended [4,5,6][4][5][6].
MSI high tumors are associated with a better prognosis in curative settings, however, in mCRC, it appears to confer a negative prognosis. As a predictive biomarker, a large amount of evidence suggests possible resistance to 5-FU in MSI-H tumors [10]. This is due to the high mutational load eliciting an endogenous immune anti-tumor response, which is counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, resisting tumor elimination [11]. Based on these considerations, MSI-H CRCs are highly responsive to immunotherapy, such as anti-PD-1 [11]. Current guidelines recommend MSI testing in all CRC patients, to not only identify HNPCC but to guide adjuvant treatment decisions and to identify patients likely to benefit from immunotherapy in stage IV disease.
HNPCC is an autosomal dominant condition caused by genomic mutations in DNA MMR genes, MLH1, MSH2, MSH6 and PMS2 [7]. Inactivating mutations in the MMR result in a high level of MSI (MSI-H) and subsequently an increased risk of cancer, particularly colon and endometrial [8].

4.1.2. KRAS

KRAS belongs to the RAS family of oncogenes and is mutated in 40–50% of CRCs [13], most commonly via point mutations [14,15][14][15]. Whilst some studies have suggested a prognostic role for RAS [16[16][17][18][19],17,18,19], its main utility is as a predictive biomarker. Tumors with a mutation in codon 12 or 13 of exon 2 of the KRAS gene are essentially unresponsive to EGFR-antibody (EGFR-ab) therapy. Similarly, mutation in KRAS outside of exon 2 and mutation in NRAS are predictive for poor response to EGFR-ab therapy [20,21][20][21]. This is also highlighted in studies by Karapetis et al. and Amado et al., who demonstrated that KRAS predicts response to cetuximab and panitumumab in advanced CRC, respectively [68,69][68][69]. The study by Karapetis et al., correlated tumor mutation status of the KRAS gene with survival in advanced CRC patients receiving either cetuximab or supportive care. Their study found that for patients with wild-type KRAS tumors (KRASWT), treatment with cetuximab as compared with supportive care alone significantly improved OS (median, 9.5 vs. 4.8 months; HR for death, 0.55; 95% CI, 0.41 to 0.74; p < 0.001) and PFS (median, 3.7 months vs. 1.9 months; HR for progression or death, 0.40; 95% CI, 0.30 to 0.54; p < 0.001) [68]. Similarly, Amado and colleagues assessed the impact of KRAS mutations on PFS in mCRC patients on PFS following treatment with panitumumab. They found PFS was significantly greater in patients receiving panitumumab with KRASWT, (HR, 0.45; 95% CI: 0.34 to 0.59) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36) [69]. These practice-changing discoveries have defined restrictions for the use for EGFR-ab therapy to patients with mCRC with wild-type RAS (RASWT), sparing up to 60% of patients’ futile exposure to toxicity and saving needless cost [22].
An additional consideration in RASWT patients is the impact of tumor sidedness on targeted therapy. A recent study by Holch and colleagues investigated the prognostic and predictive relevance of primary tumor location. Their meta-analysis of first line clinical trials concluded that patients with left-sided RASWT mCRC had significantly greater survival benefit from anti-EGFR treatment compared with anti-VEGF treatment when added to standard chemotherapy (HR, 0.71; 95% CI, 0.58–0.85; p = 0.0003). In contrast, patients with right-sided RASWT mCRC demonstrated significantly improved PFS when treated with chemotherapy plus VEGF-ab therapy (HR, 1.53; 95% CI, 1.16–2.01; p = 0.003) [12]. Nonetheless, due to the molecular heterogeneity within left- and right-sided tumors, caution regarding treatment decisions needs to be exercised when basing therapy on the location of tumor in the colon [123,128][123][128].

4.1.3. BRAF (V600E)

The prognostic impact of the most common BRAF mutation in mCRC, BRAFV600E, is well characterized [129]. The survival rate of patients carrying the mutant form is decreased by approximately 50% compared to patients with wild-type BRAF (BRAFWT) [130,131,132,133][130][131][132][133]. This is highlighted in a pooled analysis of the CAIRO, CAIRO2, COIN and Focus studies, where patients with BRAF mutations demonstrated worse median PFS and OS compared with patients that had BRAFWT tumors (PFS: 6.2 vs. 7.7 months, respectively; HR, 1.34; 95% CI, 1.17–1.54; p < 0.001; OS: 11.4 vs. 17.2 months, respectively; HR, 1.91; 95% CI, 1.66–2.19; p < 0.001) [133]. However, it is important to note that not all BRAF mutations exhibit the same clinical behavior. One previous study has suggested that BRAFnon-V600E mutations have more favorable outcomes compared to BRAFV600E mutation or BRAFWT tumors in mCRC (60.7 vs 11.4 vs. 43.0 months, respectively; p < 0.001) [23]. In addition to prognostic implications, BRAF mutations may serve as a predictive biomarker for triplet combination therapy of mitogen-activated protein kinase (MEK), BRAF inhibition plus EGFR-targeted therapies. This is highlighted in a recent phase II study by Corcoran and colleagues who found patients with BRAFV600E mCRC receiving triplet therapy had a 21% response rate (95% CI, 12.5–43.3%) compared to 10% response for patients in the dabrafenib plus panitumumab arm (95% CI, 1.2–31.7%) [134]. In addition, the ongoing phase III BEACON CRC trial, where patients are receiving triplet combination of binimetinib, encorafenib and cetuximab, demonstrated an overall response rate of 48% (95% CI, 29.4% to 67.5%), median PFS of 8 months (95% CI, 5.6 to 9.3 months) and median OS of 15.3 months (95% CI, 9.6 months to not reached) [135]. Based on these results, the US Food and Drug Administration (FDA) granted a Breakthrough Designation to this triplet therapy for BRAFV600E CRC patients whom failed one or two prior lines of therapy for metastatic disease [136].
Somatic BRAF mutations, most frequently V600E, have been described in a significant proportion of sporadic MSI-H CRC but not in HNPCC. Thus, clinical BRAF mutation testing has been proposed as a means to identify MSI-H CRC cases that do not require germline MMR gene testing [24].

4.1.4. Carcinoembryonic Antigen (CEA)

CEA is one of the most extensively used tumor markers worldwide [25]. Despite its poor sensitivity and specificity [26[26][27],27], a rising CEA post curative surgery often correlates with relapse. Thus, CEA is useful in providing early detection of recurrence and allows clinicians a means for early detection and surgical resection of metastases [25,28][25][28]. The benefits of CEA as a reliable predictor or recurrence and survival after curative surgery in patients with CRC is highlighted in a recent retrospective study by Baqar and colleagues. In their study of 623 CRC patients, elevated CEA (≥5 ng/mL) was a predictor of recurrence (HR, 1.8; 95% CI, 1.09–3.00; p = 0.002) and of OS (HR, 7.79; 95% CI, 1.00–3.19; p = 0.046) [28].

4.1.5. Irinotecan Toxicity and UGT1A1*28

Irinotecan hydrochloride is an anti-neoplastic topoisomerase inhibitor that is widely used in combination with 5-FU and leucovorin chemotherapy for first line treatment of mCRC and as a single agent in second-line salvage therapy of 5-FU refractory mCRC. The principle dose-limiting toxicities associated with irinotecan are delayed diarrhea and severe neutropenia; these toxicities are reversible, not cumulative and related to irinotecan dose [137]. Irinotecan is metabolized into toxic 7-ethyl-10-hydroxycamptothecin (SN-38) via the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A (UGT1A) and the inactivated byproduct, SN-38, excreted in bile. The effect of genetic polymorphisms of the UGT1A1 gene in predicting irinotecan-associated toxicity has gained interest. Currently, over 100 genetic variants of UGT1A1 exist, the wild-type allele, UGT1A1*1, being associated with normal enzyme activity and the most common variant allele, UGT1A1*28, being investigated as a cause for increased irinotecan toxicity [138]. The findings from four pharmacogenetic trials, assessing the impact of several UGT1A1 variants, found that patients homozygous for UGT1A1*28 experienced significantly more serious hematological side effects [139,140,141,142][139][140][141][142]. Based on this evidence, the United States (US) Food and Drug Administration (FDA) amended the irinotecan label in 2005 to include UGT1A1*28/*28 as a risk factor for severe neutropenia, stating that when administered as a single-agent, a reduction in the starting dose by at least one level or irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele [138]. In addition, Hoskins and colleagues performed a meta-analysis assessing the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) based on UGT1A1 variants. Their findings concluded that the risk of toxicity was higher among patients with UGT1A1*28/*28 genotype than among those with UGT1A1*1/*1 or UGT1A1*1/*28 genotype for both medium (OR = 3.22; 95% CI, 1.52 to 6.81; p = 0.008) and high (OR = 27.8; 95% CI, 4.0 to 195; p = 0.005) doses of irinotecan, only. Despite black box warnings in the US by the FDA, these warnings have not been replicated in other jurisdictions such as Australia most likely due to conflicting studies [143,144,145][143][144][145]. In summary, despite the significance of UGT1A1*28 as a potential biomarker for irinotecan toxicity, genotyping for UGT1A1 is not current clinical practice for determining risk of hematologic toxic effects. Instead, the current clinical protocol suggests close clinical monitoring for patients receiving irinotecan, particularly during the first cycle of chemotherapy, with drug doses adjusted based on standard clinical tests such as white blood cell counts.

4.1.6. 5-FU Toxicity and DPD Deficiency

The DPYD gene encodes the enzyme dihydropyrimidine dehydrogenase (DPD), which functions as the rate-limiting step in the metabolism of fluoropyrimidine chemotherapies [146]. Greater than 80% of 5-FU is metabolized by DPD, with factors such as age, race, comorbidities and concomitant therapies influencing metabolism. Reduced activity of DPD impacts on the ability to metabolize 5-FU at normal rates and may result in life threatening toxicity [30]. DPYD variants that do not affect DPD activity in a clinically relevant manner include c.85T > C, *9A, rs1801265, p.C29R; c.1627A > G, *5, rs1801159, p.I543V; c.2194G > A, *6, rs1801160, p.V7321. Conversely, variants that have been shown to have deleterious effects on DPD activity, resulting in 5-FU toxicity, include DYPD*2A and DPYD*13. While variants c.2846A > T and c.1129–5923C > G have been shown to have moderately reduced DPD activity [147]. A multicenter study of 17 hospitals assessing DPYD genotype-guided dosing in patients receiving fluoropyrimidines (capecitabine or fluorouracil) was carried out by Henricks and colleagues [148]. Their study found DPYD genotype-based dose reductions improved patient safety and fluoropyrimidine treatment. Specifically, patients with either the DPYD*2A or c.1679T > G variant benefited from an initial 50% dose reduction of fluoropyrimidines. While patients that were c.1236G > A or c.2846A > T carriers, a 25% dose reduction was not enough to lower the risk of severe toxicity and a larger dose reduction of 50% was suggested in these patients. The authors highlight the need for additional prospective studies to validate and further refine these findings [148]. Currently prospective testing for DPYD mutations is not routinely performed in clinical practice due to associated costs (approximately $300 in Australia) and long test turnaround times (3–4 weeks) which can be unsatisfactory for developing a therapeutic strategy for patients who require immediate treatment. Thus, for DPYD testing to be routinely used in clinical practice, the problematic turnaround time and lack of funding for tests are barriers that would need to be overcome.

4.2. Biomarkers Associated with Familial Cancer Syndromes

4.2.1. Adenomatous Polyposis Coli (APC)

APC is a tumor suppressor gene that is mutated in more than 80% of CRCs and is a common germline mutation in the autosomal dominant FAP syndrome [31]. This disease is characterized by numerous colonic adenomas which, without recognition and intervention, results in the development of early-onset CRC [32]. Clinical diagnosis of FAP is based on genetic testing of the APC gene via an in vitro synthesized-protein assay [33]. A positive test justifies surveillance and familial screening with colorectal endoscopy and aids in surgical management and planning.

4.2.2. MLH1, MSH2, MSH6 and PMS2

As previously discussed in Section 4.1.1, diagnosis for HNPCC involves confirmation of a pathogenic germline mutation in one of several DNA MMR genes, including MLH1, MSH2, MSH6 and PMS2 and/or loss of DNA MMR proteins via immunohistochemistry (IHC) [9]. Germline testing is usually performed on patients with MSI as identified by IHC and in whom acquired methylation has been excluded.

4.2.3. SMAD4 and BMPR1A

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by the occurrence of juvenile polyps predominantly in the gastrointestinal tract, resulting in an increased risk of CRC [149]. Genetic testing for germline mutations of SMAD4 or BMPR1A genes are found in approximately 40–60% of JPS cases [150].

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