The Growing Challenge of Young Adults With Colorectal Cancer

Although the incidence of colorectal cancer is declining in the overall US population, the rates of colorectal cancer are rising among adolescent and young adult (AYA) patients-defined as individuals under 45 years of age. This population includes patients deemed too young for routine colorectal cancer screening, which in the United States is typically initiated at age 50 for men and women at average risk. Clinicopathologic differences have long been observed between AYAs and older patients with colorectal cancer. In addition, recently available high-throughput DNA sequencing techniques have revealed different rates of genetic alterations between these two groups, indicating potential molecular differences in the disease state and suggesting the need for alternative treatment strategies in younger patients. AYA patients with colorectal cancer often receive more aggressive treatment regimens than their older counterparts, without a corresponding improvement in survival. Furthermore, these younger patients have particular survivorship issues that warrant attention from the oncology community. In this review, we address specific issues pertaining to AYA patients with colorectal cancer, including evaluation for hereditary colorectal cancer syndromes, clinicopathologic and biologic features unique to AYA patients with colorectal cancer, treatment outcomes, and survivorship.

Introduction

Colorectal cancer is the fourth most common cancer diagnosed in the United States, and is the second most deadly malignancy, after lung cancer.[1,2] In 2017, an estimated 135,430 people will be diagnosed with colorectal cancer, and 50,260 will die from their disease.[1,2] The incidence of colorectal cancer in the overall US population is declining, due in large part to an increase in colonoscopic screening.[3-5] However, the rate of colorectal cancer is rising among adolescent and young adult (AYA) patients (Figure 1).[6-8] In fact, 5.7% of patients with newly diagnosed colorectal cancer are under 45 years of age and 20.5% are younger than 55 years of age.[1] For individuals under age 50, the incidence of colorectal cancer rose by 22% from 2000 to 2013, mostly accounted for by tumors of the distal colon and rectum.[9] The etiology accounting for this rise in incidence remains unclear.

Familial and Hereditary Colorectal Cancer Syndromes

Individuals whose first-degree relatives have developed colorectal cancer have an increased lifetime relative risk (RR) of developing colorectal cancer themselves (RR, 2.25); the risk is greater if that relative is under 45 years of age (RR, 3.87). Those with more than one relative affected by colorectal cancer are at even greater risk (RR, 4.25).[10] Patients with familial colorectal cancer are diagnosed at a younger age than those with sporadic colorectal cancer, and a family history of the disease does not significantly elevate colorectal cancer risk in those 60 years of age or older.[11] Approximately 30% of patients with colorectal cancer have a positive family history of this malignancy; however, only 3% to 5% of patients have an identifiable syndrome of hereditary colorectal cancer (Figure 2; Table 1).[10,12] Investigating for an underlying hereditary syndrome is a critical step in the evaluation of any young patient with colorectal cancer.

Hereditary colorectal cancer syndromes are more common among younger patients. In a study of 450 patients diagnosed with colorectal cancer before the age of 50 years, 72 (16%) had a germline mutation indicative of a hereditary colorectal cancer syndrome.[13] In another study, up to 35% of patients under 35 years of age had an underlying hereditary colorectal cancer syndrome.[14] In this review article, we will briefly describe the most common germline mutations accounting for hereditary colorectal cancer.

Mismatch repair (MMR) deficiency

The most common hereditary colorectal cancer syndrome is hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. Lynch syndrome is an autosomal dominant disorder caused by germline mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) or germline deletions in the EPCAM gene (resulting in loss of MSH2 protein expression); these genetic alterations result in tumors with high microsatellite instability (MSI-high). In addition to posing an increased risk of colorectal cancer, HNPCC puts patients at increased risk for developing endometrial, gastric, ovarian, hepatobiliary, pancreatic, urinary tract, and small bowel cancers, as well as malignancies of the central nervous system (usually glioblastoma).[15] Patients with a subtype of HNPCC known as Muir-Torre syndrome also are prone to developing cutaneous sebaceous gland adenomas and keratoacanthomas.[16] Patients with HNPCC (including 41% of MLH1 mutation carriers, 48% of MSH2 mutation carriers, and 12% of MSH6 mutation carriers) are at high risk for developing colorectal cancer by the age of 70 years.[17] It is recommended that patients with HNPCC undergo frequent colonoscopy screening (every 1 to 2 years), beginning at the age of 20 to 25 years.[18]

All patients diagnosed with MSI-high colorectal cancer before age 50 should be considered for referral to a genetic counselor for HNPCC testing.[19] HNPCC should be suspected in families meeting the Revised Bethesda Guidelines or Amsterdam II criteria (Table 2).[20] If the tumor is found to be MSI-high, patients should be referred for germline testing of MMR genes.

Importantly, treatment recommendations differ for patients with MSI-high tumors. Studies have shown that patients with stage II disease do not benefit from adjuvant chemotherapy with fluorouracil (5-FU), in part because patients with MSI-high colorectal tumors tend to have an overall favorable prognosis compared with patients who have MSI-low or microsatellite stable (MSS) tumors. In fact, patients with MSI-high stage II disease actually have inferior overall survival (OS) outcomes when treated with adjuvant 5-FU compared with surgery alone.[21]

In metastatic MSI-high colorectal cancer, programmed death 1 (PD-1) checkpoint blockade with pembrolizumab provides a survival benefit, which is likely related to the higher loads of mutation-associated neoantigens and tumor infiltrating lymphocytes observed in this patient population.[22-24]

APC mutations

Familial adenomatous polyposis (FAP) is the second most common hereditary colorectal cancer syndrome. It is caused by a germline mutation in the APC gene and is inherited in an autosomal dominant fashion. Patients with FAP typically present with at least 100 adenomatous polyps in the second or third decade of their life and have a lifetime colorectal cancer risk approaching 100%. Total proctocolectomy with ileal pouch–anal anastomosis is the recommended management approach.[18]

Attenuated FAP (AFAP), a subtype of classic FAP in which patients have fewer than 100 adenomas, is caused by germline APC mutations near the 5Ê¹ end of the gene or in an alternatively spliced region of exon 9.[25,26] AFAP typically presents in the fourth or fifth decade of life and may be asymptomatic; the lifetime risk of colorectal cancer in this group is approximately 80%.

Individuals with FAP commonly have congenital hypertrophy of the retinal pigment epithelium, a benign condition that does not affect vision; and asymptomatic retinal lesions.[27] Gardner syndrome-an autosomal dominant form of polyposis characterized by tumors of the upper gastrointestinal tract, desmoid tumors, and osteomas-is a variant of classic FAP.[28] Patients with FAP should undergo upper endoscopic surveillance for premalignant conditions every 1 to 3 years, beginning at 20 to 25 years of age.[18]

MUTYH mutations

MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome that clinically resembles AFAP because patients with this genetic mutation typically have fewer than 100 polyps. The MUTYH gene encodes a protein of the same name, which functions as part of the DNA base excision repair system in response to oxidative stress. Biallelic mutations in MUTYH result in frequent G:C and T:A transversions in APC and KRAS.[29] It is estimated that individuals with the MUTYH mutation have a 43% chance of developing colorectal cancer by the age of 60 years.[30] There are also increased risks of developing duodenal, gastric, hepatobiliary, bladder, ovarian, endometrial, breast, and skin cancers.[31,32] In contrast, heterozygous MUTYH mutation carriers have only a small increased risk of developing colorectal cancer (RR, 1.27).[33] Screening guidelines for patients with MAP are similar to guidelines for patients with AFAP: colonoscopies starting at the age of 18 to 20 years and upper endoscopies starting at around 25 to 30 years, repeated every 1 to 2 years.[18]

Clinicopathologic Features of Colorectal Cancer in AYA Patients

Compared with colorectal cancer in older adults, AYA patients present with more advanced tumors, possibly because of delays in diagnosis due to the low rate of colonoscopic screening in younger patients. Prior to diagnosis, colorectal cancer patients younger than 50 years of age have symptomatic complaints for 1.6 to 2.9 months longer than older patients (≥ 50 years old).[34,35] AYA patients more often present with advanced-stage (III or IV) disease, and colorectal cancers in AYA patients appear histologically more aggressive. AYA patients are significantly more likely to have mucinous colorectal cancer, signet ring cell carcinoma, and/or poorly differentiated tumors.[36,37] It has also been shown that patients under 50 years of age with early-stage rectal cancer are more likely to have lymph node–positive disease than their older counterparts.[38]

Tumor sidedness has long been thought to affect survival in patients with metastatic colorectal cancer and has recently emerged as a prognostic and predictive biomarker. For example, patients with right-sided tumors have inferior OS and benefit less from treatment with cetuximab (regardless of KRAS mutational status) compared with those who have left-sided tumors.[39-43] The incidence of left- and right-sided colorectal cancers is clearly influenced by age (Figure 3) and sex.[44,45] Thirty-seven percent of patients under the age of 45 years with metastatic colorectal cancer have right-sided primary tumors, compared with 44% of those 55 years of age or older (and these rates are 40% vs 49% when considering women only).[46] Some clinicians hypothesize that as women age and their estrogen levels decrease, the estrogen-mediated protective effect against development of right-sided colorectal cancers is lost.[47] Thus, AYA colorectal cancer patients tend to have more left-sided and poorly differentiated tumors.

Molecular Features of Colorectal Cancer in AYA Patients

The clinicopathologic features of colorectal tumors in AYA patients are likely explained by underlying molecular differences in tumor biology compared with tumors in older patients. Mutation profile and methylation phenotype differences between colorectal tumor samples from AYA patients and those from older adults should be investigated. The MSI and MLH1 promoter methylation that occur in HNPCC account for the vast majority of MSI-high colorectal cancers in AYA patients, with MSS disease observed in most other AYA patients. MSI tumors occur more frequently in very young colorectal cancer patients (those under 30 years of age) than in patients over age 50 (27% vs 13%, respectively; P < .01), but this likely reflects the higher prevalence of HNPCC among these younger patients.[36] When comparing patients under 40 years of age with those over age 60, MSI in the younger cohort is seen exclusively in those with hereditary colon cancer; MSI in older patients is most often a result of promoter hypermethylation of the DNA repair genes MLH1 and MSH2.[48,49] MSI-high tumors tend to be more right-sided, possibly contributing to the rightward shift of colorectal tumors in older patients.[49]

BRAF mutations

Mutations of the BRAF gene (typically at location V600E) virtually never occur in patients with MSI-high tumors due to HNPCC; therefore, the presence of a BRAF mutation essentially excludes a diagnosis of HNPCC.[50] The rate of BRAF mutations is roughly consistent between patients younger than 40 years old and those 40 years of age and older, at approximately 10% to 12%.[51-53] Others have demonstrated an increase in the rate of BRAF mutations in patients over age 60 compared with those 60 years of age or younger (10.6% vs 5.1%; P < .001), but this distinction does not persist if MSS patients only are evaluated (5.1% vs 4.9%; P = .97).[54] Indeed, based on reports in the medical literature to date, there appears to be no significant difference in BRAF mutation status to account for the more aggressive phenotype seen in AYA patients.

CpG island methylator phenotype (CIMP)

Approximately 20% of colorectal tumors are CIMP-high, leading to widespread genomic hypermethylation, which is believed to silence tumor suppressor genes and promote carcinogenesis.[55] CIMP-high tumors tend to be right-sided, poorly differentiated, MSI-high, KRAS–wild-type, and BRAF-mutated; and they occur more often in women and older patients.[55,56] AYA patients tend to have CIMP-low tumors; the exception is patients with HNPCC, who have MSI-high and CIMP-high tumors.[48,56]

LINE-1 hypomethylation

As previously described, most colorectal tumors from AYA patients are hypomethylated. Long interspersed nuclear element 1 (LINE-1) repeat sequences can be used to quantify tumor DNA methylation. LINE-1 hypomethylation is seen most often in tumors from AYA patients without HNPCC; tumors in older patients and MSI-high tumors have higher levels of methylation.[57] In addition, patients with LINE-1 hypomethylated tumors have inferior cancer-specific survival and OS compared with patients whose tumors are hypermethylated.[57,58] The negative prognostic association of LINE-1 hypomethylation with survival is more pronounced in MSI-high colorectal tumors.[59]

Other somatic mutations

KRAS mutations, which are common oncogenic drivers in colorectal cancer, occur at a similar frequency in tumors from AYA and older patients (at approximately 30% to 40%).[36,51] Other common somatic colorectal cancer–associated mutations occurring in the tumor suppressor genes TP53 and APC also occur at similar frequencies in tumors from AYA and older patients.[60] SMAD4 mutations may be more common in AYA patients and have been implicated in the combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia that predisposes patients to development of colorectal cancer at a young age.[61,62] Interestingly, tumors from AYA patients may have more frequent mutations in the tumor suppressor gene FBXW7 and in POLE.[60] AYA patients harboring a POLE mutation in their tumors may benefit from treatment with immune checkpoint inhibitors (anti–PD-1 or anti–programmed death ligand 1 antibodies), given their impaired DNA polymerase proofreading and large tumor mutational burdens and neoantigen loads.[22] High-throughput sequencing tests should be offered to AYA patients with colorectal cancer (especially those 30 years of age or younger) in an attempt to delineate potentially actionable tumor mutations and to assess tumor mutational burden.[63]

ERCC1 protein expression

ERCC1 contributes to nucleotide excision repair in response to DNA damage. Accordingly, low tumor expression of ERCC1 protein is a positive predictive biomarker for response to oxaliplatin and corresponding OS in patients with colorectal cancer.[64,65] Although rates of ERCC1 expression are similar between AYA and older patients with colorectal cancer, low levels of ERCC1 in AYA patients may actually be predictive of inferior OS outcomes compared with older patients whose tumors express low levels of ERCC1.[61] These findings need to be validated further in clinical trials with larger patient cohorts.

Consensus Molecular Subtypes (CMS)

Recent work has demonstrated that colorectal cancers can be subdivided into four consensus molecular subtypes based on gene expression patterns: MSI immune (CMS1), canonical (CMS2), metabolic (CMS3), and mesenchymal (CMS4).[66] While the median ages of patients in each group are similar, there was a trend towards more younger patients having the CMS4 subtype, which is associated with a more advanced cancer stage at the time of diagnosis and inferior OS compared with the other subtypes.[67] Analysis by patient age has not been directly conducted using data from the Cancer Genome Atlas, although this would be an interesting study.

Treatment Patterns and Outcomes

Given that AYA patients with colorectal cancer tend to present at more advanced stages and with more aggressive pathologic features than are seen in their older counterparts, clinicians tend to believe that the AYA patients have worse outcomes. This reasoning leads to the selection of more aggressive therapies in AYA patients. However, this rationale is not necessarily supported by available data. In one published analysis of the Surveillance, Epidemiology, and End Results Program database, 279,623 patients with colorectal cancer were sorted into three age groups: 20 to 40 years old, 41 to 50 years old, and over age 50. The middle group faired the best in terms of 5-year colorectal cancer–specific survival (CRC-SS; 67.1%), followed by the youngest group (65.1%) and then the oldest group (62.8%; P < .001).[37]

A similar study of 258,024 patients compared those 50 years of age and older with patients under age 50. The younger group had superior 5-year CRC-SS for localized disease (95.1% vs 91.9%; P < .001), regional disease (76.0% vs 70.3%; P < .001), and metastatic disease (21.3% vs 14.1%; P < .001).[68] However, in another study of 369 patients with colorectal cancer, those who were 30 years old or younger had inferior 5-year CRC-SS vs those 50 years of age or older (48% vs 78%; P < .001).[36] In a study of 69,835 patients with resected nonmetastatic colorectal cancer, those aged 40 years or younger had improved 5-year CRC-SS compared with those over 40 years of age for both stage II disease (90.5% vs 85.2%; P < .001) and stage III disease (65.9% vs 59.8%; P < .001).[69] Finally, patients under age 40 who had operable colorectal cancer were sorted into one of four groups: 25 years or younger (group 1), 26 to 30 years (group 2), 31 to 35 years (group 3), and 36 to 40 years (group 4). Patients over age 30 had more favorable clinicopathologic tumor characteristics and better 5-year CRC-SS rates (80.6% in group 3 and 82.5% in group 4) compared with those 30 years of age or younger (with rates of 71.0% in group 1 and 75.1% in group 2; P < .002).[70]

AYA patients with colorectal cancer are a heterogeneous group; patients who are 30 years of age or younger (the very young) have worse CRC-SS compared with older patients, but this difference does not persist when the patient age is raised to incorporate all those previously categorized as AYA (patients younger than 45 years of age).

KEY POINTS

The incidence of colorectal cancer (CRC) in younger patients is increasing, with a dramatic rise in left-sided colon and rectal cancers.
Younger patients with CRC tend to receive more aggressive therapy than older patients, without a commensurate increase in survival.
Identification of a hereditary CRC syndrome is crucial to guiding appropriate screening, definitive surgery, and surveillance regimens.
Comprehensive molecular tumor profiling should be offered to young patients with CRC, to explore novel therapeutic options.

As mentioned previously, younger patients with colorectal cancer are likely to receive more aggressive cancer treatments than their older counterparts. Patients with metastatic disease are more likely to receive cancer-directed surgery to the primary tumor if they are younger as opposed to older than 50 years of age (70.8% vs 66.6%; P < .001). The same age-related difference applies to delivery of radiation therapy in the setting of metastatic rectal cancer (49.1% vs 41.9%; P < .001).[68] AYA patients under age 50 are more likely to receive adjuvant chemotherapy and multiagent adjuvant chemotherapy than their older counterparts, with no corresponding 5-year CRC-SS benefit for those with stage II disease (RR, 0.90; 95% CI, 0.69–1.17) and minimal benefit for those with stage III (RR, 0.89; 95% CI, 0.81–0.97) and stage IV (RR, 0.84; 95% CI, 0.79–0.90) disease.[71]

Management Recommendations for AYA Patients

Adjuvant therapy

Aggressive adjuvant therapy of colorectal cancer in AYA patients, especially those with early-stage disease, leads to only modest gains in survival; the treatment strategy for these younger patients should be reconsidered. For AYA patients with colon cancer, we recommend following standard guidelines regarding adjuvant therapy: no adjuvant treatment for stage I disease, single-agent capecitabine or 5-FU/leucovorin for the treatment of high-risk MSS stage II disease, and a regimen of leucovorin, 5-FU, and oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPEOX) for stage III disease.

Risk-adapted screening

As previously described in this review, identification of an underlying hereditary colorectal cancer syndrome is vital to guiding screening and surveillance plans. Patients with a hereditary colorectal cancer syndrome often require more frequent endoscopies and colonoscopies, depending on the specific germline mutation involved. (For further information, please refer to the discussion of hereditary colorectal cancer syndromes in this article.)

Treatment of metastatic disease

Molecular profiling of AYA patients with metastatic colorectal cancer is extremely important in guiding therapy (eg, use of anti–epidermal growth factor receptor therapies for RAS–wild-type patients) and identifying novel drug targets (eg, BRAF mutations and MMR deficiency). Clinical trials should be offered to patients whenever available and appropriate. Very young patients (those under age 30) have a very poor prognosis and are frequently offered more aggressive treatments to improve survival (eg, use of leucovorin, 5-FU, oxaliplatin, and irinotecan [FOLFOXIRI] plus bevacizumab in the first-line setting). However, minimal data exist regarding the best therapeutic selection for this patient population and more research is clearly necessary.

Older AYA patients with BRAF–wild-type, MMR-proficient tumors should be managed in the same way as older patients with metastatic colorectal cancer, using first-line therapy consisting of FOLFOX, CAPEOX, or FOLFIRI plus a biologic agent (eg, bevacizumab or, in patients with RAS–wild-type disease, cetuximab or panitumumab), second-line therapy with 5-FU/leucovorin plus the alternative chemotherapy backbone (oxaliplatin or irinotecan) not used in the first-line plus a biologic agent (as above or using ziv-aflibercept or ramucirumab, preferably in combination with irinotecan), and third-line therapy with regorafenib or trifluridine/tipiracil.

Survivorship considerations

AYA patients have unique survivorship issues that warrant special consideration by the treating oncologist, given that more patients with early-stage colorectal cancer in this population are living with treatment complications for longer periods of time. These include postsurgical complications related to ostomies and altered digestion, as well as acute and long-term effects of chemotherapy, including peripheral neuropathy, infertility, sexual dysfunction, fatigue, and risk of secondary malignancies. AYA patients should receive age-appropriate cancer screening, and women with a history of colorectal cancer and HNPCC should also be screened for endometrial cancer using annual endometrial sampling and transvaginal ultrasound.[72] The added psychosocial stress of experiencing a life-threatening illness at a young age and the concomitant financial burden can be especially devastating. Thus, in addition to physical interventions, AYA patients should be promptly referred for consultation with social workers and mental health professionals as appropriate. Lastly, AYA patients should have a survivorship care plan outlining prior treatments, as well as standard-of-care surveillance follow-up, imaging, and laboratory studies.

Conclusions

Although perhaps not a distinct clinical entity, multiple characteristics of colorectal cancer in AYA patients are demonstrably different from those observed in older patients. Clinicopathologic features and underlying tumor biology (methylation status, MSI, and somatic mutations) in AYA patients contrast with those in their older counterparts. Thus, colorectal tumors in AYA patients have more unfavorable histologic features, are usually diagnosed at a more advanced stage, more frequently involve left-sided primaries, and are MSS (in patients without HNPCC). Despite this aggressive phenotype, CRC-SS is not decreased in AYA patients and is often superior compared with that of older patients. AYA patients are often overtreated in the adjuvant setting, with negligible survival benefit. Colorectal cancer in very young patients (those under age 30) is associated with especially poor CRC-SS and reflects the heterogeneity of the disease in AYA patients. The identification of a hereditary colorectal cancer syndrome is paramount to guiding recommendations for surveillance and potential definitive surgery. The recent increase in distal colon and rectal cancers in AYA patients remains unexplained. More work clearly must be done to better understand tumor biology in this younger group of patients, and broader molecular tumor profiling (eg, high-throughput sequencing) should be explored in order to elucidate potential drug targets. Finally, AYA patients require a unique approach to survivorship in a disease that is unfortunately becoming more commonplace.

Financial Disclosure:Dr. Marshall serves as a speaker, consultant, and CMO for Amgen, Bayer, Caris, Celgene, Genentech, and Taiho. The other authors have no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgement: The authors thank Marion Hartley, PhD, Science Writer for Clinical Research at the Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, for editing this manuscript.

References:

3. Doubeni CA, Corley DA, Quinn VP, et al. Effectiveness of screening colonoscopy in reducing the risk of death from right and left colon cancer: a large community-based study. Gut. 2016 Oct 12. [Epub ahead of print]

4. Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med. 2013;369:1095-105.

5. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116:544-73.

6. Siegel R, DeSantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64:104-17.

7. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Colon and rectum. SEER*Explorer, beta release; April 15, 2016. http://seer.cancer.gov/explorer. Accessed April 17, 2017.

8. Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. 2009;18:1695-8.

9. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017 Mar 1. [Epub ahead of print]

10. Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001;96:2992-3003.

11. Fuchs CS, Giovannucci EL, Colditz GA, et al. A prospective study of family history and the risk of colorectal cancer. N Engl J Med. 1994;331:1669-74.

12. Grady WM. Genetic testing for high-risk colon cancer patients. Gastroenterology. 2003;124:1574-94.

13. Pearlman R, Frankel WL, Swanson B, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3:464-71.

14. Mork ME, You YN, Ying J, et al. High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer. J Clin Oncol. 2015;33:3544-9.

15. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014;109:1159-79.

16. John AM, Schwartz RA. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74:558-66.

17. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304-10.

18. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal. Version 2.2016. https://www.nccn.org/professionals/physician_gls/pdf/
genetics_colon.pdf. Accessed April 17, 2017.

19. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110:223-62.

20. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-8.

21. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219-26.

22. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.

23. Le DT, Uram JN, Wang H, et al. Programmed death-1 blockade in mismatch repair deficient colorectal cancer. J Clin Oncol. 2016;34(suppl):abstr 103.

24. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22:813-20.

25. Spirio L, Olschwang S, Groden J, et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993;75:951-7.

26. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol. 2007;61:153-61.

27. Chen CS, Phillips KD, Grist S, et al. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) in familial colorectal cancer. Fam Cancer. 2006;5:397-404.

28. Gardner EJ, Stephens FE. Cancer of the lower digestive tract in one family group. Am J Hum Genet. 1950;2:41-8.

29. Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet. 2002;30:227-32.

30. Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 2009;27:3975-80.

31. Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009;137:1976-85.

32. Win AK, Reece JC, Dowty JG, et al. Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer. 2016;139:1557-63.

33. Tenesa A, Campbell H, Barnetson R, et al. Association of MUTYH and colorectal cancer. Br J Cancer. 2006;95:239-42.

34. Ben-Ishay O, Brauner E, Peled Z, et al. Diagnosis of colon cancer differs in younger versus older patients despite similar complaints. Isr Med Assoc J. 2013;15:284-7.

35. Chen FW, Sundaram V, Chew TA, Ladabaum U. Advanced stage colorectal cancer in persons younger than 50 years not associated with longer duration of symptoms or time to diagnosis. Clin Gastroenterol Hepatol. 2016 Nov 14. [Epub ahead of print]

36. Khan SA, Morris M, Idrees K, et al. Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg. 2016;51:1812-7.

37. Wang R, Wang MJ, Ping J. Clinicopathological features and survival outcomes of colorectal cancer in young versus elderly: a population-based cohort study of SEER 9 registries data (1988-2011). Medicine (Baltimore). 2015;94:e1402.

38. Meyer JE, Cohen SJ, Ruth KJ, et al. Young age increases risk of lymph node positivity in early-stage rectal cancer. J Natl Cancer Inst. 2016;108.

39. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary tumor location on overall survival and progression-free survival in patients with metastatic colorectal cancer: analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(suppl):abstr 3504.

40. Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51:1405-14.

41. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2016 Oct 10. [Epub ahead of print]

42. Schrag D, Weng S, Brooks G, et al. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol. 2016;34(suppl):abstr 3505.

43. Lee MS, Advani SM, Morris J, et al. Association of primary site and molecular features with progression-free survival and overall survival of metastatic colorectal cancer after anti-epidermal growth factor receptor therapy. J Clin Oncol. 2016;34(suppl):abstr 3506.

44. Snaebjornsson P, Jonasson L, Jonsson T, et al. Colon cancer in Iceland-a nationwide comparative study on various pathology parameters with respect to right and left tumor location and patient age. Int J Cancer. 2010;127:2645-53.

45. Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol. 2012;25:1128-39.

46. Hendifar A, Yang D, Lenz F, et al. Gender disparities in metastatic colorectal cancer survival. Clin Cancer Res. 2009;15:6391-7.

47. Caiazza F, Ryan EJ, Doherty G, et al. Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol. 2015;5:19.

48. Magnani G, Furlan D, Sahnane N, et al. Molecular features and methylation status in early onset (≤ 40 years) colorectal cancer: a population based, case-control study. Gastroenterol Res Pract. 2015;2015:132190.

49. Yiu R, Qiu H, Lee SH, Garcia-Aguilar J. Mechanisms of microsatellite instability in colorectal cancer patients in different age groups. Dis Colon Rectum. 2005;48:2061-9.

50. Toon CW, Walsh MD, Chou A, et al. BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for Lynch syndrome. Am J Surg Pathol. 2013;37:1592-602.

51. Vatandoust S, Price TJ, Ullah S, et al. Metastatic colorectal cancer in young adults: a study from the South Australian population-based registry. Clin Colorectal Cancer. 2016;15:32-6.

52. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-54.

53. Tie J, Gibbs P, Lipton L, et al. Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer. 2011;128:2075-84.

54. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466-74.

55. Shiovitz S, Bertagnolli MM, Renfro LA, et al. CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology. 2014;147:637-45.

56. Perea J, Rueda D, Canal A, et al. Age at onset should be a major criterion for subclassification of colorectal cancer. J Mol Diagn. 2014;16:116-26.

57. Antelo M, Balaguer F, Shia J, et al. A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLoS One. 2012;7:e45357.

58. Ogino S, Nosho K, Kirkner GJ, et al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst. 2008;100:1734-8.

59. Inamura K, Yamauchi M, Nishihara R, et al. Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis. J Natl Cancer Inst. 2014;106.

60. Kothari N, Teer JK, Abbott AM, et al. Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers. Cancer. 2016;122:2828-35.

61. Heeke AC, Xiu J, Reddy SK, et al. Molecular characterization of colorectal tumors in young patients compared with older patients and impact on outcome. J Clin Oncol. 2016;34(suppl 4S):abstr 505.

62. Schwenter F, Faughnan ME, Gradinger AB, et al. Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J Gastroenterol. 2012;47:795-804.

63. Subbiah V, Bupathi M, Kato S, et al. Clinical next-generation sequencing reveals aggressive cancer biology in adolescent and young adult patients. Oncoscience. 2015;2:646-58.

64. Shirota Y, Stoehlmacher J, Brabender J, et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol. 2001;19:4298-304.

65. Choueiri MB, Shen JP, Gross AM, et al. ERCC1 and TS expression as prognostic and predictive biomarkers in metastatic colon cancer. PLoS One. 2015;10:e0126898.

66. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350-6.

67. Dienstmann R, Guinney J, Delorenzi M, et al. Colorectal cancer subtyping consortium (CRCSC) identification of a consensus of molecular subtypes. J Clin Oncol. 2014;32(suppl 5s):abstr 3511.

68. Abdelsattar ZM, Wong SL, Regenbogen SE, et al. Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening. Cancer. 2016;122:929-34.

69. Li Q, Cai G, Li D, et al. Better long-term survival in young patients with non-metastatic colorectal cancer after surgery, an analysis of 69,835 patients in SEER database. PLoS One. 2014;9:e93756.

70. Li Q, Zhuo C, Cai G, et al. Pathological features and survival outcomes of young patients with operable colon cancer: are they homogeneous? PLoS One. 2014;9:e102004.

71. Kneuertz PJ, Chang GJ, Hu CY, et al. Overtreatment of young adults with colon cancer: more intense treatments with unmatched survival gains. JAMA Surg. 2015;150:402-9.

72. El-Shami K, Oeffinger KC, Erb NL, et al. American Cancer Society colorectal cancer survivorship care guidelines. CA Cancer J Clin. 2015;65:428-55.

73. Turcot J, Despres JP, St Pierre F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum. 1959;2:465-8.

74. McGarrity TJ, Amos CI, Baker MJ. Peutz-Jeghers syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. Seattle, WA: GeneReviews® [Internet]; 1993.

75. Larsen Haidle J, Howe JR. Juvenile polyposis syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. Seattle, WA: GeneReviews® [Internet]; 1993.

76. Church JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis Colon Rectum. 2014;57:396-7.

77. Bodo S, Colas C, Buhard O, et al. Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents. Gastroenterology. 2015;149:1017-29.

78. Eng C. Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol. 1998;12:701-10.

79. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology. 1999;116:1453-6.