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.
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. 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. 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). 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. 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. In another study, up to 35% of patients under 35 years of age had an underlying hereditary colorectal cancer syndrome. 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). Patients with a subtype of HNPCC known as Muir-Torre syndrome also are prone to developing cutaneous sebaceous gland adenomas and keratoacanthomas. 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. 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.
All patients diagnosed with MSI-high colorectal cancer before age 50 should be considered for referral to a genetic counselor for HNPCC testing. HNPCC should be suspected in families meeting the Revised Bethesda Guidelines or Amsterdam II criteria (Table 2). 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.
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]
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.
Attenuated FAP (AFAP), a subtype of classic FAP in which patients have fewer than 100 adenomas, is caused by germline APC mutations near the 5ʹ 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. 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. Patients with FAP should undergo upper endoscopic surveillance for premalignant conditions every 1 to 3 years, beginning at 20 to 25 years of age.
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. It is estimated that individuals with the MUTYH mutation have a 43% chance of developing colorectal cancer by the age of 60 years. 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). 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.
1. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: colon and rectum cancer. http://seer.cancer.gov/statfacts/html/colorect.html. Accessed April 17, 2017.
2. American Cancer Society. Colorectal cancer facts & figures. https://www.cancer.org/research/cancer-facts-statistics/colorectal-cancer-facts-figures.html. Accessed April 17, 2017.
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.