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The Growing Challenge of Young Adults With Colorectal Cancer

The Growing Challenge of Young Adults With Colorectal Cancer

Oncology (Williston Park). 31(5):381-389.
Figure 1. Colorectal Cancer Incidence by Age at Diagnosis, 1975–2013
Figure 2. Approximate Prevalence of Sporadic and Familial Colorectal Cancer
Table 1. Hereditary Colorectal Cancer Syndromes
Table 2. Revised Bethesda Guidelines and Amsterdam II Criteria
Figure 3. Trend in Colorectal Tumor Primary Location by Age

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.[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 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.[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]


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