Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

Pearlman R1, Frankel WL2, Swanson B2, Zhao W2, Yilmaz A2, Miller K2, Bacher J2, Bigley C1, Nelsen L1, Goodfellow PJ3, Goldberg RM1, Paskett E1, Shields PG1, Freudenheim JL4, Stanich PP5, Lattimer I1, Arnold M6, Liyanarachchi S7, Kalady M8, Heald B8, Greenwood C9, Paquette I10, Prues M11, Draper DJ12, Lindeman C12, Kuebler JP13, Reynolds K14, Brell JM15, Shaper AA16, Mahesh S17, Buie N18, Weeman K19, Shine K20, Haut M21, Edwards J21, Bastola S22, Wickham K22, Khanduja KS23, Zacks R24, Pritchard CC25, Shirts BH25, Jacobson A25, Allen B26, de la Chapelle A7, Hampel H1; Ohio Colorectal Cancer Prevention Initiative Study Group.

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Abstract

IMPORTANCE:

Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined.

OBJECTIVE:

To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC.

DESIGN, SETTING, AND PARTICIPANTS:

Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing.

MAIN OUTCOMES AND MEASURES:

Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status.

RESULTS:

In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation.

CONCLUSIONS AND RELEVANCE:

Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.