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

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.

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran

“…But more than half of our early onset cases did not have any family history of CRC in FDR\SDR, so we cannot rely only on clinical criteria to find LSs and IHC for MMR recommended for all early onset CRCs. These findings are in line with those reported by other studies, which found Germline testing with a multigene panel should be addressed for all early onset CRCs 46 49. Moreover, Hampel et al suggested tumour sequencing approach as a replacement for current multitest LS screening,50 but these new strategies are not widely available in Iran and are too expensive.…”

Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility

“…About 5-10 percent of cancers are considered hereditary and occur in individuals genetically predisposed to developing cancer (1). Inherited defects in DNA repair genes have been implicated in cancer susceptibility in colon (2), breast (3,4), and ovarian (5) cancers. Early identification of cancer-susceptible individuals can aid in risk stratification, screening, and prevention.…”

The impact of young adult colorectal cancer: incidence and trends in Colorado

“…There is emerging evidence that screening may not account for all of the decrease in CRC incidence [18], although it is unclear what role increased awareness and earlier detection may play, or if the trend may be driven by underlying dietary and lifestyle changes [13]. Additionally, recent research has shown a higher prevalence of germline cancer susceptibility mutations in patients with YA CRC, and a full third of those mutation-positive patients did not meet testing criteria for the gene(s) in which they had a mutation [19]. While recent guidelines by the US Preventive Services Task Force [6] and National Comprehensive Cancer Network [7] do not yet recommend screening earlier than age 50 for individuals of average risk, these genetic and epidemiologic findings point to a changing CRC population that is younger and more genomically unstable.…”