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