05/26/2023

Genomic Landscapes of Early-Onset Versus Average-Onset Colorectal Cancer Populations

ASCO 2023 PRESENTATION
Authors Michael H. Storandt, Qian Shi, Cathy Eng, Christopher Hanyoung Lieu, Melissa Conrad Stoppler, Thomas J. George, Elizabeth Mauer, Emily Teslow, Amit Mahipal, Zhaohui Jin

Background:Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age < 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years).

Methods:This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values).

Results:In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p < 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p < 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers.

Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC.

eoCRC (n = 2,379) aoCRC (n = 8,627) p-value/q-value
Baseline characteristics
Median age at diagnosis (IQR) 43 (38, 47) 64 (57,72) < 0.001
Gender: male 1,275 (54%) 4,967 (58%) < 0.001
Stage IV 1,389 (81%) 5,278 (80%) 0.030
Left sided/rectal primary * 840 (85%) 2,530 (75%) < 0.001
Immunologic markers
TMB ≥ 10 124 (5.7%) 614 (7.6%) 0.002
MSI-H 97 (4.2%) 564 (6.7%) < 0.001
dMMR 25 (2.6%) 253 (6.9%) < 0.001
Somatic mutations profiles **
BRAF 111 (4.7%) 845 (9.8%) < 0.001
BRAF V600E/MSI-H 1 (1.0%) 262 (46%)
RNF43 68 (2.9%) 515 (6.0%) < 0.001
AMER1 83 (3.5%) 503 (5.8%) < 0.001
ZNRF3 24 (1.0%) 192 (2.2%) 0.008
Germline mutation profiles **
eoCRC (N = 1,413) aoCRC(N = 4,898)
Overall prevalence 6.9% 5.0% 0.006
TP53 5 (0.4%) 2 ( < 0.1%) 0.2
APC 9 (0.6%) 11 (0.2%) 0.4
ATM 11 (0.8%) 19 (0.4%) 0.4
RAD51C 4 (0.3%) 3 ( < 0.1%) 0.4

* Include patients with CRC tissue sequenced. ** list first 4 mutations based on the lowest q values in order of prevalence.

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