Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer

Abstract

DnA copy number aberrations (cnA) are frequently observed in colorectal cancers (cRc). there is an urgent need for cnA-based biomarkers in clinics,. n for Stage iii cRc, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol's accuracy and robustness by a systematic benchmark with microarray, high-coverage wholeexome and-genome approaches, where the low-coverage WGS-derived cnA segments were highly accordant (pcc >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (p = 0.0139, HR = 1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage iii patients. Extensive copy number aberrations (CNA) are a hallmark of cancers with genome instability and are observed among a wide variety of epithelial malignancies originating from the colon, breast, cervix, prostate, bladder and stomach 1. High levels of CNAs are associated with cancer progression and poor prognosis. Thus, there is general interest in profiling CNAs as potential biomarkers associated with specific clinical outcome. The focus of our study was colorectal cancer (CRC), the third most common cancer worldwide , with ~1.8 million estimated new cases yearly. The majority of CRCs demonstrates an extensive CNAs and as a result, are designated as belonging to the chromosomal-instability (CIN) molecular subtype. To accurately profile CNAs and evaluate their prognostic significance in CRC, a variety of methods have been used which include karyotyping, fluorescent in-situ hybridization (FISH), and chromosomal microarrays, such as comparative genomic hybridization (CGH) arrays and single nucleotide polymorphisms (SNP) arrays. Citing some examples, with karyotyping, Bardi et al. found that loss of chromosome 18 was correlated with shorter overall survival in early-stage patients (N = 150) 2. Personeni et al. 3 using FISH identified that changes in EGFR copy number predicted overall survival for EGFR-targeted therapy in a metastatic CRC cohort (N = 87). Using SNP-arrays, Sheffer et al. identified deletions of 8p, 4p, and 15q were associated with poor survival in a mixed-stage cohort (N = 130) 4. Other microarray-based studies 5-7 using smaller numbers of patients (N <100) identified various CNAs associated with poor survival that included sub-...

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