Germline Profiling and Molecular Characterization of Early Onset Metastatic Colorectal Cancer

Abstract

Background: Early onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC. Methods: 330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed. Results: Of the 330 EO mCRC patients, 31 carried pathogenic or likely pathogenic germline mutations, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes, including four in MUTHY, three in RAD50, one in TP53, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC, including TP53, APC, KRAS, SMAD4, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43, RBM10, TSC, and BRAF V600E mutations were more commonly observed in EO mCRC, while APC, ASXL1, DNMT3B, and MET genes were more commonly altered in AO patients. At the pathway level, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGFb pathway (p = 0.023) were associated with unfavorable OS in EO mCRC. Conclusions: Approximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

“…Several studies have reported chemoresistance and anti-EGFR resistance in patients with SMAD4 -mutated mCRC ( 16 – 18 ), leading to poor prognosis. Furthermore, SMAD4 and RNF43 mutations were more commonly observed in early onset mCRC (≤55 years) ( 19 ).…”

Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities

“…Studies have found that GSK3B deletion leaves HSCs in a precancerous state, and progression to acute myeloid leukaemia (AML) is facilitated after GSK3A deletion. 196 Although the mutation frequency of E3 ubiquitin ligase is lower than that of other WNT inhibitors, mutations of RNF43 (which mediates ubiquitin degradation of Frizzled) are still detected in the adenoma tissues of patients with GC, 218 early-onset metastatic CRC, 219 and Lynch syndrome. 220 RNF43 mutations are highly enriched in GC with microsatellite instability (MSI), promoting the development of GC cell resistance to DDR radiation and chemotherapy.…”

Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy

“…Due to the importance of the HR pathway in cancer progression and drug resistance [ 43 ], the cancer relevance of FANC gene alterations at DNA and gene expression levels in various cancers has been considered. For example, germline mutations in FANCD2 , the representative of the FA pathway, are likely linked with the increased risk of metastatic CRC [ 44 ]. The overexpression of FANCD2 also predicts the increased probability of either lymph node metastasis or liver metastasis, which is reasonably associated with poor prognostic outcomes among CRC patients [ 45 ].…”

“…As summarized in Table 1 , among 22 FANC genes, FANCS/BRCA1 and FANCD2/BRCA2 , high-risk hereditary breast-ovarian cancer syndrome susceptibility genes, are the most investigated as CRC susceptibility genes beyond its well-known predispositions [ 27 , 28 , 29 , 30 , 31 , 44 , 73 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Recent findings revealed that the prevalence of BRCA1/2 PVs among early-onset (1.3%) [ 30 ] and unselected patients with CRC (3.9%) [ 88 ] is more frequent than would be happening by chance.…”