Genetic variants in germline TP53 and MDM2 SNP309 are not associated with early onset colorectal cancer

Purpose Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Methods Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Results Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p=0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p<0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. Conclusions EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.

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“…KRAS and BRAF mutations were detected using PCR/LDR approaches as previously described (18, 19, 20, 41). …”

Section: Methodsmentioning

confidence: 99%

EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer

Khan

Zeng

Shia

et al. 2016

Pathol. Oncol. Res.

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“…Contrarily, another meta-analysis suggests that pathogenic variants in BRCA1 increase CRC risk (OR = 1.56) but not in BRCA2 [ 111 ]. Another gene that deserves attention in this section is TP53 , where pathogenic variants have been recurrently found in familial/early onset and unselected CRC patients [ 3 , 4 , 5 , 6 , 28 , 32 , 102 , 112 , 113 , 114 , 115 ]. As occurs with other non-CRC genes, the debate about TP53 ’s causal role in CRC predisposition is open for discussion.…”

Section: Non-crc Hereditary Cancer Genesmentioning

confidence: 99%

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Terradas

Capellà

Valle

2020

JCM

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In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene–environmental interactions, may explain the missing heritability in CRC.

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A High-Frequency Regulatory Polymorphism in the p53 Pathway Accelerates Tumor Development

et al. 2010

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Summary MDM2, a negative regulator of p53, is elevated in many cancers that retain wild-type p53. A single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the affinity of Sp1 resulting in elevated MDM2 levels. We generated mice carrying either the MDM2SNP309T or the MDM2SNP309G allele to address the impact of MDM2SNP309G on tumorigenesis. Mdm2SNP309G/G cells exhibit elevated Mdm2 levels, reduced p53 levels, and decreased apoptosis. Importantly, some Mdm2SNP309G/G mice succumbed to tumors before one year of age, suggesting that this allele increases tumor risk. Additionally, the Mdm2SNP309G allele potentiates the tumor phenotype and alters tumor spectrum in mice inheriting a p53 hot-spot mutation. These data provide causal evidence for increased cancer risk in carriers of the Mdm2SNP309G allele.

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Genetic variants in germline TP53 and MDM2 SNP309 are not associated with early onset colorectal cancer

Cited by 9 publications

References 31 publications

EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer

EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

A High-Frequency Regulatory Polymorphism in the p53 Pathway Accelerates Tumor Development

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