DNA Damage Response Protein Mutations Associated with Response to Radiotherapy in Gastrointestinal Malignancies

Abstract

The prevalence of DNA damage response (DDR) protein mutations among gastrointestinal (GI) malignancies is not well characterized. As next-generation sequencing (NGS) has become more commercially available, there is an opportunity to better establish the role of mutations in DDR proteins and their response to radiotherapy. Understanding somatic genetic aberrations that can influence radiation response can help guide patient-specific radiotherapy (RT). In this current study, commercially available DNA sequencing was conducted on patients with GI cancers to identify significant genetic mutations in the DDR pathway and to quantify their associations with local control. A total of 65 solid tumor biopsy specimens from pathologically confirmed GI cancers underwent molecular profiling with NGS. All patients were treated with external beam radiation therapy to primary lesions or to distant metastases. Clinical outcomes were measured from time of RT to time of progression or last follow-up and included RT to primary lesions and distant metastases. In addition to looking at each gene individually, unsupervised hierarchical clustering with K = 2 clusters was used to identify tumor mutational profiles. DDR pathway genes included MGMT, MLH1, MSH2/6, PTEN, P53, ATM and BRCA 1/2. Univariate Cox proportional hazards models were fit for 16 genes for the outcome of local control (LC) after RT as well as for the two resulting clusters. A multiple testing correction was applied to the gene-specific results to control the false discovery rate (FDR). Patients were treated with RT to the primary or metastatic site for colorectal (CRC, n = 25), gastroesophageal (GE, n = 5), liver and bile duct (LBD, n = 8), pancreatic (PC, n = 22) and other (OC, n = 5) GI cancers. Ninety two percent of patients had at least one mutation in the DDR pathway with mutations in TOPO1/2 (65%), PTEN (54%) and MGMT (52%) occurring most frequently. Overall, no individual gene was significantly associated with LC after the multiple testing correction, with MLH1 and MSH6 having the strongest association (HR = 0.33, p = 0.03, FDR = 0.25). Two identified clusters based on MLH1/MSH6 mutations had improved LC compared to those without (HR = 0.33, p = 0.03). Mutations in DNA damage response proteins are common in gastrointestinal malignancies. In our analysis, tumors with mutations in the DNA repair genes MLH1 and MSH6 had better local control compared to those without these mutations. DNA damage and repair proteins represent a promising target for novel drug therapies in conjunction with radiotherapy.