Increased Levels of Genomic Instability and Mutations in Homologous Recombination Genes in Locally Advanced Rectal Carcinomas.

Luisa Matos Do Canto,Silvia R Rogatto,Jan Baumbach,Bruna E Catin Kupper,Maria Dirlei Ferreira De Souza Begnami,Mads M Aagaard,Samuel Aguiar,Simon J Larsen,Annabeth Høgh Petersen,Cristóvam Scapulatempo-Neto

doi:10.3389/fonc.2019.00395

Abstract

Pre-operative 5-fluoracil-based chemoradiotherapy (nCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC). Patients with pathological complete response (pCR–0% of tumor cells in the surgical specimen after nCRT) have better overall survival and lower risk of recurrence in comparison with incomplete responders (pIR). Predictive biomarkers to be used for new therapeutic strategies and capable of stratifying patients to avoid overtreatment are needed. We evaluated the genomic profiles of 33 pre-treatment LARC biopsies using SNP array and targeted-next generation sequencing (tNGS). Based on the large number of identified genomic alterations, we calculated the genomic instability index (GII) and three homologous recombination deficiency (HRD) scores, which have been reported as impaired DNA repair markers. We observed high GII in our LARC cases, which was confirmed in 165 rectal cancer cases from TCGA. Patients with pCR presented higher GII compared with pIR. Moreover, a negative correlation between GII and the fraction of tumor cells remaining after surgery was observed (ρ = –0.382, P = 0.02). High HRD scores were detected in 61% of LARC, of which 70% were incomplete responders. Using tNGS (105 cancer-related genes, 13 involved in HR and 5 in mismatch repair pathways), we identified 23% of cases with mutations in HR genes, mostly in pIR cases (86% of mutated cases). In agreement, the analysis of the TCGA dataset (N = 145) revealed 21% of tumors with mutations in HR genes. The HRD scores were shown to be predictive of better response to PARP-inhibitors and platinum-based chemotherapy in breast and ovarian cancer. Our results suggest that the same strategy could be applied in a set of LARC patients with HRD. In conclusion, we identified high genomic instability in LARC, which was related to alterations in the HR pathway, especially in pIR. These findings suggest that patients with impaired HRD would clinically benefit from PARP-inhibitors and platinum-based therapy.

Highlights

Several studies have demonstrated that colorectal cancer (CRC) is a heterogeneous disease and that rectal and colon tumors differ in many aspects [1]
The double strand breaks (DSB) are mostly repaired by non-homologous end joining (NHEJ) and homologous recombination (HR) repair mechanisms
Considering that the fraction of tumor cells remaining in the surgical specimen after neoadjuvant 5-fluorouracil-based chemo and radiotherapy (nCRT) is a surrogate of treatment response, we evaluated the correlation between the genomic instability index (GII) and the % of viable tumor cells identified after surgery

Summary

Introduction

Several studies have demonstrated that colorectal cancer (CRC) is a heterogeneous disease and that rectal and colon tumors differ in many aspects [1]. Chromosomal instability (CIN) and MSI are well-recognized mechanisms in CRC. CIN results from high levels of chromosomal mis-segregation, defects on telomere stability and/or DNA damage response [4]. The ability to predict HR deficiency (HRD), and impaired DNA damage repair, can be determinant of response to chemotherapeutic agents, as reported in breast cancer [7,8,9]. Scores used to capture large-scale transition (LST), telomeric allelic imbalance (tAI), and homologous recombination deficiency-loss of heterozygosity (HRD-LOH) have been used as tools to predict HRD [7,8,9,10,11]. Tumors with high scores are very likely to carry a deficient DNA damage repair system, resulting in a better response to platinum-based therapy [10]

Methods

Results

Conclusion