Comparative Genomic Analysis of Primary and Synchronous Metastatic Colorectal Cancers

Abstract

Approximately 50% of patients with primary colorectal carcinoma develop liver metastases. Understanding the genetic differences between primary colon cancer and their metastases to the liver is essential for devising a better therapeutic approach for this disease. We performed whole exome sequencing and copy number analysis for 15 triplets, each comprising normal colorectal tissue, primary colorectal carcinoma, and its synchronous matched liver metastasis. We analyzed the similarities and differences between primary colorectal carcinoma and matched liver metastases in regards to somatic mutations and somatic copy number alterationss. The genomic profiling demonstrated mutations in APC(73%), KRAS (33%), ARID1A and PIK3CA (6.7%) genes between primary colorectal and metastatic liver tumors. TP53 mutation was observed in 47% of the primary samples and 67% in liver metastatic samples. The grouped pairs, in hierarchical clustering showed similar somatic copy number alteration patterns, in contrast to the ungrouped pairs. Many mutations (including those of known key cancer driver genes) were shared in the grouped pairs. The ungrouped pairs exhibited distinct mutation patterns with no shared mutations in key driver genes. Four ungrouped liver metastasis samples had mutations in DNA mismatch repair genes along with hypermutations and a substantial number of copy number alterations. Our results suggest that about half of the metastatic colorectal carcinoma had the same clonal origin with their primary colorectal carcinomas, whereas remaining cases were genetically distinct from their primary carcinomas. These findings underscore the need to evaluate metastatic lesions separately for optimized therapy, rather than to extrapolate from primary tumor data.

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

“…Interestingly, our study also reports high occurrence of p.Q472H (21 out of 22 patients) type of mutation which highlights the role of p.Q472H mutation in the KDR gene. This is also substantiated by the study in which p.Q472H has been found to be mutated in large intestine carcinomas [12].…”

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…45-48 Together, these findings indicate major differences between liver metastases and primary CRC as well as peritoneal metastases, including differences in immune cell infiltration and inhibitory molecule expression, which may be at least partly induced by the liver environment. We therefore suggest that TIL of MMR-proficient LM-CRC may be more sensitive to PD-1/PD-L1 blockade and other checkpoint inhibitors than TIL of MMR-proficient primary CRC and CRC metastases at other anatomical locations.…”

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

“…Screening, surgery, and medical therapies are successful in the management of early-stage colorectal REVIEW cancer, but far less effi cacious in advanced stages of the disease. A key reason for the limited success of colorectal cancerdirected therapies is the cancer's intrinsic heterogeneity, which is more prominent in the metastatic setting ( 5,6 ). Molecular characterization of colorectal cancers revealed that heterogeneity plays an important role, especially in the context of resistance to therapy.…”