Copy number and transcriptome alterations associated with metastatic lesion response to treatment in colorectal cancer.

Autor: Gambaro K; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada.; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Marques M; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada.; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., McNamara S; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada., Couetoux du Tertre M; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada., Diaz Z; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada., Hoffert C; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada.; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Srivastava A; Canadian National Centres of Excellence-Exactis Innovation, 5450 Cote-des-Neiges, Montreal, Quebec, H3T 1Y6, Canada.; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Hébert S; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Samson B; Charles LeMoyne Hospital, 3120 Taschereau Blvd., Greenfield Park, Quebec, J4V 2H1, Canada., Lespérance B; Sacré-Coeur de Montréal, 5400 Boul. Gouin O, Montreal, Quebec, H4J 1C5, Canada., Ko YJ; Sunnybrook Health Science Centre, 2075 Bayview Ave., Toronto, Ontario, M4N 3M5, Canada., Dalfen R; St. Mary's Hospital, 3830 Lacombe, Montreal, Quebec, H3T 1M5, Canada., St-Hilaire E; Georges Dumont Hospital, 220 Avenue Universite, Moncton, New Brunswick, E1C 2Z3, Canada., Sideris L; Hôpital Maisonneuve Rosemont, 5415 Assumption Blvd, Montreal, Quebec, H1T 2M4, Canada., Couture F; Hôtel-Dieu de Quebec, 11 Cote du Palais, Montreal, Quebec, G1R 2J6, Canada., Burkes R; Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada., Harb M; Moncton Hospital, 135 Macbeath Ave, Moncton, New Brunswick, E1C 6Z8, Canada., Camlioglu E; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Gologan A; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Pelsser V; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Constantin A; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Greenwood CMT; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada.; Gerald Bronfman Department of Oncology, McGill University, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada.; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Tejpar S; Digestive Oncology Unit, Katholieke Universiteit Leuven, Oude Markt 13, Leuven, 3000, Belgium., Kavan P; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Kleinman CL; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada.; Department of Human Genetics, Lady Davis Research Institute, McGill University, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada., Batist G; McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2021 Apr; Vol. 11 (4), pp. e401.
DOI: 10.1002/ctm2.401
Abstrakt: Background: Therapeutic resistance is the main cause of death in metastatic colorectal cancer. To investigate genomic plasticity, most specifically of metastatic lesions, associated with response to first-line systemic therapy, we collected longitudinal liver metastatic samples and characterized the copy number aberration (CNA) landscape and its effect on the transcriptome.
Methods: Liver metastatic biopsies were collected prior to treatment (pre, n = 97) and when clinical imaging demonstrated therapeutic resistance (post, n = 43). CNAs were inferred from whole exome sequencing and were correlated with both the status of the lesion and overall patient progression-free survival (PFS). We used RNA sequencing data from the same sample set to validate aberrations as well as independent datasets to prioritize candidate genes.
Results: We identified a significantly increased frequency gain of a unique CN, in liver metastatic lesions after first-line treatment, on chr18p11.32 harboring 10 genes, including TYMS, which has not been reported in primary tumors (GISTIC method and test of equal proportions, FDR-adjusted p = 0.0023). CNA lesion profiles exhibiting different treatment responses were compared and we detected focal genomic divergences in post-treatment resistant lesions but not in responder lesions (two-tailed Fisher's Exact test, unadjusted p ≤ 0.005). The importance of examining metastatic lesions is highlighted by the fact that 15 out of 18 independently validated CNA regions found to be associated with PFS in this study were only identified in the metastatic lesions and not in the primary tumors.
Conclusion: This investigation of genomic-phenotype associations in a large colorectal cancer liver metastases cohort identified novel molecular features associated with treatment response, supporting the clinical importance of collecting metastatic samples in a defined clinical setting.
(© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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