title: Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection.
abstract: Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients' clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter-metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three-year progression-free and overall survival rate of 23% and 66% respectively, versus 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2-0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1-0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts.
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anita
authors.initials: A
authors.lastname: Sveen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Inger Marie
authors.initials: IM
authors.lastname: Løes
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Sharmini
authors.identifier: 0000-0003-4353-9279
authors.initials: S
authors.lastname: Alagaratnam
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Computer Science, University of Oslo, Oslo, Norway.
authors.forename: Gro
authors.identifier: 0000-0002-2044-4712
authors.initials: G
authors.lastname: Nilsen
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Maren
authors.initials: M
authors.lastname: Høland
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Computer Science, University of Oslo, Oslo, Norway.
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjærde
authors.affiliation: Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Halfdan
authors.initials: H
authors.lastname: Sorbye
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kaja Christine Graue
authors.identifier: 0000-0001-5509-0638
authors.initials: KC
authors.lastname: Berg
authors.affiliation: Department of Digestive Surgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Arild
authors.initials: A
authors.lastname: Horn
authors.affiliation: Department of Digestive Surgery, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Jon-Helge
authors.initials: JH
authors.lastname: Angelsen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.|K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.|Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D056915:DNA Copy Number Variations / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016896:Treatment Outcome