title: Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing.
abstract: Colorectal cancer (CRC) patients have poor prognosis after formation of distant metastasis. Understanding the molecular mechanisms by which genetic changes facilitate metastasis is critical for the development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. A comprehensive portrait of somatic alterations in CRC and the changes between primary and metastatic tumors has yet to be developed. We performed whole genome sequencing of two primary CRC tumors and their matched liver metastases. By comparing to matched germline DNA, we catalogued somatic alterations at multiple scales, including single nucleotide variations, small insertions and deletions, copy number aberrations and structural variations in both the primary and matched metastasis. We found that the majority of these somatic alterations are present in both sites. Despite the overall similarity, several de novo alterations in the metastases were predicted to be deleterious, in genes including FBXW7, DCLK1 and FAT2, which might contribute to the initiation and progression of distant metastasis. Through careful examination of the mutation prevalence among tumor cells at each site, we also proposed distinct clonal evolution patterns between primary and metastatic tumors in the two cases. These results suggest that somatic alterations may play an important role in driving the development of colorectal cancer metastasis and present challenges and opportunities when considering the choice of treatment.
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: tao.xie@pfizer.com.
authors: Tao
authors: T
authors: Xie
authors: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: yongbeom.cho@samsung.com.
authors: Yong Beom
authors: YB
authors: Cho
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: Kai.Wang4@pfizer.com.
authors: Kai
authors: K
authors: Wang
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: DonghuiStephen.Huang@pfizer.com.
authors: Donghui
authors: D
authors: Huang
authors: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: hhk0719@hotmail.com.
authors: Hye Kyung
authors: HK
authors: Hong
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: yla.choi@samsung.com.
authors: Yoon-La
authors: YL
authors: Choi
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: younghyeh.ko@samsung.com.
authors: Young Hyeh
authors: YH
authors: Ko
authors: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: biovictory2@gmail.com.
authors: Do-Hyun
authors: DH
authors: Nam
authors: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: juyoun.jin@samsung.com.
authors: Juyoun
authors: J
authors: Jin
authors: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: heekyoungyang@gmail.com.
authors: Heekyoung
authors: H
authors: Yang
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: Julio.Fernandez@pfizer.com.
authors: Julio
authors: J
authors: Fernandez
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: Shibing.Deng@pfizer.com.
authors: Shibing
authors: S
authors: Deng
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: Paul.Rejto@pfizer.com.
authors: Paul A
authors: PA
authors: Rejto
authors: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: wooyong123.lee@samsung.com.
authors: Woo Yong
authors: WY
authors: Lee
authors: Oncology Research, Pfizer Worldwide Research and Development, San Diego, CA, USA. Electronic address: mao_m@yahoo.com.
authors: Mao
authors: M
authors: Mao
mesh_terms: D000368:Aged; D015820:Cadherins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D000089742:Doublecortin-Like Kinases; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D054643:INDEL Mutation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D015820:Cadherins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C502404:FAT2 protein, human; C513273:FBXW7 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D044767:Ubiquitin-Protein Ligases; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases
keywords: Colorectal cancer; Metastasis; Somatic alteration; Whole genome sequencing