title: Massive interstitial copy-neutral loss-of-heterozygosity as evidence for cancer being a disease of the DNA-damage response.
abstract: BACKGROUND
  The presence of loss-of-heterozygosity (LOH) mutations in cancer cell genomes is commonly encountered. Moreover, the occurrences of LOHs in tumor suppressor genes play important roles in oncogenesis. However, because the causative mechanisms underlying LOH mutations in cancer cells yet remain to be elucidated, enquiry into the nature of these mechanisms based on a comprehensive examination of the characteristics of LOHs in multiple types of cancers has become a necessity.
  
  
  METHODS
  We performed next-generation sequencing on inter-Alu sequences of five different types of solid tumors and acute myeloid leukemias, employing the AluScan platform which entailed amplification of such sequences using multiple PCR primers based on the consensus sequences of Alu elements; as well as the whole genome sequences of a lung-to-liver metastatic cancer and a primary liver cancer. Paired-end sequencing reads were aligned to the reference human genome to identify major and minor alleles so that the partition of LOH products between homozygous-major vs. homozygous-minor alleles could be determined at single-base resolution. Strict filtering conditions were employed to avoid false positives. Measurements of LOH occurrences in copy number variation (CNV)-neutral regions were obtained through removal of CNV-associated LOHs.
  
  
  RESULTS
  We found: (a) average occurrence of copy-neutral LOHs amounting to 6.9% of heterologous loci in the various cancers; (b) the mainly interstitial nature of the LOHs; and (c) preference for formation of homozygous-major over homozygous-minor, and transitional over transversional, LOHs.
  
  
  CONCLUSIONS
  The characteristics of the cancer LOHs, observed in both AluScan and whole genome sequencings, point to the formation of LOHs through repair of double-strand breaks by interhomolog recombination, or gene conversion, as the consequence of a defective DNA-damage response, leading to a unified mechanism for generating the mutations required for oncogenesis as well as the progression of cancer cells.
authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. ykumar@ust.hk.
authors.forename: Yogesh
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authors.lastname: Kumar
authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. jyangad@ust.hk.
authors.forename: Jianfeng
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authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. thuac@connect.ust.hk.
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authors.affiliation: Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China. chenlein39@hotmail.com.
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authors.affiliation: Department of Oncology, Nanjing First Hospital, and Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. michelle.xuzhi@gmail.com.
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authors.affiliation: Jiangsu Key Laboratory of Cancer Molecular Biology and Translational Medicine, Jiangsu Cancer Hospital, Nanjing, China. xulin83@vip.sina.com.
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authors.affiliation: Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China. huxiaoxia@gmail.com.
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authors.affiliation: Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China. drake015@163.com.
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authors.affiliation: Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China. 13701792437@139.com.
authors.forename: Jian-Min
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authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. yili@surgery.cuhk.edu.hk.
authors.forename: Yi
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authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. wpoon@surgery.cuhk.edu.hk.
authors.forename: Wai-Sang
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authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China. weiqingw@sina.com.
authors.forename: Weiqing
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authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Dongcheng District, Beijing, 100050, China. zlwtt@gmail.com.
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authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. bcmwk@ust.hk.
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authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. frankwpun@gmail.com.
authors.forename: Frank W
authors.initials: FW
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authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. bcsauyat@ust.hk.
authors.forename: Peggy
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authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. hycab@ust.hk.
authors.forename: Timothy H Y
authors.initials: TH
authors.lastname: Cheong
authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. xding@connect.ust.hk.
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. bcnskaa@ust.hk.
authors.forename: Siu-Kin
authors.initials: SK
authors.lastname: Ng
authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. ystang@ust.hk.
authors.forename: Shui-Ying
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authors.lastname: Tsang
authors.affiliation: Department of Oncology, Nanjing First Hospital, and Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. jinfeichen@sohu.com.
authors.forename: Jin-Fei
authors.initials: JF
authors.lastname: Chen
authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST, and Department of Automation, Tsinghua University, Beijing, 100084, China. 1223114512@qq.com.
authors.forename: Peng
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authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST, and Department of Automation, Tsinghua University, Beijing, 100084, China. shaoli@mail.tsinghua.edu.cn.
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authors.affiliation: Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China. hywangk@vip.sina.com.
authors.forename: Hong-Yang
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authors.affiliation: Division of Life Science, Applied Genomics Centre and Centre for Statistical Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. hxue@ust.hk.
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mesh_terms: D000483:Alleles; D002877:Chromosomes, Human / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA