Integrated Cancer Genomics Division, Translational Genomics Research Institute, 445 N. Fifth Ave, Phoenix, AZ 85004, USA ; Virginia G Piper Cancer Center, 10290 N. 92nd St, Scottsdale, AZ 85258, USA.
Neurogenomics Division, Translational Genomics Research Institute, 445 N. Fifth Ave, Phoenix, AZ 85004, USA.
Genome Med. 2012 Jul 4;4(7):56. doi: 10.1186/gm357. eCollection 2012.
Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scale clinical trials are daunting, this targeted genomic approach offers a new perspective and hope for improved treatments. Cancers of the ampulla of Vater are rare tumors that comprise only about 0.2% of gastrointestinal cancers. Consequently, they are often treated as either distal common bile duct or pancreatic cancers.
We analyzed DNA from a resected cancer of the ampulla of Vater and whole blood DNA from a 63 year-old man who underwent a pancreaticoduodenectomy by whole genome sequencing, achieving 37× and 40× coverage, respectively. We determined somatic mutations and structural alterations.
We identified relevant aberrations, including deleterious mutations of KRAS and SMAD4 as well as a homozygous focal deletion of the PTEN tumor suppressor gene. These findings suggest that these tumors have a distinct oncogenesis from either common bile duct cancer or pancreatic cancer. Furthermore, this combination of genomic aberrations suggests a therapeutic context for dual mTOR/PI3K inhibition.
Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.
近年来，癌症治疗的重点集中在使用选择性治疗药物靶向基因组异常。在罕见肿瘤中，大规模临床试验令人望而却步，这种靶向基因组方法为改善治疗提供了新的视角和希望。壶腹癌是一种罕见的肿瘤，仅占胃肠道癌的 0.2%左右。因此，它们通常被视为远端胆总管癌或胰腺癌进行治疗。
我们通过全基因组测序分析了一名接受胰十二指肠切除术的 63 岁男性的壶腹癌切除组织和全血 DNA，分别达到 37×和 40×的覆盖度。我们确定了体细胞突变和结构改变。
我们发现了相关的异常，包括 KRAS 和 SMAD4 的有害突变，以及 PTEN 肿瘤抑制基因的纯合性焦点缺失。这些发现表明，这些肿瘤的发生机制与胆总管癌或胰腺癌不同。此外，这种基因组异常的组合提示存在双重 mTOR/PI3K 抑制的治疗背景。
全基因组测序可以阐明致癌背景，并揭示罕见癌症中的潜在治疗弱点。
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