PURPOSE: A73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. PATIENTS AND METHODS: Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. RESULTS: The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. CONCLUSION: POLD1 mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.
PURPOSE: A73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. PATIENTS AND METHODS: Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. RESULTS: The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. CONCLUSION: POLD1 mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.
Authors: Monica M Bertagnolli; Mark Redston; Carolyn C Compton; Donna Niedzwiecki; Robert J Mayer; Richard M Goldberg; Thomas A Colacchio; Leonard B Saltz; Robert S Warren Journal: J Clin Oncol Date: 2011-07-11 Impact factor: 44.544
Authors: Jantine L Westra; Ludolf G Boven; Pieter van der Vlies; Hendrika Faber; Birgit Sikkema; Michael Schaapveld; Trijnie Dijkhuizen; Harry Hollema; Charles H C M Buys; John T M Plukker; Klaas Kok; Robert M W Hofstra Journal: Genes Chromosomes Cancer Date: 2005-06 Impact factor: 5.006
Authors: Naiyer A Rizvi; Matthew D Hellmann; Alexandra Snyder; Pia Kvistborg; Vladimir Makarov; Jonathan J Havel; William Lee; Jianda Yuan; Phillip Wong; Teresa S Ho; Martin L Miller; Natasha Rekhtman; Andre L Moreira; Fawzia Ibrahim; Cameron Bruggeman; Billel Gasmi; Roberta Zappasodi; Yuka Maeda; Chris Sander; Edward B Garon; Taha Merghoub; Jedd D Wolchok; Ton N Schumacher; Timothy A Chan Journal: Science Date: 2015-03-12 Impact factor: 47.728
Authors: Giuseppe Toffoli; Manish R Sharma; Elena Marangon; Bianca Posocco; Elizabeth Gray; Quan Mai; Angela Buonadonna; Blase N Polite; Gianmaria Miolo; Gianna Tabaro; Federico Innocenti Journal: Clin Cancer Res Date: 2016-08-09 Impact factor: 12.531
Authors: Xiaobei Zhao; Anyou Wang; Vonn Walter; Nirali M Patel; David A Eberhard; Michele C Hayward; Ashley H Salazar; Heejoon Jo; Matthew G Soloway; Matthew D Wilkerson; Joel S Parker; Xiaoying Yin; Guosheng Zhang; Marni B Siegel; Gary B Rosson; H Shelton Earp; Norman E Sharpless; Margaret L Gulley; Karen E Weck; D Neil Hayes; Stergios J Moschos Journal: PLoS One Date: 2015-06-15 Impact factor: 3.240
Authors: S Bamford; E Dawson; S Forbes; J Clements; R Pettett; A Dogan; A Flanagan; J Teague; P A Futreal; M R Stratton; R Wooster Journal: Br J Cancer Date: 2004-07-19 Impact factor: 7.640
Authors: Claire Palles; Jean-Baptiste Cazier; Kimberley M Howarth; Enric Domingo; Angela M Jones; Peter Broderick; Zoe Kemp; Sarah L Spain; Estrella Guarino; Estrella Guarino Almeida; Israel Salguero; Amy Sherborne; Daniel Chubb; Luis G Carvajal-Carmona; Yusanne Ma; Kulvinder Kaur; Sara Dobbins; Ella Barclay; Maggie Gorman; Lynn Martin; Michal B Kovac; Sean Humphray; Anneke Lucassen; Christopher C Holmes; David Bentley; Peter Donnelly; Jenny Taylor; Christos Petridis; Rebecca Roylance; Elinor J Sawyer; David J Kerr; Susan Clark; Jonathan Grimes; Stephen E Kearsey; Huw J W Thomas; Gilean McVean; Richard S Houlston; Ian Tomlinson Journal: Nat Genet Date: 2012-12-23 Impact factor: 38.330
Authors: Paul Little; Heejoon Jo; Alan Hoyle; Angela Mazul; Xiaobei Zhao; Ashley H Salazar; Douglas Farquhar; Siddharth Sheth; Maheer Masood; Michele C Hayward; Joel S Parker; Katherine A Hoadley; Jose Zevallos; D Neil Hayes Journal: NAR Cancer Date: 2021-10-06