Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS)

Sukanya Horpaopan; Jutta Kirfel; Sophia Peters; Michael Kloth; Robert Hüneburg; Janine Altmüller; Dmitriy Drichel; Margarete Odenthal; Glen Kristiansen; Christian Strassburg; Jacob Nattermann; Per Hoffmann; Peter Nürnberg; Reinhard Büttner; Holger Thiele; Philip Kahl; Isabel Spier; Stefan Aretz

doi:10.1186/s13053-017-0082-9

Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS)

Hered Cancer Clin Pract. 2017 Nov 29:15:22. doi: 10.1186/s13053-017-0082-9. eCollection 2017.

Authors

Sukanya Horpaopan^{1

2

3}, Jutta Kirfel^{4

5}, Sophia Peters¹, Michael Kloth⁶, Robert Hüneburg^{5

7}, Janine Altmüller^{8

9}, Dmitriy Drichel⁸, Margarete Odenthal⁶, Glen Kristiansen^{4

5}, Christian Strassburg^{5

7}, Jacob Nattermann^{5

7}, Per Hoffmann^{1

10

11}, Peter Nürnberg⁸, Reinhard Büttner⁶, Holger Thiele⁸, Philip Kahl¹², Isabel Spier^{1

5}, Stefan Aretz^{1

5

13}

Affiliations

¹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
² Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
³ Center of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok, Thailand.
⁴ Institute of Pathology, University of Bonn, Bonn, Germany.
⁵ Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
⁶ Institute of Pathology, University of Cologne, Cologne, Germany.
⁷ Department of Internal Medicine I, University of Bonn, Bonn, Germany.
⁸ Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
⁹ Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
¹⁰ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
¹¹ Institute of Medical Genetics and Pathology, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
¹² Heinz-Werner-Seifert-Institut für Dermatopathologie Bonn, Bonn, Germany.
¹³ Institute of Human Genetics, Center for Hereditary Tumor Syndromes, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany.

Abstract

Background: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified.

Methods: To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing.

Results: The BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected.

Conclusions: Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS.

Keywords: Exome sequencing; Familial colorectal cancer (CRC); Hyperplastic polyposis syndrome (HPS); Serrated pathway; Serrated polyposis syndrome (SPS); Somatic mutations.