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Colorectal cancer risk and patients’ survival: influence of polymorphisms in genes somatically mutated in colorectal tumors

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Abstract

Purpose

The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations.

Methods

After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive Allele‐Specific PCR™ genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients’ survival (406 cases).

Results

In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively).

Conclusion

Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.

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Acknowledgments

We would like to thank all patients and blood donors for their participation in this research study on CRC susceptibility and prognosis. This work has been supported by the Grant Agency of the Czech Republic (GACR) and the Ministry of Education, Youth and Sport of the Czech Republic. [Grant Numbers: CZ:GA CR:GA304/12/1585, CZ:GA CR:GA304/10/1286, and Prvouk-P27/LF1/1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Ethical standard

According to the Helsinki declaration, all patients and blood donors provided a written informed consent and approved the use of their biological samples for genetic studies (Medical ethics manual; WMA) [54]. The study was approved by the Ethics Committees of the Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague (Czech Republic); Institute for Clinical and Experimental Medicine and Faculty Thomayer Hospital, Prague (Czech Republic).

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Authors and Affiliations

  1. Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany

    Stefanie Huhn, Melanie Bevier, Kari Hemminki & Asta Försti

  2. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14200, Prague, Czech Republic

    Barbara Pardini & Alessio Naccarati

  3. Human Genetics Foundation (HuGeF), 10126, Turin, Italy

    Barbara Pardini, Alessio Naccarati, Ludmila Vodickova & Pavel Vodicka

  4. 1st Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, 12000, Prague, Czech Republic

    Ludmila Vodickova & Pavel Vodicka

  5. Department of Oncology, General Teaching Hospital, 12808, Prague, Czech Republic

    Jan Novotny

  6. Center of Primary Health Care Research, Clinical Research Center, Lund University, 20502, Malmö, Sweden

    Kari Hemminki & Asta Försti

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  1. Stefanie Huhn
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Correspondence to Stefanie Huhn.

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Huhn, S., Bevier, M., Pardini, B. et al. Colorectal cancer risk and patients’ survival: influence of polymorphisms in genes somatically mutated in colorectal tumors. Cancer Causes Control 25, 759–769 (2014). https://doi.org/10.1007/s10552-014-0379-1

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