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Genotype-phenotype correlations
Original research
Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants
  1. Kasper A Overbeek1,
  2. Mar DM Rodríguez-Girondo2,
  3. Anja Wagner3,
  4. Nienke van der Stoep4,
  5. Peter C van den Akker5,
  6. Jan C Oosterwijk5,
  7. Theo A van Os5,
  8. Lizet E van der Kolk6,
  9. Hans F A Vasen7,
  10. Frederik J Hes4,
  11. Djuna L Cahen1,
  12. Marco J Bruno1,
  13. Thomas P Potjer4
  1. 1 Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
  2. 2 Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
  3. 3 Department of Clinical Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  4. 4 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  6. 6 Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  7. 7 Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Mr Thomas P Potjer, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; T.P.Potjer{at}lumc.nl

Abstract

Background Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants.

Methods Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families.

Results We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%).

Conclusions Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk.

  • clinical genetics
  • gastroenterology
  • genetic screening/counselling
  • pancreas and biliary tract
  • oncology
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/jmedgenet-2019-106562

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    Footnotes

    • Contributors The study was initiated and designed by KAO, AW and TPP. Variant analysis and interpretation was performed by NvdS. Clinical pedigree information was collected by KAO, AW, PCvdA, JCO, TvO, LEvdK and TPP. Statistical data analysis was performed by MR-G and the results were interpreted by KAO, MR-G, DLC, MJB and TPP. The manuscript was drafted by KAO and TPP, and critically reviewed by HFAV, FH, DLC and MJB. All authors approved the final manuscript.

    • Funding TPP is supported by a grant from the Dutch Cancer Society (#UL 2015-7511).

    • Competing interests DLC is a consultant to Tramedico. MJB received research funding from Boston Scientific, Cook Medical, and Pentax Medical. He is a consultant to Boston Scientific, Cook Medical, Pentax Medical and Mylan. The other authors have no potential competing interests to disclose.

    • Patient consent for publication Not required.

    • Ethics approval The creation of the Dutch national database for familial melanoma received ethical approval from the institutional review board of the Leiden University Medical Center (#C14.064).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Study data are available upon reasonable request.