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. 2021 Apr;58(4):264-269.
doi: 10.1136/jmedgenet-2019-106562. Epub 2020 Jun 1.

Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants

Kasper A Overbeek  1 , Mar Dm Rodríguez-Girondo  2 , Anja Wagner  3 , Nienke van der Stoep  4 , Peter C van den Akker  5 , Jan C Oosterwijk  5 , Theo A van Os  5 , Lizet E van der Kolk  6 , Hans F A Vasen  7 , Frederik J Hes  4 , Djuna L Cahen  1 , Marco J Bruno  1 , Thomas P Potjer  8
Affiliations

Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants

Kasper A Overbeek et al. J Med Genet. 2021 Apr.

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.

Keywords: clinical genetics; gastroenterology; genetic screening/counselling; oncology; pancreas and biliary tract.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Visualisation of variant frequencies and pancreatic cancer occurrence. PDAC, pancreatic ductal adenocarcinoma.
Figure 2
Figure 2
Cumulative pancreatic cancer incidence for c.67G>C, p.(Gly23Arg) carriers, with 95% CIs shown as dashed lines.
See this image and copyright information in PMC

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