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. 2022 Nov 1;6(6):pkac074.
doi: 10.1093/jncics/pkac074.

Impact of Transcript (p16/p14ARF) Alteration on Cancer Risk in CDKN2A Germline Pathogenic Variant Carriers

Michael R Sargen  1 , Hildur Helgadottir  2 , Xiaohong R Yang  1 , Mark Harland  3 , Jessica N Hatton  1 , Kristine Jones  1   4 , Belynda D Hicks  1   4 , Amy Hutchinson  1   4 , Michael Curry  5 , Margaret A Tucker  1 , Alisa M Goldstein  1 , Ruth M Pfeiffer  1
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Impact of Transcript (p16/p14ARF) Alteration on Cancer Risk in CDKN2A Germline Pathogenic Variant Carriers

Michael R Sargen et al. JNCI Cancer Spectr. .

Abstract

Background: Few studies have evaluated the relationship between CDKN2A germline pathogenic variants (GPV), transcript (p16/p14ARF) alteration, and cancer risk.

Methods: Standardized incidence ratios (SIRs) comparing cancer risk with the general population were calculated for 385 CDKN2A GPV carriers from 2 large cohorts (259 United States and 126 Swedish individuals) using Poisson regression; statistical significance was defined as P less than .002 (Bonferroni correction). Cumulative incidence is reported for melanoma and nonmelanoma cancer.

Results: Incidence was increased for melanoma (SIR = 159.8, 95% confidence interval [CI] = 132.1 to 193.2), pancreatic cancer (SIR = 24.1, 95% CI = 14.7 to 39.4), head and neck squamous cell carcinoma (SIR = 16.2, 95% CI = 9.5 to 27.6), and lung cancer (SIR = 5.6, 95% CI = 3.4 to 9.1) in GPV carriers. Similar associations were observed with p16 alteration. Combined p16 and p14ARF alteration was associated with increased incidence of esophageal cancer (SIR = 16.7, 95% CI = 5.7 to 48.9) and malignant peripheral nerve sheath tumor (SIR = 113.0, 95% CI = 16.4 to 780.9), although cancer events were limited (n < 5 for each malignancy). Cumulative incidence at age 70 years for melanoma and nonmelanoma cancer was 68.3% (95% CI = 68.0% to 68.6%) and 35.2% (95% CI = 34.9% to 35.6%), respectively. A total 89% of smoking-related cancers (lung, head and neck squamous cell carcinoma, pancreatic, esophageal) occurred in ever smokers.

Conclusion: These findings highlight the impact of p16 and p14ARF alteration on cancer risk. Smoking was an important risk factor for smoking-related cancers in our study.

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Figures

Figure 1.
Figure 1.
Cumulative incidence of melanoma and the most prevalent nonmelanoma cancer types in individuals with CDKN2A germline pathogenic variants. Cumulative incidence accounting for competing mortality was estimated nonparametrically for melanoma and nonmelanoma cancer types in US and Swedish CDKN2A germline pathogenic variant carriers using the Aalen-Johansen estimator. Follow-up started at birth and ended at incidence of the cancer of interest, death from other causes, or end of follow-up.
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