Skip to main content
Download PDF

CDKN2A germline alterations and the relevance of genotype-phenotype associations in cancer predisposition

Hereditary Cancer in Clinical Practice volume 19, Article number: 21 (2021) Cite this article

Abstract

Although CDKN2A is well-known as a susceptibility gene for melanoma and pancreatic cancer, germline variants have also been anecdotally associated with a broader range of neoplasms including neural system tumors, head and neck squamous cell carcinomas, breast carcinomas, as well as sarcomas. The CDKN2A gene encodes for two distinct tumor suppressor proteins, p16INK4A and p14ARF, however, the independent association of germline alterations affecting these two proteins with cancer is under-appreciated. Here, we reviewed CDKN2A germline alterations reported among individuals and families with cancer in the literature, specifically addressing the cancer phenotypes in relation to the molecular consequence on p16INK4A and p14ARF. While melanoma is observed to associate with variants affecting both p16INK4A and p14ARF transcripts, it is noted that variants affecting p14ARF are more frequently observed with a heterogenous range of cancers. Finally, we reflected on the implications of this inferred genotype-phenotype association in clinical practice and proposed that clinical management of CDKN2A germline variant carriers should involve dedicated cancer genetics services, with multidisciplinary input from various healthcare professionals.

Peer Review reports

Background

CDKN2A (cyclin dependent kinase inhibitor 2A, OMIM 600160) is a tumor suppressor gene that encodes for two proteins, namely p16INK4A and p14ARF, critical for the regulation of cell cycle pathways. Genetic and epigenetic alterations inactivating CDKN2A are frequently encountered in a myriad of cancers, with base sequence-altering events more common in cancer types such as melanoma, head and neck squamous cell carcinoma (HNSCC), pancreatic cancer, lung cancer, esophageal cancer, and glioblastoma multiforme (GBM) [1,2,3]. Germline alterations in CDKN2A are most frequently associated with predisposition to melanoma and pancreatic cancer [4,5,6,7,8], detected through gene-panel testing in about 38% of melanoma-prone families [6, 9] but there have been sporadic reports implicating susceptibility to other neoplasms such as neural system tumors (NSTs), breast cancer, multiple myeloma, HNSCC, and sarcoma [10,11,12,13,14,15,16,17,18]. It is plausible that the varying cancer types reported with CDKN2A genetic alterations can be distinguished by the different variant effects on p16INK4A and p14ARF, although evidence to date are limited and conflicting [12, 13, 16, 19,20,21]. Here, we reviewed the spectrum of CDKN2A germline variants and associated neoplasms reported in literature, focusing on the relationship between distinct variant consequences on p16INK4A/p14ARF with the reported phenotypes. Variants evaluated include those detected in affected individuals through sequencing and/or classified as pathogenic or likely pathogenic in ClinVar database (version 2020-09-08, https://www.ncbi.nlm.nih.gov/clinvar/) without conflicts in interpretation.

p16INK4A/p14ARF locus in the CDKN2A gene

The CDKN2A gene spans 27.5 kb on chromosome 9p21 and is associated with over 10 transcript variants, of which the largest two encode for p16INK4A and p14ARF [22]. p16INK4A is a 156 amino acid protein translated from a transcript of three exons (exons 1α,2,3; RefSeq NM_000077), known to negatively regulate cell cycle progression through inhibition of cyclin-dependent kinases [23]. The largest transcript produces p14ARF (RefSeq NM_058195), a 132 amino acid protein, encoded via an alternative open-reading frame and first exon (exon 1β), with an established role of promoting p53 function through sequestration of MDM2 [24]. Consequently, p16INK4A and p14ARF are distinct proteins with different roles and no sequence homology, sharing only the use of same exons 2 and 3. Notably, although both tumor suppressors are encoded by three exons of similar size (exon1α: 421 bp, exon 1β: 486 bp, exon 2: 307 bp, exon 3: 490 bp), the bulk of translated sequence is localized to exon 1α/1β and exon 2.

Spectrum of p16INK4A/p14ARF variants associated with neoplasms

There are differences in molecular consequences of CDKN2A variants reported in literature on p16INK4A and p14ARF, which is expected given the use of different open-reading frames. Most of the p16INK4A-affecting variants are missense changes (28/55) followed by protein-disrupting variants (20/55, including truncating and null effects), occurring on exon1α and exon 2 (Table 1). In comparison, almost one-third of these reported variants fall within intron 1 of p14ARF transcript corresponding to exon1α of p16INK4A, followed by missense (16/62) and protein-disrupting (13/62) changes, which are mostly concentrated in exon 2 of p14ARF. Due to the difference in transcript architecture, there is an overall higher likelihood of encountering variants outside of protein sequence-coding regions (e.g. intronic, 3-prime untranslated region) in p14ARF compared to p16INK4A.

Table 1 Pathogenic/likely pathogenic germline variants in CDKN2A affecting p16INK4A, p14ARF transcripts and the associated neoplasms reported in the literature
Full size table

Based on the distribution of reported neoplasms with germline CDKN2A variants in Table 1, the association with melanoma is evidently irrespective of variant consequence on both p16INK4A and p14ARF. Variants affecting p16INK4A coding transcript are more frequently observed with pancreatic cancer and HNSCC (23/55) compared to p14ARF (8/29). This association is supported by an analysis of Dutch melanoma families demonstrating pancreatic cancer events in 58% of families with p16INK4A-affecting variants but none among p14ARF-affecting carrier families [87]. Intriguingly, a broader spectrum of cancers – e.g. uterine cancer, NSTs, GBM, non-Hodgkin’s lymphoma – is noted to co-occur with p14ARF-affecting variants. Moreover, variants with a loss-of-function consequence exclusive to p14ARF, namely deletion of exon 1β, Glu33Glyfs*30 and Arg88*, were observed in individuals with adenocarcinomas of uterus, bladder and stomach, respectively. This apparent distinction of cancers observed with predicted loss either of p16INK4A or p14ARF function is congruent with the independent roles of both tumor suppressors in regulation of cell cycle progression and p53 pathway. In particular, the range of neoplasms co-occuring with p14ARF variants is reminiscent of Li-Fraumeni syndrome, which is characterized by constitutional mutations in TP53 and diminished p53 activity. Indeed, a dysregulated p53 pathway was observed exclusively in the malignant peripheral nerve sheath tumor (MPNST) of a germline CDKN2A deletion carrier diagnosed with synchronous HNSCC and MPNST [16]. It is also noteworthy that manifestations of neural system-related tumors such as MPNST, GBM, astrocytoma, and schwannoma were consistently reported together with families harbouring gross deletion of the CDKN2A locus and/or involving loss of an intact p14ARF [12, 13, 16, 62, 88], suggesting a constitutional deficiency of p14ARF associated with NSTs.

Collectively, these observed trends imply that CDKN2A-associated cancer susceptibility could be dependent on molecular consequence of the variant and affected transcript. While inferring this genotype-phenotype relationship is currently limited by the potential bias resulting from a p16INK4A-centric focus in CDKN2A-related literature, an appreciation for this distinction in p16INK4A/p14ARF and larger case-cohort studies designed to address the causal effect of the specific variants will provide clarity in the future.

Implications on clinical management

Presently, clinical genetic testing for CDKN2A is indicated for individuals with multiple primary melanoma and/or a family history of melanoma or pancreatic cancer [89]. However, the expanded spectrum of phenotype accompanying germline alterations in CDKN2A suggests that it may be relevant to consider CDKN2A as a candidate for tumor predisposition beyond melanoma and pancreatic cancer in clinical practice. Indeed, numerous carriers of pathogenic/likely pathogenic variants (P/LPV) listed in Table 1 reported a variable family history of cancers, including sarcoma, leukemia, lymphoma, astrocytoma and cancers of the breast, lung, and prostate. It has been alluded that constitutional deficiency in CDKN2A phenotypically mirrors the broad tumor spectrum characteristic of Li-Fraumeni syndrome [13, 16, 18, 90], hence clinicians and genetic professionals should consider CDKN2A as a differential diagnosis for cancers such as HNSCC, NSTs, breast cancer, and sarcomas. One potential approach is to evaluate at-risk individuals with an assessment tool built upon a scoring system that accounts for the spectrum of personal and family history of cancers, such as one proposed tailored-approach for clinical management of hereditary melanoma [91]. Additionally, it is important to be mindful that identification of CDKN2A genetic alterations has been historically restricted to the p16INK4A transcript, which would exclude the alternative coding region specific to p14ARF (i.e. exon 1β). This could result in missed diagnoses especially for neoplasms potentially driven by p14ARF deficiency, therefore it is imperative that genetic professionals comprehensively interrogate for alterations in both transcripts.

Current guidelines for clinicians managing individuals tested positive for CDKN2A germline P/LPV are directed towards surveillance for melanoma and pancreatic cancer. Carriers are recommended to undergo bi-annual comprehensive skin examination including scalp and genitalia by a dermatologist, supplemented with total body photography and dermoscopy [92, 93]. Earlier detection of melanoma and non-melanoma skin cancers have been demonstrated among carriers compliant to surveillance [94, 95], although larger cohort studies will be required to better evaluate the outcomes and factors influencing successful melanoma screening. Annual pancreatic surveillance with contrast-enhanced magnetic resonance imaging and/or endoscopic ultrasound is recommended for CDKN2A pathogenic variant carriers beginning age 40 years regardless of family history given their high lifetime risk [96] and emerging evidence supporting the potential for downstaging and improved 5-year overall survival [97,98,99]. Patients are also encouraged to adopt lifestyle modifications to reduce cancer risk, including regular exercise, healthy diet, limiting alcohol intake, practicing sun-smart behaviour and smoking cessation. Healthcare professionals caring for CDKN2A carriers should have a heightened index of suspicion for malignancies beyond melanoma and pancreatic cancer. Although there are currently no formal recommendations for surveillance beyond melanoma and pancreatic cancer, clinicians should monitor the presentation of neoplasms within patients’ families and consider individualized discussion on the risk and benefit of screening, especially for prevalent cancers. Additionally, at-risk family members should be offered familial genetic testing given that up to 44% of relatives of index patients carry the familial variant, of whom 96% were observed to comply with surveillance [100]. Considering the broad range of management strategies, a multidisciplinary approach to care through a centralized cancer genetics service will benefit these patients [101].

With the rapid uptake of multigene panel testing in clinical setting, new data will continuously re-frame our understanding on the genotype-phenotype associations relevant to CDKN2A. This is exemplified by a recent analysis evaluating the clinical phenotype and molecular results of hereditary cancer predisposition testing in 165,000 individuals, which revealed an association of germline CDKN2A pathogenic variants with increased risk for breast cancer (odds ratio: 3.35, 95% CI: 1.43–7.75) [102]. Clinicians should keep abreast with the constant updates given that this is an evolving field and that clinical management of individuals harbouring germline CDKN2A variants will likely recalibrate with time.

Conclusion

Cancer susceptibility among germline variant carriers of CDKN2A extend beyond the well-known predisposition to melanoma and pancreatic cancer, potentially associated with a multitude of cancers. The spectrum of associated cancer types may be driven by specific molecular consequences on p16INK4A and/or p14ARF, warranting validation in future studies. Clinicians and genetic professionals should be cognizant of this expanded range of phenotypes and consider CDKN2A as a candidate gene for tumor predisposition syndrome in individuals and families presenting with such broad spectrum of cancers.

Availability of data and materials

No new data or material. The data used and analysed in this review are derived from ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and cited publications.

Abbreviations

bp:

Base pairs

CI:

Confidence interval

GBM:

Glioblastoma multiforme

HNSCC:

Head and neck squamous cell carcinoma

kb:

Kilobase

MPNST:

Malignant peripheral nerve sheath tumor

NST:

Neural system tumor

P/LPV:

Pathogenic/likely pathogenic variants

References

  1. Zhao R, Choi BY, Lee M-H, Bode AM, Dong Z. Implications of genetic and epigenetic alterations of CDKN2A (p16(INK4a)) in cancer. EBioMedicine. 2016;8:30–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020;578:82–93.

    Article  CAS  Google Scholar 

  3. Potrony M, Puig-Butillé JA, Aguilera P, Badenas C, Carrera C, Malvehy J, et al. Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. J Am Acad Dermatol. 2014;71:888–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goldstein AM. Familial melanoma, pancreatic cancer and germline CDKN2A mutations. Hum Mutat. 2004;23:630.

    Article  PubMed  CAS  Google Scholar 

  5. Goldstein AM, Struewing JP, Fraser MC, Smith MW, Tucker MA. Prospective risk of cancer in CDKN2A germline mutation carriers. J Med Genet. 2004;41:421–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Casula M, Paliogiannis P, Ayala F, De Giorgi V, Stanganelli I, Mandalà M, et al. Germline and somatic mutations in patients with multiple primary melanomas: a next generation sequencing study. BMC Cancer. 2019;19:772.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bartsch DK, Sina-Frey M, Lang S, Wild A, Gerdes B, Barth P, et al. CDKN2A germline mutations in familial pancreatic cancer. Ann Surg. 2002;236:730–7.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319:2401–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44:99–106.

    Article  CAS  PubMed  Google Scholar 

  10. Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M, Måsbäck A, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst. 2000;92:1260–6.

    Article  CAS  PubMed  Google Scholar 

  11. Prowse AH, Schultz DC, Guo S, Vanderveer L, Dangel J, Bove B, et al. Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred. J Med Genet. 2003;40:e102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bahuau M, Vidaud D, Jenkins RB, Bièche I, Kimmel DW, Assouline B, et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 1998;58:2298–303.

    CAS  PubMed  Google Scholar 

  13. Sargen MR, Merrill SL, Chu EY, Nathanson KL. CDKN2A mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature. Br J Dermatol. 2016;175:785–9.

    Article  CAS  PubMed  Google Scholar 

  14. Dilworth D, Liu L, Stewart AK, Berenson JR, Lassam N, Hogg D. Germline CDKN2A mutation implicated in predisposition to multiple myeloma. Blood. 2000;95:1869–71.

    Article  CAS  PubMed  Google Scholar 

  15. Cabanillas R, Astudillo A, Valle M, de la Rosa J, Álvarez R, Durán NS, et al. Novel germline CDKN2A mutation associated with head and neck squamous cell carcinomas and melanomas. Head Neck. 2013;35:E80–4.

    Article  PubMed  Google Scholar 

  16. Chan SH, Lim WK, Michalski ST, Lim JQ, Ishak NDB, Met-Domestici M, et al. Germline hemizygous deletion of CDKN2A-CDKN2B locus in a patient presenting with li-Fraumeni syndrome. NPJ Genome Med. 2016;1:16015.

    Article  Google Scholar 

  17. Shah V, Boyd KD, Houlston RS, Kaiser MF. Constitutional mutation in CDKN2A is associated with long term survivorship in multiple myeloma: a case report. BMC Cancer. 2017;17:718.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Jouenne F, Chauvot de Beauchene I, Bollaert E, Avril M-F, Caron O, Ingster O, et al. Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. J Med Genet. 2017;54:607–12.

    Article  CAS  PubMed  Google Scholar 

  19. Rizos H, Darmanian AP, Holland EA, Mann GJ, Kefford RF. Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF. J Biol Chem. 2001;276:41424–34.

    Article  CAS  PubMed  Google Scholar 

  20. Laud K, Marian C, Avril MF, Barrois M, Chompret A, Goldstein AM, et al. Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma. J Med Genet. 2006;43:39–47.

    Article  CAS  PubMed  Google Scholar 

  21. Randerson-Moor JA, Harland M, Williams S, Cuthbert-Heavens D, Sheridan E, Aveyard J, et al. A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet. 2001;10:55–62.

    Article  CAS  PubMed  Google Scholar 

  22. Yates AD, Achuthan P, Akanni W, Allen J, Allen J, Alvarez-Jarreta J, et al. Ensembl 2020. Nucleic Acids Res. 2020;48:D682–8.

    Article  CAS  PubMed  Google Scholar 

  23. Romagosa C, Simonetti S, López-Vicente L, Mazo A, Lleonart ME, Castellvi J, et al. p16 Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene Nature Publishing Group. 2011;30:2087–97.

    Article  CAS  PubMed  Google Scholar 

  24. Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239–47.

    Article  CAS  PubMed  Google Scholar 

  25. Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril M-F, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818–28.

    Article  CAS  PubMed  Google Scholar 

  26. Huang K-L, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, et al. Pathogenic germline variants in 10,389 adult cancers. Cell. 2018;173:355–370.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Binni F, Antigoni I, De Simone P, Majore S, Silipo V, Crisi A, et al. Novel and recurrent p14 mutations in Italian familial melanoma. Clin Genet. 2010;77:581–6.

    Article  CAS  PubMed  Google Scholar 

  28. Hewitt C, Lee Wu C, Evans G, Howell A, Elles RG, Jordan R, et al. Germline mutation of ARF in a melanoma kindred. Hum Mol Genet. 2002;11:1273–9.

    Article  CAS  PubMed  Google Scholar 

  29. Potjer TP, Helgadottir H, Leenheer M, van der Stoep N, Gruis NA, Höiom V, et al. CM-score: a validated scoring system to predict CDKN2A germline mutations in melanoma families from Northern Europe. J Med Genet. 2018;55:661–8.

    Article  CAS  PubMed  Google Scholar 

  30. Pedace L, De Simone P, Castori M, Sperduti I, Silipo V, Eibenschutz L, et al. Clinical features predicting identification of CDKN2A mutations in Italian patients with familial cutaneous melanoma. Cancer Epidemiol. 2011;35:e116–20.

    Article  CAS  PubMed  Google Scholar 

  31. Harland M, Taylor CF, Chambers PA, Kukalizch K, Randerson-Moor JA, Gruis NA, et al. A mutation hotspot at the p14ARF splice site. Oncogene. 2005;24:4604–8.

    Article  CAS  PubMed  Google Scholar 

  32. Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17:569–77.

    Article  CAS  PubMed  Google Scholar 

  33. Puig S, Potrony M, Cuellar F, Puig-Butille JA, Carrera C, Aguilera P, et al. Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. Genet Med. 2016;18:727–36.

    Article  PubMed  Google Scholar 

  34. Monzon J, Liu L, Brill H, Goldstein AM, Tucker MA, From L, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med. 1998;338:879–87.

    Article  CAS  PubMed  Google Scholar 

  35. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94:894–903.

    Article  CAS  PubMed  Google Scholar 

  36. Pollock PM, Spurr N, Bishop T, Newton-Bishop J, Gruis N, van der Velden PA, et al. Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families: evidence for common founders and independent mutations. Hum Mutat. 1998;11:424–31.

    Article  CAS  PubMed  Google Scholar 

  37. Flores JF, Pollock PM, Walker GJ, Glendening JM, Lin AH, Palmer JM, et al. Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds. Oncogene. 1997;15:2999–3005.

    Article  CAS  PubMed  Google Scholar 

  38. MacGeoch C, Bishop JA, Bataille V, Bishop DT, Frischauf AM, Meloni R, et al. Genetic heterogeneity in familial malignant melanoma. Hum Mol Genet. 1994;3:2195–200.

    Article  CAS  PubMed  Google Scholar 

  39. Walker GJ, Hussussian CJ, Flores JF, Glendening JM, Haluska FG, Dracopoli NC, et al. Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum Mol Genet. 1995;4:1845–52.

    Article  CAS  PubMed  Google Scholar 

  40. Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3:464–71.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Casula M, Colombino M, Satta MP, Cossu A, Lissia A, Budroni M, et al. Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy. Eur J Cancer. 2007;43:137–43.

    Article  CAS  PubMed  Google Scholar 

  42. Taylor NJ, Mitra N, Goldstein AM, Tucker MA, Avril M-F, Azizi E, et al. Germline variation at CDKN2A and associations with nevus phenotypes among members of melanoma families. J Invest Dermatol. 2017;137:2606–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. FitzGerald MG, Harkin DP, Silva-Arrieta S, MacDonald DJ, Lucchina LC, Unsal H, et al. Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population. Proc Natl Acad Sci U S A. 1996;93:8541–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yurgelun MB, Chittenden AB, Morales-Oyarvide V, Rubinson DA, Dunne RF, Kozak MM, et al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2019;21:213–23.

    Article  CAS  PubMed  Google Scholar 

  45. Orlow I, Begg CB, Cotignola J, Roy P, Hummer AJ, Clas BA, et al. CDKN2A germline mutations in individuals with cutaneous malignant melanoma. J Invest Dermatol. 2007;127:1234–43.

    Article  CAS  PubMed  Google Scholar 

  46. McWilliams RR, Wieben ED, Rabe KG, Pedersen KS, Wu Y, Sicotte H, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur J Hum Genet. 2011;19:472–8.

    Article  CAS  PubMed  Google Scholar 

  47. Monnerat C, Chompret A, Kannengiesser C, Avril M-F, Janin N, Spatz A, et al. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Familial Cancer. 2007;6:453–61.

    Article  CAS  PubMed  Google Scholar 

  48. Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, et al. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet. 1998;7:209–16.

    Article  CAS  PubMed  Google Scholar 

  49. Hocevar M, Avbelj M, Perić B, Zgajnar J, Besić N, Battelino T. High prevalence of germline CDKN2A mutations in Slovenian cutaneous malignant melanoma families. Croat Med J. 2006;47:851–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Harland M, Cust AE, Badenas C, Chang Y-M, Holland EA, Aguilera P, et al. Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom. Hered Cancer Clin Pract. 2014;12:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Fargnoli MC, Chimenti S, Keller G, Soyer HP, Dal Pozzo V, Höfler H, et al. CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds. J Invest Dermatol. 1998;111:1202–6.

    Article  CAS  PubMed  Google Scholar 

  52. Lynch HT, Brand RE, Hogg D, Deters CA, Fusaro RM, Lynch JF, et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer. 2002;94:84–96.

    Article  CAS  PubMed  Google Scholar 

  53. Fiala EM, Jayakumaran G, Mauguen A, et al. Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. Nat Cancer. 2021. https://doi.org/10.1038/s43018-021-00172-1.

  54. Ghiorzo P, Gargiulo S, Pastorino L, Nasti S, Cusano R, Bruno W, et al. Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma. Hum Mol Genet. 2006;15:2682–9.

    Article  CAS  PubMed  Google Scholar 

  55. Helsing P, Nymoen DA, Ariansen S, Steine SJ, Maehle L, Aamdal S, et al. Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas. Genes Chromosomes Cancer. 2008;47:175–84.

    Article  CAS  PubMed  Google Scholar 

  56. de Snoo FA, Kroon MW, Bergman W, ter Huurne JAC, Houwing-Duistermaat JJ, van Mourik L, et al. From sporadic atypical nevi to familial melanoma: risk analysis for melanoma in sporadic atypical nevus patients. J Am Acad Dermatol. 2007;56:748–52.

    Article  PubMed  Google Scholar 

  57. Begg CB, Orlow I, Hummer AJ, Armstrong BK, Kricker A, Marrett LD, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005;97:1507–15.

    Article  CAS  PubMed  Google Scholar 

  58. MacKie RM, Andrew N, Lanyon WG, Connor JM. CDKN2A germline mutations in U.K. patients with familial melanoma and multiple primary melanomas. J Invest Dermatol. 1998;111:269–72.

    Article  CAS  PubMed  Google Scholar 

  59. Majore S, De Simone P, Crisi A, Eibenschutz L, Binni F, Antigoni I, et al. CDKN2A/CDK4 molecular study on 155 Italian subjects with familial and/or primary multiple melanoma. Pigment Cell Melanoma Res. 2008;21:209–11.

    Article  CAS  PubMed  Google Scholar 

  60. Platz A, Hansson J, Månsson-Brahme E, Lagerlöf B, Linder S, Ringborg U, et al. Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma. J Natl Cancer Inst Oxford Academic. 1997;89:697–702.

    Article  CAS  PubMed  Google Scholar 

  61. Abdel-Rahman MH, Pilarski R, Massengill JB, Christopher BN, Noss R, Davidorf FH. Melanoma candidate genes CDKN2A/p16/INK4A, p14ARF, and CDK4 sequencing in patients with uveal melanoma with relative high-risk for hereditary cancer predisposition. Melanoma Res. 2011;21:175–9.

    Article  CAS  PubMed  Google Scholar 

  62. Petronzelli F, Sollima D, Coppola G, Martini-Neri ME, Neri G, Genuardi M. CDKN2A germline splicing mutation affecting both p16(ink4) and p14(arf) RNA processing in a melanoma/neurofibroma kindred. Genes Chromosomes Cancer. 2001;31:398–401.

    Article  CAS  PubMed  Google Scholar 

  63. Kannengiesser C, Dalle S, Leccia M-T, Avril MF, Bonadona V, Chompret A, et al. New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment. Genes Chromosomes Cancer. 2007;46:751–60.

    Article  CAS  PubMed  Google Scholar 

  64. Maubec E, Chaudru V, Mohamdi H, Blondel C, Margaritte-Jeannin P, Forget S, et al. Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family. J Am Acad Dermatol. 2012;67:1257–64.

    Article  CAS  PubMed  Google Scholar 

  65. Landi MT, Goldstein AM, Tsang S, Munroe D, Modi W, Ter-Minassian M, et al. Genetic susceptibility in familial melanoma from northeastern Italy. J Med Genet. 2004;41:557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yakobson E, Eisenberg S, Isacson R, Halle D, Levy-Lahad E, Catane R, et al. A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families. Eur J Hum Genet. 2003;11:288–96.

    Article  CAS  PubMed  Google Scholar 

  67. de Torre C, Martínez-Escribano J. Novel CDKN2A mutation detected in Spanish melanoma pedigree. Exp Dermatol. 2010;19:e333–5.

    Article  PubMed  Google Scholar 

  68. Nagore E, Montoro A, García-Casado Z, Botella-Estrada R, Insa A, Lluch A, et al. Germline mutations in CDKN2A are infrequent in female patients with melanoma and breast cancer. Melanoma Res. 2009;19:211–4.

    Article  CAS  PubMed  Google Scholar 

  69. Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8:15–21.

    Article  CAS  PubMed  Google Scholar 

  70. Newton Bishop JA, Harland M, Bennett DC, Bataille V, Goldstein AM, Tucker MA, et al. Mutation testing in melanoma families: INK4A, CDK4 and INK4D. Br J Cancer. 1999;80:295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gruis NA, van der Velden PA, Sandkuijl LA, Prins DE, Weaver-Feldhaus J, Kamb A, et al. Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nat Genet. 1995;10:351–3.

    Article  CAS  PubMed  Google Scholar 

  72. van der Velden PA, Sandkuijl LA, Bergman W, Hille ET, Frants RR, Gruis NA. A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple mole melanoma (FAMMM) syndrome families. Genome Res. 1999;9:575–80.

    PubMed  PubMed Central  Google Scholar 

  73. Vasen HF, Gruis NA, Frants RR, van Der Velden PA, Hille ET, Bergman W. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000;87:809–11.

    Article  CAS  PubMed  Google Scholar 

  74. Schneider-Stock R, Giers A, Motsch C, Boltze C, Evert M, Freigang B, et al. Hereditary p16-Leiden mutation in a patient with multiple head and neck tumors. Am J Hum Genet. 2003;72:216–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Harinck F, Kluijt I, van der Stoep N, Oldenburg RA, Wagner A, Aalfs CM, et al. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas. J Med Genet. 2012;49:362–5.

    Article  CAS  PubMed  Google Scholar 

  76. Cremin C, Lee MK-C, Hong Q, Hoeschen C, Mackenzie A, Dixon K, et al. Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening. Cancer Med. 2020;9:4004–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Vanneste R, Smith E, Graham G. Multiple neurofibromas as the presenting feature of familial atypical multiple malignant melanoma (FAMMM) syndrome. Am J Med Genet A. 2013;161A:1425–31.

    Article  PubMed  CAS  Google Scholar 

  78. Ruiz A, Puig S, Malvehy J, Lázaro C, Lynch M, Gimenez-Arnau AM, et al. CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia. J Med Genet. 1999;36:490–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Karagianni F, Njauw C-N, Kypreou KP, Stergiopoulou A, Plaka M, Polydorou D, et al. CDKN2A/CDK4 status in Greek patients with familial melanoma and association with clinico-epidemiological parameters. Acta Derm Venereol. 2018;98:862–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yu KK, Zanation AM, Moss JR, Yarbrough WG. Familial head and neck cancer: molecular analysis of a new clinical entity. Laryngoscope. 2002;112:1587–93.

    Article  CAS  PubMed  Google Scholar 

  81. Larre Borges A, Borges AL, Cuéllar F, Puig-Butillé JA, Scarone M, Delgado L, et al. CDKN2A mutations in melanoma families from Uruguay. Br J Dermatol. 2009;161:536–41.

    Article  CAS  PubMed  Google Scholar 

  82. Erlandson A, Appelqvist F, Wennberg A-M, Holm J, Enerbäck C. Novel CDKN2A mutations detected in western Swedish families with hereditary malignant melanoma. J Invest Dermatol. 2007;127:1465–7.

    Article  CAS  PubMed  Google Scholar 

  83. Lowery MA, Wong W, Jordan EJ, Lee JW, Kemel Y, Vijai J, et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J Natl Cancer Inst. 2018;110:1067–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Pastorino L, Bonelli L, Ghiorzo P, Queirolo P, Battistuzzi L, Balleari E, et al. CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma. Pigment Cell Melanoma Res. 2008;21:700–9.

    Article  CAS  PubMed  Google Scholar 

  85. Ghiorzo P, Fornarini G, Sciallero S, Battistuzzi L, Belli F, Bernard L, et al. CDKN2A is the main susceptibility gene in Italian pancreatic cancer families. J Med Genet. 2012;49:164–70.

    Article  CAS  PubMed  Google Scholar 

  86. Knappskog S, Geisler J, Arnesen T, Lillehaug JR, Lønning PE. A novel type of deletion in the CDKN2A gene identified in a melanoma-prone family. Genes Chromosomes Cancer. 2006;45:1155–63.

    Article  CAS  PubMed  Google Scholar 

  87. Overbeek KA, Rodríguez-Girondo MD, Wagner A, van der Stoep N, van den Akker PC, Oosterwijk JC, et al. Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants. J Med Genet. 2020. https://doi.org/10.1136/jmedgenet-2019-106562.

  88. Pasmant E, Laurendeau I, Héron D, Vidaud M, Vidaud D, Bièche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007;67:3963–9.

    Article  CAS  PubMed  Google Scholar 

  89. Leachman SA, Carucci J, Kohlmann W, Banks KC, Asgari MM, Bergman W, et al. Selection criteria for genetic assessment of patients with familial melanoma. J Am Acad Dermatol. 2009;61:677.e1–14.

    Article  Google Scholar 

  90. Zhang Y, Xiong Y. Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Mol Cell. 1999;3:579–91.

    Article  CAS  PubMed  Google Scholar 

  91. Leachman SA, Lucero OM, Sampson JE, Cassidy P, Bruno W, Queirolo P, et al. Identification, genetic testing, and management of hereditary melanoma. Cancer Metastasis Rev. 2017;36:77–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Katalinic A, Waldmann A, Weinstock MA, Geller AC, Eisemann N, Greinert R, et al. Does skin cancer screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. Cancer. 2012;118:5395–402.

    Article  PubMed  Google Scholar 

  93. Halpern AC, Marchetti MA, Marghoob AA. Melanoma surveillance in “high-risk” individuals. JAMA Dermatol. 2014;150:815–6.

    Article  PubMed  Google Scholar 

  94. van der Rhee JI, de Snoo FA, Vasen HFA, Mooi WJ, Putter H, Gruis NA, et al. Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families. J Am Acad Dermatol. 2011;65:289–96.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Moloney FJ, Guitera P, Coates E, Haass NK, Ho K, Khoury R, et al. Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study. JAMA Dermatol. 2014;150:819–27.

    Article  PubMed  Google Scholar 

  96. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the international Cancer of the pancreas screening (CAPS) consortium. Gut. 2020;69:7–17.

    Article  CAS  PubMed  Google Scholar 

  97. Vasen H, Ibrahim I, Ponce CG, Slater EP, Matthäi E, Carrato A, et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. J Clin Oncol. 2016;34:2010–9.

    Article  CAS  PubMed  Google Scholar 

  98. Paiella S, Capurso G, Cavestro GM, Butturini G, Pezzilli R, Salvia R, et al. Results of first-round of surveillance in individuals at high-risk of pancreatic cancer from the AISP (Italian Association for the Study of the Pancreas) Registry. Am J Gastroenterol. 2019;114:665–70.

    Article  PubMed  Google Scholar 

  99. Canto MI, Almario JA, Schulick RD, Yeo CJ, Klein A, Blackford A, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 2018;155:740–751.e2.

    Article  PubMed  Google Scholar 

  100. Levin T, Mæhle L. Uptake of genetic counseling, genetic testing and surveillance in hereditary malignant melanoma (CDKN2A) in Norway. Familial Cancer. 2017;16:257–65.

    Article  CAS  PubMed  Google Scholar 

  101. Chiang J, Ngeow J. The management of BRCA1 and BRCA2 carriers in Singapore. Chin Clin Oncol. 2020;9(5):62.

    Article  PubMed  Google Scholar 

  102. LaDuca H, Polley EC, Yussuf A, Hoang L, Gutierrez S, Hart SN, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med. 2020;22:407–15.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

No separate funding for this review.

Author information

Authors and Affiliations

  1. Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore

    Sock Hoai Chan, Jianbang Chiang & Joanne Ngeow

  2. Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore

    Joanne Ngeow

  3. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, 308232, Singapore

    Joanne Ngeow

Authors
  1. Sock Hoai Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianbang Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joanne Ngeow
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SHC analyzed the data and wrote the manuscript. JBC and JN contributed to writing of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Joanne Ngeow.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

JN receives funding from AstraZeneca for ovarian cancer research. All other authors have no disclosures. All other authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chan, S.H., Chiang, J. & Ngeow, J. CDKN2A germline alterations and the relevance of genotype-phenotype associations in cancer predisposition. Hered Cancer Clin Pract 19, 21 (2021). https://doi.org/10.1186/s13053-021-00178-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13053-021-00178-x

Keywords

Hereditary Cancer in Clinical Practice

ISSN: 1897-4287