CDKN2A was first identified as melanoma predisposition tumour suppressor gene and has been successively studied. The previous researches have not established any noteworthy association with breast cancer. Therefore, through extensive literature search and in-silico analysis, we have tried to focus on the role of CDKN2A in breast cancer. CDKN2A variants in breast cancer were collected from different databases. The overall percentage of variants (approximately 5.8%) and their incidence frequency in breast cancer cases were found to be very low as compared to the number of samples screened in different studies. Exon 2 was identified as the major region of alternations. Approximately 42.8% were entire gene deletions, while 24.2% were missense mutations. These variants cannot be ignored because of their pathogenic effects as interpreted by the bioinformatics tools used in the present study. Earlier studies have shown that CDKN2A excludes the predisposition of germline variants, but interestingly shares common breast cancer germline variants with other carcinomas. Most of the data have revealed this gene as rarely mutated or deleted in breast cancer. However, few association studies have shown that in addition to being a ‘multiple’ tumour suppressor gene, it is mutated/deleted more in breast cancer cell lines as compared to breast cancer tissues or blood samples; thus, this gene cannot be neglected as a breast cancer candidate gene. The deletion/malfunctioning of CDKN2A in different tumours including breast cancer has recently led to the discovery of many clinical CDK inhibitors. Furthermore, these collected genetic variants will also be helpful in developing diagnostic, preventive, and treatment approaches for patients.
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Carol ED, Jiemin M, Ann GS, Lisa AN, Ahmedin J. Breast Cancer Statistics, 2017, Racial Disparity in Mortality by State. CA Cancer J Clin. 2017;67:439–48.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
Zhu K, Liu Q, Zhou Y, Tao C, Zhao Z, Sun J, Xu H. Oncogenes and tumour suppressor genes: comparative genomics and network perspectives. BMC Genom. 2015;16:8.
Schwab M (ed). CDKN2A. In: Encyclopedia cancer. 3rd ed. Berlin: Springer; 2011. p. 705–11.
Liggett WH, Sidransky D. Role of the p16 tumour suppressor gene in cancer. J Clin Oncol. 1998;16:1197–206.
Agarwal P, Mohammad F, Kabir L, Deinnocentes P, Bird RC. Tumour suppressor gene p16/INK4A/CDKN2A and its role in cell cycle exit, differentiation, and determination of cell fate. In: Cheng Y (ed). Tumor Suppressor Genes. InTech. 2012;1–35.
Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumour suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239–47.
Brenner AJ, Paladugu A, Wang H, Olopade OI, Dreyling MH, Aldaz CM. Preferential loss of expression of p16(INK4a) rather than p19(ARF) in breast cancer. Clin Cancer Res. 1996;2:1993–8.
Rocco JW, Sidransky D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res. 2001;264:42–55.
Byeon I-JL, Li J, Ericson K, Selby TL, Tevelev A, Kim H-J, O’Maille P, Tsai M-D. Tumour suppressor p16INK4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Mol Cell. 1998;1:421–31.
Carraro M, Minervini G, Giollo M, et al. Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI. Hum Mutat. 2017;38:1042–50.
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.
Cicenas J, Kvederaviciute K, Meskinyte I, Meskinyte-Kausiliene E, Skeberdyte A, Cicenas J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers (Basel). 2017;9:42.
Kamb A, Shattuck-Eidens D, Eeles R, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet. 1994;8:22–6.
Pollock PM, Pearson JV, Hayward NK. Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes Chromosomes Cancer. 1996;15:77–88.
Bian Y-S, Osterheld M-C, Fontolliet C, Bosman FT, Benhattar J. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s oesophagus. Gastroenterology. 2002;122:1113–21.
Silva J, Silva JM, Domínguez G, García JM, Cantos B, Rodríguez R, Larrondo FJ, Provencio M, España P, Bonilla F. Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol. 2003;199:289–97.
Vengoechea J, Tallo C. A germline deletion of 9p21.3 presenting as familial melanoma, astrocytoma and breast cancer: clinical and genetic counselling challenges. J Med Genet. 2017;54:682–4.
Helgadottir H, Höiom V, Tuominen R, Nielsen K, Jönsson G, Olsson H, Hansson J. Germline CDKN2A mutation status and survival in familial melanoma cases. J Natl Cancer Inst. 2016;108:djw135.
Zhao R, Choi BY, Lee M-H, Bode AM, Dong Z. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. Ebiomedicine. 2016;8:30–9.
Klinker M, Masback A. High frequency of multiple melanomas and breast and pancreas carcinomas in melanoma families susceptibility to cutaneous malignant. J Natl Cancer Inst. 2001;93:323–5.
Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368:753–6.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS, Johnson BE, Skolnick MH. A cell cycle regulator potentially involved in genesis of many tumour types. Science. 1994;264:436–40.
Gadhikar MA, Zhang J, Shen L, et al. CDKN2A/p16 deletion in head and neck cancer cells is associated with cdk2 activation, replication stress, and vulnerability to CHK1 inhibition. Cancer Res. 2018;78:781–97.
Choi W, Ochoa A, McConkey DJ, et al. Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset. Eur Urol. 2017;72:354–65.
Bai M, Yu N-Z, Long F, Feng C, Wang X-J. Effects of CDKN2A (p16INK4A/p14ARF) Over-expression on proliferation and migration of human melanoma A375 cells. Cell Physiol Biochem. 2016;40:1367–76.
Sarkar D, Leung EY, Baguley BC, Finlay GJ, Askarian-Amiri ME. Epigenetic regulation in human melanoma: past and future. Epigenetics. 2015;10:103–21.
Wang H-L, Zhou P-Y, Liu P, Zhang Y. RETRACTED ARTICLE: Role of p16 gene promoter methylation in gastric carcinogenesis: a meta-analysis. Mol Biol Rep. 2014;41:4481–92.
He D, Zhang Y, Zhang N, Zhou L, Chen J, Jiang Y, Shao C. Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein–Barr virus-associated gastric carcinomas. Med Oncol. 2015;32:92.
Peng D, Zhang H, Sun G. The relationship between P16 gene promoter methylation and gastric cancer: a meta-analysis based on Chinese patients. J Cancer Res Ther. 2014;10 Suppl:292–5.
Berggren P, Kumar R, Sakano S, et al. Detecting homozygous deletions in the CDKN2A(p16INK4a)/ARF(p14ARF) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res. 2003;9:235–42.
de Snoo FA, Bishop DT, Bergman W, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res. 2008;14:7151–7.
Nagore E, Montoro A, Garcia-Casado Z, Botella-Estrada R, Insa A, Lluch A, Lopez-Guerrero JA, Guillen C. Germline mutations in CDKN2A are infrequent in female patients with melanoma and breast cancer. Melanoma Res. 2009;19:211–4.
Musgrove EA, Liuschkis R, Cornish AL, Lee CSL, Setlur V, Seshadri R, Sutherland RL. Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21Waf1/cip1 in human breast cancer. Int J Cancer. 1995;63:584–91.
Berns EM, Klijn JG, Smid M, van Staveren IL, Gruis N, Foekens J. Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. Br J Cancer. 1995;72:964–7.
Smith-Sørensen B, Hovig E. CDKN2A (p16INK4A) somatic and germline mutations. Hum Mutat. 1996;7:294–303.
Han M-R, Deming-Halverson S, Cai Q, Wen W, Shrubsole MJ, Shu X-O, Zheng W, Long J. Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study. Breast Cancer. 2015;22:544–51.
Jones A, Mitter R, Springall R, Graham T, Winter E, Gillett C, Hanby A, Tomlinson I, Sawyer E, Phyllodes Tumour Consortium. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoural genetic heterogeneity and new genetic changes on recurrence. J Pathol. 2008;214:533–44.
Herman JG, Merlo A, Mao L, Herman G, Lapidus G, Issa J, Davidson E. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers DNA methylation in all common human cancers. Cancer. 1995;55:4525–30.
Gonzalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM, Jones PA. Methylation of the 5′ CpG island of the p16/CDKN2 tumour suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995;55:4531–5.
Jovanovic J, Rønneberg JA, Tost J, Kristensen V. The epigenetics of breast cancer. Mol Oncol. 2010;4:242–54.
Spitzwieser M, Entfellner E, Werner B, Pulverer W, Pfeiler G, Hacker S, Cichna-Markl M. Hypermethylation of CDKN2A exon 2 in tumour, tumour-adjacent and tumour-distant tissues from breast cancer patients. BMC Cancer. 2017;17:260.
Chan PA, Duraisamy S, Miller PJ, et al. Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 28. 2007;1:683–93.
Betts MJ, Russell RB. Amino acid properties and consequences of substitutions. In: Bioinformatics for geneticists. Chichester: Wiley, p. 289–316. https://onlinelibrary.wiley.com/doi/pdf/10.1002/0470867302.ch14.
Morris LGT, Chan TA, Sloan M, Cancer K, Program P, Sloan M, Cancer K, Sloan M, Cancer K. Therapeutic targeting of tumour suppressor genes. Cancer. 2015;121:1357–68.
Lai D, Visser-Grieve S, Yang X. Tumour suppressor genes in chemotherapeutic drug response. Biosci Rep. 2012;32:361–74.
Liu Y, Hu X, Han C, Wang L, Zhang X, He X, Lu X. Targeting tumour suppressor genes for cancer therapy. Bioessays. 2015;37:1277–86.
Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES. The meaning of p16ink4a expression in tumours: functional significance, clinical associations and future developments. Cell Cycle. 2011;10:2497–503.
Chen S, Sun H, Miao K, Deng CX. CRISPR-Cas9: from genome editing to cancer research. Int J Biol Sci. 2016;12:1427–36.
Kwapisz D. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat. 2017;166:41–54.
Ramos-Esquivel A, Hernandez-Steller H, Savard M-F, Landaverde DU. (2018) Cyclin-dependent kinase 4/6 inhibitors as first-line treatment for post-menopausal metastatic hormone receptor-positive breast cancer patients: a systematic review and meta-analysis of phase III randomized clinical trials. Breast Cancer. https://doi.org/10.1007/s12282-018-0848-6.
Iwata H. Clinical development of CDK4/6 inhibitor for breast cancer. Breast Cancer. 2018;25:402–6.
Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3:39–55.
Kassem L, Shohdy KS, Lasheen S, Abdel-rahman O, Bachelot T. Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Breast Cancer. 2018;25:17–27.
Ilorasertib in treating patients with CDKN2A-deficient advanced or metastatic solid cancers that cannot be removed by surgery. 2015–2017. clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02540876 (Identifier: NCT02540876).
Edessa D, Sisay M. Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib. Breast Cancer Targets Ther. 2017;9:567–79.
Tang B, Li Y, Qi G, Yuan S, Wang Z, Yu S, Li B, He S. Clinicopathological significance of CDKN2A promoter hypermethylation frequency with pancreatic cancer. Sci Rep. 2015;5:13563.
Su L, Wang H, Miao J, Liang Y. Clinicopathological significance and potential drug target of CDKN2A/p16 in endometrial carcinoma. Sci Rep. 2015;5:13238.
Chakravarti A, DeSilvio M, Zhang M, et al. Prognostic value of p16 in locally advanced prostate cancer: a study based on radiation therapy oncology group protocol 9202. J Clin Oncol. 2007;25:3082–9.
Ameri A, Alidoosti A, Hosseini Y, Parvin M, Emranpour MH, Taslimi F, Salehi E, Fadavi P. Prognostic value of promoter hypermethylation of retinoic acid receptor beta (RARB) and CDKN2 (p16/MTS1) in prostate cancer. Chin J Cancer Res. 2011;23:306–11.
Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10:R75.
Quesnel B, Fenaux P, Philippe N, Fournier J, Bonneterre J, Preudhomme C, Peyrat JP. Analysis of p16 gene deletion and point mutation in breast carcinoma. Br J Cancer. 1995;72:351–3.
Cancer Genome Atlas Network TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54.
Guerini-Rocco E, Piscuoglio S, Ng CKY, et al. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations. J Pathol. 2016;238:677–88.
Jones A, Mitter R, Springall R, Graham T, Winter E, Gillett C, Hanby A, Tomlinson I, Sawyer E, Phyllodes Tumour Consortium. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence. J Pathol. 2008;214:533–44.
Brenner AJ, Aldaz CM. Chromosome 9p allelic loss and p16/CDKN2 in breast cancer and evidence of p16 inactivation in immortal breast epithelial cells. Cancer Res. 1995;55:2892–5.
Tan WJ, Lai JC, Thike AA, Lim JCT, Tan SY, Koh VCY, Lim TH, Bay BH, Tan MH, Tan PH. Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups. Breast Cancer Res Treat. 2014;145:635–45.
Dwyer JB, Clark BZ. Low-grade fibromatosis-like spindle cell carcinoma of the breast. Arch Pathol Lab Med. 2015;139:552–7.
Ross JS, Badve S, Wang K, et al. Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. Arch Pathol Lab Med. 2015;139:642–9.
Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.
Hollestelle A, Nagel JH, Smid M, et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat. 2010;121:53–64.
Hu X, Stern HM, Ge L, et al. Genetic alterations and oncogenic pathways associated with breast cancer subtypes. Mol Cancer Res. 2009;7:511–22.
Xu L, Sgroi D, Sterner CJ, Beauchamp RL, Pinney DM, Keel S, Ueki K, Rutter JL, Buckler AJ, Louis DN. Mutational analysis of CDKN2 (MTS1/p16ink4) in human breast carcinomas. Cancer Res. 1994;54:5262–4.
Spirin K, Simpson JF, Miller CW, Koeffler HP. Molecular analysis of INK4 genes in breast carcinomas. Int J Oncol. 1997;11:737–44.
Rush EB, Abouezzi Z, Borgen PI, Anelli A. Analysis of MTS1/CDK4 in female breast carcinomas. Cancer Lett. 1995;89:223–6.
Prowse AH, Schultz DC, Guo S, Vanderveer L, Dangel J, Bove B, Cairns P, Daly M, Godwin AK. Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred. J Med Genet. 2003;40:e102.
Monnerat C, Chompret A, Kannengiesser C, et al. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6:453–61.
Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67–7.
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Aftab, A., Shahzad, S., Hussain, H.M.J. et al. CDKN2A/P16INK4A variants association with breast cancer and their in-silico analysis. Breast Cancer 26, 11–28 (2019). https://doi.org/10.1007/s12282-018-0894-0
- Breast cancer
- Variant analysis