A common variant of CDKN2A (p16) predisposes to breast cancer

Background: A common missense variant of the CDKN2A gene (A148T) predisposes to malignant melanoma in Poland. An association between malignant melanoma and breast cancer has been reported in several families with CDKN2A mutations, Objective: To determine whether this variant also predisposes to breast cancer. Methods: Genotyping was undertaken in 4209 cases of breast cancer, unselected for family history, from 18 hospitals throughout Poland and in 3000 controls. Results: The odds ratio (OR) associated with the CDKN2A allele for women diagnosed with breast cancer before the age of 50 was 1.5 (p = 0.002) and after age 50 it was 1.3 (p = 0.2). The effect was particularly strong for patients diagnosed at or before the age of 30 (OR = 3.8; p = 0.0002). Conclusions:CDKN2A appears to be a low penetrance breast cancer susceptibility gene in Poland. The association should be confirmed in other populations.

[1]  J. Kładny,et al.  CDKN2A common variants and their association with melanoma risk: a population-based study. , 2005, Cancer research.

[2]  J. Kładny,et al.  CDKN 2 A Common Variants and Their Association with Melanoma Risk : A Population-Based Study , 2005 .

[3]  J. Lubiński,et al.  CHEK2 is a multiorgan cancer susceptibility gene. , 2004, American journal of human genetics.

[4]  Y. Iwamoto,et al.  Alterations of the p16INK4a/p14ARF pathway in clear cell sarcoma , 2004, Cancer science.

[5]  R. Scott,et al.  Germline mutation and large deletion analysis of the CDKN2A and ARF genes in families with multiple melanoma or an aggregation of malignant melanoma and breast cancer , 2004, International journal of cancer.

[6]  T. Kręcicki,et al.  Inactivation of the cyclin‐dependent kinase inhibitor 2A (CDKN2A) gene in squamous cell carcinoma of the larynx , 2004, Molecular carcinogenesis.

[7]  A. Godwin,et al.  Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred , 2003, Journal of medical genetics.

[8]  R. Schneider-Stock,et al.  Hereditary p16-Leiden mutation in a patient with multiple head and neck tumors. , 2003, American journal of human genetics.

[9]  J. Barrett,et al.  An assessment of the CDKN2A variant Ala148Thr as a nevus/melanoma susceptibility allele. , 2002, The Journal of investigative dermatology.

[10]  K. Lamperska,et al.  Analysis of mutations in the p16/CDKN2A gene in sporadic and familial melanoma in the Polish population. , 2002, Acta biochimica Polonica.

[11]  G. Landberg,et al.  Methylation of the p16(Ink4a) tumor suppressor gene 5'-CpG island in breast cancer. , 2001, Cancer letters.

[12]  F. Bosman,et al.  Methylation Silencing and Mutations of the p14ARF and p16INK4a Genes in Colon Cancer , 2001, Laboratory Investigation.

[13]  J. Fraumeni,et al.  Germ-line p 53 Mutations Predispose to a Wide Spectrum of Early-onset Cancers 1 , 2001 .

[14]  A. Jakubowska,et al.  Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. , 2000, American journal of human genetics.

[15]  Kerstin,et al.  High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. , 2000, Journal of the National Cancer Institute.

[16]  P. Bruzzi,et al.  Characterization of ligurian melanoma families and risk of occurrence of other neoplasia , 1999, International journal of cancer.

[17]  D. Duffy,et al.  CDKN2A variants in a population-based sample of Queensland families with melanoma. , 1999, Journal of the National Cancer Institute.

[18]  C. Markopoulos,et al.  Alterations of p16-pRb Pathway and Chromosome Locus 9p21–22 in Sporadic Invasive Breast Carcinomas , 1998, Molecular medicine.

[19]  G. Peters,et al.  The p16INK4a/CDKN2A tumor suppressor and its relatives. , 1998, Biochimica et biophysica acta.

[20]  E Gabrielson,et al.  Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Bisogna,et al.  Hypomethylation and increased gene expression of p16INK4a in primary and metastatic breast carcinoma as compared to normal breast tissue , 1998, Oncogene.

[22]  M. Tucker,et al.  CDKN2A mutations in multiple primary melanomas. , 1998, The New England journal of medicine.

[23]  R. Sutherland,et al.  Cancer‐associated mis‐sense and deletion mutations impair p16INK4 CDK inhibitory activity , 1996, International journal of cancer.

[24]  P. Goodfellow,et al.  Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. , 1995, The New England journal of medicine.

[25]  H. Varmus,et al.  Mutations associated with familial melanoma impair p16INK4 function , 1995, Nature Genetics.

[26]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.