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The CDKN2A (p16) Gene and Human Cancer
Molecular Medicine volume 3, pages 5–20 (1997)
CDKN2A, the gene encoding the cell-cycle inhibitor p16CDKN2A, was first identified in 1994. Since then, somatic mutations have been observed in many cancers and germline alterations have been found in kindreds with familial atypical multiple mole/melanoma (FAMMM), also known as atypical mole syndrome. In this review we tabulate the known mutations in this gene and discuss specific aspects, particularly with respect to germline mutations and cancer predisposition.
CDKN2A has been given different names (p16INK4, p16INK4A, CDK4I, MTS1, and p16) by different investigators, but was recently assigned the designation CDKN2A (for cyclin dependent kinase inhibitor 2A) by the Human Genome Organisation nomenclature committee. The gene is composed of 3 exons, with one alternatively spliced exon (E1-β). It is situated on chromosome 9p21, in a region that shows a high frequency of loss of heterozygosity (LOH) in numerous tumor types (1). The gene itself is mutated (or inactivated in some way) in many types of human cancers. In this sense, CDKN2A bears a striking resemblance to the paradigmatic tumor suppressor gene, p53. CDKN2A may prove to be as important a regulator of cell growth as p53.
An interesting parallel between these two genes can be drawn upon examination of the tumor spectrum observed in families carrying germline mutations. Although both genes are somatically altered in a wide variety of cancers, there is a more specific pattern of malignancy associated with germline mutations. For instance, CDKN2A somatic mutations (mainly deletions) are common in glioblastoma (2), but a case of glioblastoma has not yet been reported in a familial atypical multiple mole/melanoma (FAMMM) kindred, where cutaneous malignant melanoma is by far the commonest cancer (3). Similarly, colorectal and ovarian cancer frequently exhibit somatic p53 mutations (4). However, these cancers are rarely seen as part of the familial Li-Fraumeni syndrome, which typically features soft tissue sarcomas, leukemia, and brain cancers in children, and breast cancer in young women (5).
CDKN2A encodes a 156 amino acid, 16kD cell-cycle inhibitor protein, which normally blocks abnormal cell growth and proliferation by binding to complexes of cyclin-dependent kinases (CDK) 4 and 6, and cyclin D. This binding inhibits the kinase activity of the enzyme, which arrests the cell cycle in the Gl phase (Fig. 1). Mutant p16CDKN2A is unable to form stable complexes with the enzyme and, therefore, does not effectively inhibit progression of cells through inappropriate mitotic divisions. The importance of this protein as a cell-cycle regulator is demonstrated by the wide array of tumor types in which mutations of CDKN2A have been observed.
Identification of CDKN2A as a Possible Tumor Suppressor Gene
Molecular cytogenetic studies revealed frequent heterozygous and homozygous deletions of the chromosome 9p21-p22 region in melanoma and other cell lines (6,7). Linkage to markers from 9p13-p22 was reported in melanoma kindreds from the United States (8,9), Australia (10), Holland (11), and the United Kingdom (12). CDKN2A mutations were subsequently reported in several families within each cohort. However, there appear to be some families that are linked to 9p21 in which mutations in CDKN2A or the closely related adjacent gene, CDKN2B (p15), have not been found.
Homozygous deletions and intragenic mutations in CDKN2A are often observed in human cell lines. Initially, there was some controversy over the significance of these alterations, since they were detected far less frequently in corresponding primary tumors showing LOH at 9p21 (1, 13–15). This discrepancy suggested that another tumor suppressor gene is the target of LOH in the region or simply that CDKN2A is important for the maintenance of viability in cell culture. The issue has been clarified to some extent by two recent discoveries that suggest that LOH at 9p21 may be accounted for by previously undetected mutations in CDKN2A. First, microdeletions (spanning less than 200 kilobases and encompassing CDKN2A) are present; these are, however, only detectable using an array of microsatellites close to the gene and have been confirmed by fluorescent in situ hybridization (FISH) (16). Secondly, CDKN2A can be inactivated by methylation of the CpG island 5′ of the coding region (17–19). The involvement of several mechanisms in CDKN2A inactivation has been shown in a comprehensive analysis of 29 primary head and neck squamous cell carcinomas. By immunohistochemistry, 24 of the cancers showed absence of nuclear staining. Of these 24 cancers, 16 had homozygous deletions of CDKN2A, 5 had CpG methylation, 1 had a genomic rearrangement, and another had a frameshift mutation in exon 1 (20).
Germline mutations in CDKN2A reported to date are primarily point mutations (Fig. 2). They are observed in FAMMM families but also in cancer-prone kindreds which do not fit the criteria for FAMMM.
Familial Atypical Multiple Mole/Melanoma (FAMMM)
Germline mutations in CDKN2A have been reported in FAMMM pedigrees that show linkage to chromosome 9p. Hussussian et al. described eight CDKN2A germline substitutions observed in 13 of 18 American FAMMM kindreds (21). Of these, six are probably disease-related mutations since they were identified in 33 out of 36 melanoma cases in nine families. The remaining two were detected in normal controls and are thought to be nondeleterious polymorphisms.
A 19 base pair germline deletion in CDKN2A was detected in 13 of 15 Dutch FAMMM kindreds (22). This deletion is a founder mutation; the 13 families all originate from the same geographic region and share a common haplotype. CDKN2A mutations were not found in two other Dutch melanoma families. Two individuals from one of the families carrying the 19 bp deletion were homozygous for the mutation. One of these individuals had three mildly atypical nevi and died at the age of 54 from adenocarcinoma originating from an unknown primary site and the other was diagnosed with melanoma in situ at age 15. The fact that these two homozygous individuals did not have more severe phenotypes than their heterozygous relatives suggests that there may be redundancy that compensates for the lack of p16CDKN2A activity.
The Met53Ile mutation (Fig. 2) could also be a founder mutation, since the antecedents of the three Australian melanoma kindreds reported with this mutation all originally lived in Scotland (23) and another report of a family with this mutation identified the place of origin as the west of Scotland (24), although this family does not fit the FAMMM criteria. Haplotype analyses are now underway but have yet to be completed.
CDKN2A, FAMMM, and Pancreatic Cancer
Pancreatic adenocarcinoma is probably the second commonest cancer in FAMMM families. The observed/expected ratio for the frequency of pancreatic cancer among 200 individuals from nine FAMMM families was 13.4 (P < 0.001) (3). In several chromosome 9p-linked FAMMM families, a mutation in CDKN2A was found to cosegregate with both melanoma and pancreatic adenocarcinoma (21,22,25). However, this risk may be limited to a subset of families. In families where the CDKN2A mutation impaired the function of the corresponding protein (p16M) in vitro, the risk of pancreatic cancer was increased 13-fold (standardized incidence ratio: 13.1, 95% CI, 1.5–47.4), whereas no cases of pancreatic cancer were found in families with CDKN2A mutations that did not affect the function of the protein (p16W) in the assay used by this group (25).
The study of Ciotti et al. supports the association of p16M mutations and pancreatic cancer risk in FAMMM families (26). They detected a Gly101Trp missense mutation in seven Italian melanoma-prone kindreds (presumably derived from a common founder) having a combined total of three pancreatic cancers. This mutation affected the function of the p16CDKN2A protein in vitro, and was associated with increased cancer risk (27). Seven p16W melanoma-prone kindreds, on the other hand, had a total of 18 cases of melanoma, 4 cases of dysplastic naevi, and 9 cancers at other sites, but no cases of pancreatic cancer (26).
However, this excess of pancreatic cancer in FAMMM families may be attributed, in part, to ascertainment bias. Investigations of the tumor spectrum of the FAMMM syndrome revealed no excess of pancreatic tumors in a total of 15 FAMMM kindreds and 370 individuals diagnosed with melanoma (28–30). The results from Australian kindreds (N.H., unpublished data) support this lack of excess of pancreatic cancer in FAMMM pedigrees: they found one case of pancreatic cancer in 11 families with p16M mutations (0.4 cases expected). This difference is not significant (95% CI, 0.49–24.56). Overall, there were slightly more cancers of all types among these families than among those with p16W CDKN2A mutations, but again, this difference was not significant.
It may be that the risk of pancreatic cancer is related to the position or type of CDKN2A mutation; in von Hippel Lindau disease kindreds, the risk of pheochromocytoma appears to be greatest in those with missense mutations in VHL (31), and in hereditary breast cancer, the risk of ovarian cancer may depend upon the position of the mutation along the BRCA1 gene (32).
CDKN2A Mutations in Melanoma Families Apparently Not Linked to 9p
Because of the high phenocopy rate, mutations have also been reported in families inconclusive for linkage to 9p (21,23). Some cases of melanoma observed in these families appear to be sporadic in origin and, in contrast to the definitively 9p-linked families, CDKN2A mutants in these unlinked kindreds did not always segregate with the melanomas.
Non-FAMMM Kindreds with CDKN2A Mutations
CDKN2A mutations are not restricted to the FAMMM syndrome. Interestingly, however, there are no reported mutations in families with multiple cancers that do not include melanoma. A family in which pancreatic cancer was the predominant cancer has been reported (33). A p16M missense mutation (Gly101Trp) was found in all affected family members, but only one individual was affected with melanoma (followed by pancreatic cancer). Sun et al. detected a Met53Ile CDKN2A mutation in a non-FAMMM family with an excessive number of cancers. One member of the family developed two cutaneous malignant melanomas during pregnancy, but no other individuals have had melanomas or dysplastic nevi. A p16M (deletion of amino acids 96–99) mutation was reported in a family with melanoma, nonsmall cell lung cancer, and squamous cell carcinoma of the head and neck (34). It appears that CDKN2A is highly penetrant for cutaneous malignant melanoma, and the absence of this cancer in a pedigree with multiple cases of other cancers is likely to imply that a CDKN2A mutation is not present in that family (W.F., unpublished data).
CDKN2A is frequently homozygously deleted in cell lines derived from a number of tumor types (13,16,35). In melanoma cell lines where one copy of the gene is absent, the remaining copy is frequently mutated (7). The majority of point mutations observed are nonsense, missense, or frameshift mutations. Details of the coding effect of CDKN2A mutations can be found in a recent review by Pollock et al. (36). We have built upon the databases compiled by Pollock et al. (36) and Smith-Sorensen and Hovig (37) of CDKN2A somatic mutations in cell lines and in primary tumors, and present updated lists (to July 1996) in Tables 1 and 2, respectively.
It is interesting to note that alterations have been reported to occur in at least 70% of the possible 156 codons making up this small gene (deletions affecting more than one codon were counted only once). Moreover, only 11% of the germline mutations identified to date (Fig. 2) have been seen somatically (in either primary tumors or cell lines). There are several possible explanations for the latter phenomenon: (1) ascertainment bias—novel germline mutations may be detected in kindreds displaying different phenotypes than the families tested so far; (2) deleterious mutations—certain CDKN2A germline mutations may not be compatible with life; (3) somatic mutations reflect mutagenesis by a different carcinogen (i.e., ultraviolet radiation induces characteristic transitions and tandem base changes); and, (4) the lack of concordance between somatic and germline mutations may be attributed to chance.
Homozygous Deletions in Cell Lines
There have been numerous reports of homozygous deletion of the 9p21 region in cell lines derived from a wide variety of human tumors (7,35). CDKN2A has often (but not always) proven to be the target of these deletions. If a gene is the sole target of homozygous deletion, one would expect to find intragenic mutations in the DNA of cell lines without homozygous deletions. This criterion is not always met in the case of CDKN2A, however, which suggests the presence of another gene in the region that is responsible for the deletions observed; the neighboring CDKN2B gene is an obvious candidate. Microdeletions, aberrant CpG island methylation, or other regulatory mutations in CDKN2A not detected by the assays used by these investigators, may account for part of the reported absence of homozygous deletions (see above).
Cell lines with deletions of CDKN2A alone, CDKN2B alone, and with codeletion of the two genes have all been observed (2, 13,38–45). CDKN2A is usually but not always included in the smallest region of homozygous deletion (2,38,39,46). This result can be interpreted in various ways: (1) the target gene is CDKN2A in some cases and CDKN2B in others; (2) both genes together are the target of the deletions; or (3) other tumor suppressor genes are present in the region. Jen et al. (38) favor the “double target” hypothesis because the protein products of the two genes appear to have analogous biochemical activities and the region of homozygous deletion most often contains both genes. A more definitive explanation awaits further functional analyses of the genes, especially CDKN2B.
Common Tumors with a Low Frequency of CDKN2A Mutations
colon carcinoma. CDKN2A mutations are rarely observed in colon cancer (7,13,16,38). Interestingly, aberrant 5′ CpG island methylation associated with loss of transcription of CDKN2A occurs frequently in both colon cancer cell lines and primary colon tumors (18). Of all the cell lines tested, those derived from colon primaries showed the highest frequency of de novo methylation (92%). CpG island methylation accompanied by transcriptional silencing of CDKN2A was also observed in the normal colonic mucosa of individuals with and without cancer (19). It is uncertain whether this uncommon situation represents a precancerous state or normal cell function. In general, these data point to hypermethylation as an alternative mechanism of CDKN2A inactivation in colon cancer.
breast cancer. CDKN2A is homozygously deleted in 60–65% of primary breast tumors and cell lines (7,16), however point mutations in this malignancy are rare (Tables 1 and 2). Of 24 primary breast carcinomas analyzed by Brenner et al., 58% showed LOH or allelic imbalance at 9p21–22, but only 1 of 21 had an intragenic mutation (47). Xu et al. screened 37 primary breast carcinomas and 5 cell lines for alterations in CDKN2A by single-strand conformation analysis (SSCA) (48). No mutations were found in any of the tumor samples but the gene was homozygously deleted in 2 of the 5 cell lines. Herman et al. reported CpG island methylation in 33% of breast cancer cell lines (18). Thus, it would appear that the primary mechanisms of CDKN2A inactivation in breast cancer are homozygous deletion and hypermethylation, but not point mutation.
ovarian carcinoma. LOH at 9p21 has been observed in 29–48% of ovarian tumors and cell lines (7,49); however, no tumor-specific CDKN2A mutations were detected in a total of 78 primary ovarian tumors analyzed by Campbell et al. (49) and Hatta et al. (50), and homozygous deletions were seen in only 2 tumors. It is not clear whether the high rate of 9p allelic loss in this malignancy is due to mechanisms of CDKN2A inactivation other than deletions and point mutations, or whether a different tumor suppressor gene is the target of LOH. There is an interesting parallel on chromosome 18q, where LOH is extremely frequent in colon cancer. At first, the gene DCC (51) was thought to be the sole target of the LOH, but it is now apparent that DPC4 and another related gene, JV-18-1, may also be mutated or otherwise inactivated in colorectal cancers (52,53). Similarly, perhaps other 9p21 cancer genes await identification.
The frequency of intragenic mutations in CDKN2A is relatively low in uncultured tumors. However, since there are other ways of abrogating p16CDKN2A function, the frequency of inactivation of CDKN2A in a given tumor type may in fact be higher than might be predicted from sequence analysis only. If this is the case, overall, CDKN2A may be somatically altered at a similar frequency to p53.
CDKN2A Mutations, Expression Levels, and Survival
Loss of p16CDKN2A expression may be related to invasiveness or metastatic potential rather than to tumor initiation. This is supported by the study of Reed et al. (54), who performed immunohistochemical analysis of p16CDKN2A expression on 103 melanocytic lesions ranging from atypical nevi to metastatic melanomas. p16CDKN2A expression was detected in 100% of atypical nevi and melanomas in situ and in 91% of primary invasive melanomas, but in only 56% of metastatic melanomas.
Nearly 80% of pancreatic cell lines or xenografts (55) and 37% of primary pancreatic adenocarcinomas (56) have CDKN2A mutations or deletions. The status of CDKN2A may be related to the prognosis of pancreatic cancer patients: mean survival was 13.5 months longer for individuals with CDKN2A mutation-negative tumors compared with those having mutation-positive tumors (p = 0.017) (57). It is interesting that LOH at 9p21 in breast cancers, on the other hand, may not confer an adverse prognosis (58). Thus it may be that the poorer survival in pancreatic carcinomas with CDKN2A mutations is either because CDKN2A mutations have a tumor-specific effect, or because in breast cancer, another gene is the target for the LOH and this gene does not have an adverse effect on survival.
Over the last 2 years, CDKN2A has been the subject of intensive research. It clearly plays a central role in the development of both hereditary and sporadic forms of melanoma. The gene is frequently altered in tumors of many different types, although its importance in most of these cancers can only be inferred. Future reviews of CDKN2A will hopefully focus on attempts to further dissect its function and to rectify the defects in vivo.
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We thank Sophie Sun for her contribution to the tables and figures. WDF is supported by grants from Fonds de la recherche en Santé du Québec and the Cancer Research Society of Canada.
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Foulkes, W.D., Flanders, T.Y., Pollock, P.M. et al. The CDKN2A (p16) Gene and Human Cancer. Mol Med 3, 5–20 (1997). https://doi.org/10.1007/BF03401664
- Cyclin-dependent Kinase Inhibitor 1A (CDKN2A)
- Familial Atypical Multiple Mole Melanoma (FAMMM)
- CDKN2A Mutations
- FAMMM Syndrome
- Human Genome Organization Nomenclature Committee