CORRESPONDENCE

Re: High Frequency of Multiple Melanomas and Breast and Pancreas Carcinomas in CDKN2A Mutation-Positive Melanoma Families

Kamila Plna, Kari Hemminki

Affiliation of authors: Center for Nutrition and Toxicology, Department of Biosciences, Karolinska Institute, Huddinge, Sweden.

Correspondence to: Kari Hemminki, M.D., Ph.D., Center for Nutrition and Toxicology, Department of Biosciences, Karolinska Institute, Novum, S-141 57 Huddinge, Sweden (e-mail: kari.hemminki{at}cnt.ki.se).

Susceptibility to cutaneous malignant melanoma has been associated with inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16 protein (1). The recent report by Borg et al. (2) showing an increased risk of breast cancer in CDKN2A mutation carriers suggests that melanoma and breast cancer share a susceptibility gene. Using the nationwide Swedish Family-Cancer Database (3), we have previously suggested such an interaction of breast cancer and melanoma genotypes. This database has been recently updated, providing the opportunity to increase the power of our statistical analysis. The present database includes persons born in Sweden after 1934 ("offspring") and their biological parents, totaling more than 9.6 million individuals (4). Cancer cases, taken from the nationwide Swedish Cancer Registry, totaled about 88 000 cases in the offspring (including 17 528 cases of breast cancer and 8075 cases of melanoma), as compared with 21 220 cancer cases in the offspring from the previous version of the database (3). Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected number of cases. The expected numbers were calculated from age- and sex-standardized rates (5), considering offspring of the cancer-free parents as the reference group (SIR = 1.00), and 95% confidence intervals (CIs) were calculated on the basis of the Poisson distribution (5).

Cancer risk in the offspring was analyzed according to parental breast cancer and melanoma status (Table 1Go). When both parents had breast cancer, the SIRs of all cancers and of breast cancer in the offspring were 5.65 (95% CI = 2.24 to 10.60) and 18.63 (95% CI = 5.88 to 38.53), respectively. When both parents had melanoma, the SIR of melanoma in the offspring was 13.25 (95% CI = 1.25 to 37.97). When the mother had breast cancer and the father had melanoma, the SIR of all cancers in the offspring was 2.19 (95% CI = 1.53 to 2.98), and the SIRs of breast cancer and melanoma were much higher: 4.74 (95% CI = 2.64 to 7.44) and 5.70 (95% CI = 2.59 to 10.04), respectively.


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Table 1. Standardized incidence ratio (SIR) of cancer in offspring by parental breast cancer and melanoma*
 
Our data thus provide a strong indication of possible interactions among parental susceptibility genes in the offspring, because the SIRs were much lower when only one parent had breast cancer or melanoma. This result is in line with our previous finding that the breast cancer risk in daughters is increased if both parents have breast cancer (6). The data also are suggestive of an interaction among breast cancer and melanoma susceptibility genes because breast cancer in the mother and melanoma in the father increased the risk of breast cancer and melanoma in the offspring. In addition, an interaction between breast cancer and melanoma susceptibility genes was shown by the analysis of breast cancer in daughters (younger than 50 years) when the mother had a double primary first breast cancer and a second melanoma (SIR = 5.21; 95% CI = 1.64 to 10.78).

Our results, therefore, suggest that both parents contribute susceptibility genes to pathways partially shared in breast cancer and melanoma. This hypothesis could explain the only moderate familial cancer risks between discordant sites for breast cancer and melanoma in offspring when the cancer status of the parents is analyzed separately (7). The recent identification of CDKN2A as a breast cancer susceptibility gene (2) strengthens this hypothesis because CDKN2A has already been implicated as the major melanoma susceptibility gene.

REFERENCES

1 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.[Medline]

2 Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M, Masback 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.[Abstract/Free Full Text]

3 Hemminki K, Vaittinen P. Interaction of breast cancer and melanoma genotypes [letter]. Lancet 1997;350:931–2.[Medline]

4 Hemminki K, Dong C. Familial relationships in thyroid cancer by histo-pathological type. Int J Cancer 2000;85:201–5.[Medline]

5 Esteve J, Benhamou E. Raymond L. Statistical methods in cancer research. Lyon (France): International Agency for Research on Cancer; 1994.

6 Hemminki K, Vaittinen P. Male breast cancer: risk to daughters [letter]. Lancet 1999;353:1186–7.[Medline]

7 Vaittinen P, Hemminki K. Familial cancer risks in offspring from discordant parental cancers. Int J Cancer 1999; 81:12–9.[Medline]


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