Common variants of DNA repair genes and malignant melanoma
Introduction
Malignant melanoma (MM) of the skin and the eye is the most aggressive form of skin cancer and is increasing in frequency. The genetic basis of MM is complex and appears to involve multiple genes. To date, the molecular background of the majority of population-based MM cases remains undetermined.
Mutations in BRCA2 (OMIM 600185) and CHEK2 (OMIM 604373), both involved in aspects of the DNA repair process, predispose to a range of cancer types. There is sufficient evidence to suggest an association between melanoma risk, BRCA2 and CHEK2 germline alterations. The Breast Cancer Linkage Consortium estimated the relative risk of melanoma to be 2.58 in BRCA2 carriers.1 In 2002, Scott and colleagues examined 71 patients with ocular MM and pedigree and clinical data suggestive of a genetic background (bilateral cases, positive family history for the occurrence of MM, age at diagnosis <50 years). The estimated prevalence of the possible loss of function changes in BRCA2 was 3% in patients with familial ocular melanoma.2 Recently, it has been suggested that the 1100delC mutation of the CHEK2 gene may also be responsible for the occurrence of a small proportion of MM cases, especially in families with the Li-Fraumeni or Li-Fraumeni-like syndrome.3
Genetic predispositions to malignancy include causative mutations in DNA repair genes, which are of high penetrance. Most of them result from small deletions, insertions or point mutations and can be readily characterised as they are predicted to result in a loss or gain of protein function. Missense mutations, however, are much harder to classify. Nevertheless, the missense variants of DNA repair genes that have been shown to be associated with predispositions to malignancy can also be clearly pathogenic but often with a reduced penetrance compared to more obvious causative ones. Disease penetrance may be increased in compound carriers of many different common germline alterations.
In Poland, two common changes of the BRCA2 gene, T1915M and N372H, and four common CHEK2 alterations, 1100delC, VS2 + 1G → A, I157T and del5395, have been identified to date.4, 5, 6 In addition to these common changes, we have also evaluated the prevalence of the BRCA2 variant, N991D, which has not been previously assessed in the Polish population.
In this report, we have examined the seven variants and their association with the occurrence of disease in a series of consecutively collected melanoma patients and a series of control subjects from the Polish population.
Section snippets
Melanoma patients
The melanoma patient group consisted of 630 unselected individuals (351 females and 279 males) with a mean age of diagnosis of 54.5 years, who had presented with histologically confirmed malignant melanoma of the skin. The patients originated in North-western (Szczecin, Gorzów Wlkp, Zielona Góra), North-eastern (Białystok) and South-west Poland (Opole). All melanoma cases were identified from cancer registries in the five cities mentioned above. The registries capture over 95% of all
Results
We compared the prevalence of the BRCA2 and CHEK2 changes between three control groups. There were no significant differences between the frequencies of the alleles in the newborns, age- and sex-matched healthy adults with negative family history of cancer, and the adults selected at random by family doctors (Table 1). There were also no statistical differences in the examined allele frequencies in the newborns recruited from the Szczecin metropolitan region compared to other Polish cities
Discussion
To our knowledge, this is the first report of a combined BRCA2 and CHEK2 investigation performed on a large number of unselected cutaneous MM patients and controls. To date, the BRCA2 gene has been screened for germline mutations in patients with uveal melanomas that include 385 cases from the UK,9 153 patients from Israel10 and 62 cases from France.11 There has been, to our knowledge, only one report on the prevalence of BRCA2 mutations in cutaneous MM – where 116 patients from South Italy
Conflict of interest statement
None declared.
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