Abstract
A family history of cutaneous melanoma (‘melanoma’) is a well-established risk factor for melanoma. However, less is known about the possible familial associations of melanoma with other discordant cancers. A risk for discordant cancer may provide useful information about shared genetic and environmental risk factors and it may be relevant background data in clinical genetic counseling. Using the Swedish Family-Cancer Database, we assessed the relative risk (RR) for any cancer in families with increasing numbers of first-degree relatives diagnosed with melanoma, including multiple melanoma, and in reverse order RR for melanoma in families of multiple discordant cancers. Close to 9% of melanoma was familial; among these 92% were in 2-case families and 8% in families with 3 cases or more. Cancers that were associated with melanoma, in at least two independent analyses, included breast, prostate, colorectal, skin and nervous system cancers. Other associations included cancer of unknown primary, acute myeloid leukemia/myelofibrosis and Waldenström macroglobulinemia/myeloma. Significant results, which appear biologically plausible, were also obtained for rare nasal melanoma and mesothelioma. Although small samples sizes and multiple comparisons were of concern, many of the above associations were internally consistent and provide new diverse leads for discordant familial association of melanoma.
Highlights
According to the Swedish Family-Cancer Database family history of cutaneous melanoma was found for 5 to 10% of first-degree relatives (FDRs) diagnosed with this cancer, giving a familial relative risk (RR) of 2.51
The reference was families with no melanoma in FDRs; the RR in the reference families was 1.00 and the corresponding number of cases with a negative family history of melanoma is shown in the first results column
Significantly increased risks were observed for salivary gland (3.21), colorectal (2.77), pancreatic (4.46), nasal (6.35; 21.67 for nasal melanoma), breast (1.61), cervix (2.85), prostate (1.71), skin (2.62/2.32 depending on numbers of melanomas in the family) and eye cancers (3.06; 4.15 for eye melanoma), and non-Hodgkin lymphoma (3.07), myeloma (5.02) and leukemia (1.77)
Summary
According to the Swedish Family-Cancer Database family history of cutaneous melanoma was found for 5 to 10% of first-degree relatives (FDRs) diagnosed with this cancer, giving a familial relative risk (RR) of 2.51. Less is known about the possible familial associations of cutaneous melanoma (subsequently ‘melanoma’ if not specified) with other discordant cancers. Pancreatic and breast cancers, were noted in persons with multiple primary melanomas[5]. The most common high-risk gene predisposing to melanoma is CDKN2A, which is associated with pancreatic cancer[6]. In the case of melanoma, it would be pertinent to assess familial clusters, with sites which are manifested in CDKN2A and BAP1 mutation carriers, or whether the risks could be extended to as yet unknown cancer sites.
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