Familial cutaneous malignant melanoma: autosomal dominant trait possibly linked to the Rh locus.

Abstract

Segregation and linkage analyses were undertaken in families with multiple cases of cutaneous malignant melanoma (CMM) and a recently-described melanoma precursor, the dysplastic nevus syndrome (DNS). Clinical and laboratory data, including 23 genetic markers, were collected on 401 members of 14 high-risk kindreds. Pedigree analysis was compatible with an autosomal dominant mode of inheritance for the familial CMM trait. Although a similar model probably applies to the DNS trait as well, segregation analysis could not confirm the presence of a major locus. However, linkage analysis suggested that an autosomal dominant model was appropriate for the DNS, and that a DNS/CMM susceptibility gene may be located on the short arm of chromosome 1, within 30 map units of the Rh locus [maximum logarithm of odds (lod) score = 2.00].Writing in 1820, Sir William Norris presented a vivid description of the familial variant of cutaneous malignant melanoma (CMM) (1). He concluded, "These facts . . . would incline me to believe that this disease is hereditary." Modem investigations of familial melanoma began with the seminal work of E. P. Cawley (2), and it is now clear that familial melanoma is not uncommon (3), but to date there have been no formal genetic studies of familial CMM. The recent identification of a unique precursor to CMM in high-risk family members (4-6) has provided new research opportunities. Designated the dysplastic nevus syndrome (DNS) (7), because cytologic atypia of melanocytes is its histologic hallmark, this disorder forms the substrate from which most cases of familial CMM arise (8-15). Here we present segregation and linkage analyses of a series of 14 melanoma-prone kindreds, which document that the distribution of CMM and DNS in families is consistent with an autosomal dominant mode of inheritance and suggest that the DNS/CMM susceptibility gene is linked to the Rh locus. METHODSClinical Survey. The Cancer-Prone Family Registry, maintained by the Family Studies Section of the Environmental Epidemiology Branch, National Cancer Institute (16), is a nonpopulation-based series of malignancy-prone kindreds referred by physicians of the National Institutes of Health, community practitioners around the United States, and concerned family members. When this study began, there were approximately 1,000 families in the Registry, from which all kindreds with at least two living, pathologically confirmed cases of CMM were identified; the 25 kindreds found were listed in ascending numerical order by date of ascertainment. Families were contacted, seriatim, and offered an opportunity to participate in a combined clinical-laboratory evaluation of familial melanoma. Fourteen kindreds were studied; available data suggest that the remaining families are similar to those that were included. We examined, photographed, and obtained blood samples from all melanoma probands, from all additional living family members with melanoma, and from 97% of their first-degree relatives; in many cases, more distant relatives were...

An estimate of the heritable fraction of childhood cancer

“…Malignant melanoma may cluster in families, and perhaps 10% of cases are the expression of the dysplastic nevus syndrome (Greene et al, 1983). As younger cases are more likely to be familial, it is surprising that none of the 78 children reported by Bader et al (1985) or 27 children presenting with malignant melanoma in St Judes Hospital, Boston had affected relatives (Pratt et al, 1988 This figure is similar to the Registry figure (2.3%) and to others (Stewart et al, 1958;Kardos et al, 1983) but is greater than the 1.1% observed in surveys in Boston 1947--1965(Fraumeni et al, 1971) and Manchester 1954-1968(Evans & Steward, 1972.…”

Harvey-ras oncogene restriction fragment alleles in familial melanoma kindreds

“…This 'A' allele is found in two-thirds of the normal population. In one affected family member the A allele was inherited from an unaffected homozygous parent, yet there is strong evidence for a dominant mode of inheritance of the melanoma trait (Greene et al, 1983). In the second kindred there was no Ha-ras allele common to all affected individuals, although it is intriguing that two of the affected members have rare alleles.…”

“…The closely related preneoplastic condition, familial dysplastic naevus syndrome (DNS) (Greene et al, 1985b) and hereditary melanoma (HM) itself probably represent pleiotropic effects of a single highly penetrant autosomal dominant gene (Greene et al, 1985a). Although linkage analysis suggested a possible link of the HM trait with the Rh locus on the short arm of chromosome I (Greene et al, 1983), analysis with several genetic markers (Greene et al, 1983(Greene et al, , 1985a, on lp have so far failed to show close linkage.…”

Genetic determinants of cutaneous malignant melanoma in Sinclair swine

“…In humans risk of CMM is a function of family history, naevus number and size, skin and eye colour and environmental co-variates such as exposure to solar radiation (Green and Swerdlow, 1989). While there is great interest in the dissection of the genetic architecture of this important cancer, relatively few studies have employed formal statistical segregation analysis to examine the role of major genes in the inheritance of CMM or CMM in relationship to dysplastic naevi syndrome (DNS) or other related concomitants (Greene et al, 1983;Bale et al, 1986;Blangero et al, 1992;Neuman et al, 1992;Speer et al, 1992). The results from these studies are heterogeneous, yielding evidence for either a dominant major gene (Greene et al, 1983;Bale et al, 1986), or a recessive gene (Blangero et al, 1992;Neuman et al, 1992;Speer et al, 1992) that significantly alters risk of getting CMM.…”