Systemic cancer and the FAMMM syndrome

Abstract

Summary The FAMMM syndrome consists of the familial occurrence of cutaneous malignant melanoma and atypical nevi (dysplastic nevi), and is inherited as an autosomal dominant trait. Conflicting results have been reported on the question of whether the syndrome includes increased susceptibility to non-melanoma cancers. We have studied cancer of all anatomic sites and histologies in nine FAMMM families which were ascertained in a pigmented lesions clinic in the Netherlands. We evaluated two hypotheses: that the number of systemic cancers observed in the families was excessive, compared to expected incidence, based on Dutch incidence data, and that there was variation (or heterogeneity) among families in the frequency of systemic cancer. A significant excess of systemic cancer (especially digestive tract cancer) was observed. Significant heterogeneity was also found among the families; three of the nine families had marked excess in numbers of systemic cancers, and the remaining families had normal numbers of cancers among the known FAMMM gene carriers and their first degree relatives. Thus, we provide evidence of increased susceptibility to systemic cancer occurring in conjunction with the FAMMM syndrome in a subset of this resource.The familial atypical multiple mole melanoma (FAMMM) syndrome (D-2 familial type of the dysplastic nevus syndrome (Kraemer, 1983)) is characterised by the familial occurrence of malignant melanoma of the skin in combination with multiple atypical nevi (dysplastic nevi). It appears to be transmitted as a dominant, autosomal gene, with variable expressivity within families, including nonpenetrance, of the cutaneous phenotype.In one of the original reports of FAMMM pedigrees (Lynch et al., 1981a), a possible association of the syndrome with primary non-melanoma neoplasms was described. However, this association is controversial and negative findings have been reported (Greene et al., 1987). According to the authors of these two reports, differing methods of family ascertainment may account for this discrepancy. The finding of increased incidence of systemic cancer has been attributed to uncorrectable bias in favour of families prone to cancer at several sites. The study reporting no increased systemic cancer incidence has been faulted for failing to consider heterogeneity among families in the FAMMM phenotype, i.e. for pooling results from many FAMMM families rather than focusing on the supposed subset of families in which the susceptibility to systemic cancer was elevated, and for including second degree relatives.We conducted research to resolve this problem and now provide evidence of an increase in extracutaneous cancer in a subset of FAMMM families. Materials and methodsClinical and genetic studies were performed in all kindreds in which at least three individuals with melanoma occurred. These kindreds were ascertained by interviewing all melanoma patients coming to the surgical oncology department of the University Medical Center in Leiden, The Netherlands, about the presence of mela...

Familial melanoma, pancreatic cancer and germline CDKN2A mutations

“…Several studies have demonstrated an increased risk of pancreatic cancer among melanoma-prone families with CDKN2A mutations (Bergman et al, 1990;Goldstein et al, 1995;Bergman and Gruis, 1996;Ghiorzo et al, 1999;Borg et al, 2000;Vasen et al, 2000) but the precise relationship between the CDKN2A gene and pancreatic cancer remains unknown. At present, it is not possible to predict what genotype or phenotype predisposes an individual to pancreatic cancer in these families.…”

“…Some CDKN2A melanoma-prone families also have pancreatic cancer. Several studies have demonstrated an increased risk of pancreatic cancer among CDKN2A melanoma-prone families (Bergman et al, 1990;Goldstein et al, 1995;Ghiorzo et al, 1999;Borg et al, 2000;Vasen et al, 2000). In addition, germline CDKN2A mutations have been occasionally found in pancreatic cancer patients and families without familial melanoma (Moskaluk et al, 1998;Gerdes et al, 2000;Moore et al, 2000;Lal et al, 2000a;Barsch et al, 2002;Lynch et al, 2002).…”

High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL

“…Several studies have shown an increased risk of pancreatic cancer (PC) among CDKN2A melanoma-prone families (10)(11)(12)(13)(14)(15)(16). However, the precise relationship between the CDKN2A gene and PC remains unknown.…”

Reply to Fusaro

“…Fusaro points out how, in our paper (Ghiorzo et al, 1999), we omitted to mention his report on the association of systemic cancer in familial atypical multiple mole syndrome (FAMMM) (Lynch et al, 1983) and a subsequent study on cancer occurrence in FAMMM kindreds (Bergman et al, 1990) (Kopf et al, 1986;Tucker et al, 1993;Swerdlow et al, 1995;Lynch et al, 1981Lynch et al, , 1983Bergman et al, 1990). These inconsistencies may partly be explained by the reported increased risk of pancreatic cancer in melanoma kindreds with 4 different p16 mutated alleles, including Gly101Trp (Goldstein et al, 1995;Whelan et al, 1995 (Schenk et al, 1998).…”

“…Although the population-based MM cohort identified by Schenk et al (1998) (Boland et al, 1976;Gutman et al, 1991;Wassberg et al, 1996). However, both the Netherlands FAMMM syndrome families (Bergman et al, 1990) and studies on p16 mutated families with early-onset MM and PC (Whelan et al, 1995;Goldstein et al, 1995) (Schenk et al, 1995 …”