BACKGROUND Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) germline mutations. METHODS Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM–pancreatic carcinoma (FAMMM‐PC) association in concert with a CDKN2A germline mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early‐onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later‐onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A mutation. CONCLUSIONS The authors suggest that these tumors may collectively, in concert with CDKN2A mutations, constitute a “new” putative hereditary carcinoma syndrome referred to as FAMMM‐PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required. Cancer 2002;94:84–96. © 2002 American Cancer Society.

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...

Distinguishing cutaneous signs which are associated with hereditary cancer-prone syndromes are known as cancer-associated genodermatoses. Muir-Torre syndrome (M-T) is characterized by the occurrence of sebaceous hyperplasia, adenoma and carcinoma, basal cell carcinoma with sebaceous differentiation, and/or keratoacanthoma in association with visceral cancer (often multiple), and improved survival. Family studies of M-T have been either wholly lacking or too incomplete to elucidate hereditary aetiology. We describe the cutaneous phenotype of M-T in an extended kindred with a possible variant of the Cancer Family Syndrome. We emphasize the need for more thorough documentation of family histories and cancer association in this cancer-associated genodermatosis in order to clarify hereditary syndrome identification, and to improve cancer control through employment of cutaneous signs as a beacon for highly targeted forms of visceral cancer.

Hereditary cancer syndromes provide excellent models for molecular genetic studies that may aid significantly in case detection, surveillance, and management. Ultimately, molecularly based designer pharmaceuticals may emerge from this research, such as the case of trastuzumab (Herceptin) in HER-2/neu positive breast cancer, and imatinib (Gleevec) in chronic myelocytic leukemia and gastrointestinal stromal tumors. Importantly, these molecular findings may fuel significant clues to cancer control. This background is mentioned since surveillance and management of pancreatic cancer, a major concern of this manuscript, has been uniformly unsuccessful as evidenced by the close correspondence between its incidence and its mortality. Yet knowledge about its genetic and molecular pathology will hopefully ameliorate this vexing problem. One molecular genetic clue is the recently identified palladin mutation in two pancreatic cancer prone families. However, caution must be used toward the palladin mutation, as several recent publications have questioned its significance as a pancreatic cancer causing mutation. We provide a concise description of pancreatic cancer in concert with malignant melanoma in the familial atypical multiple mole melanoma (FAMMM) syndrome as a potential preventive model. This knowledge should help clinicians and basic scientists seize on the opportunity to develop more sensitive and specific screening and management programs in this disease; while a relatively small subset of pancreatic cancer may be readily identifiable through its FAMMM phenotype, coupled with its CDKN2A mutation, this hereditary disorder, given a keen knowledge of its natural history and molecular genetics, may prove to be an effective clinical preventive model.