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Abstract

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Familial atypical multiple mole melanoma (FAMMM) is an autosomal dominant disease characterized by the familial occurrence of malignant melanoma of the skin and multiple atypical precursor lesions. Germline mutations in the p16 (CDKN2A) gene have been reported in at least a quarter of such families. An association has been reported between p16 mutations and pancreatic cancer. The aim of this study was to assess the risk of developing pancreatic and other cancers in Dutch FAMMM families with a 19 bp deletion in exon 2 of the p16 gene (p16-Leiden). Mutation analysis was performed in 27 families suspected of FAMMM. Clinical and pathological data were collected from all relatives affected with cancer. A p16-Leiden mutation was identified in 19 families. These families included 86 patients with melanoma. The second most frequent cancer was pancreatic cancer, which was observed in 15 patients from 7 families. The mean age at diagnosis of pancreatic cancer was 58 years (range 38–77 years). The estimated cumulative risk of developing pancreatic cancer in putative mutation carriers by age 75 years was 17%. In 8 p16-Leiden-negative families, no cases of pancreatic cancer occurred. p16 mutation carriers have a considerable risk of developing pancreatic cancer. Further studies should evaluate the value of surveillance of the pancreas in these high-risk families. Int. J. Cancer 87:809–811, 2000. © 2000 Wiley-Liss, Inc.

Familial atypical multiple mole melanoma (FAMMM or familial dysplastic nevus syndrome) is characterized by the familial occurrence of malignant melanoma of the skin in combination with multiple atypical precursor nevi (Greene et al.,1987). The disease is inherited as an autosomal dominant trait. In 1989, linkage was reported with a gene locus on chromosome 1p36 (Bale et al.,1989); however, this finding was not confirmed in other families. Three years later, definitive linkage was obtained with a locus on chromosome 9p21 (Cannon-Albright et al.,1992). This locus encompasses the p16 (CDKN2A) gene. This cyclin-dependent kinase inhibitor is probably responsible for melanoma susceptibility in at least a quarter of all FAMMM families. Another gene reported to be involved in some rare FAMMM families is CDK4. The penetrance of the disease gene reported in the literature (the likelihood that an individual develops melanoma by age 80) varies from 53% to 100% (Cannon-Albright et al.,1994; Walker et al.,1995). Surveillance programs including regular examination of the skin from the age of about 12 years have been recommended in these families. At least 2 studies have reported that such programs led to the detection of melanoma at an earlier stage (Vasen et al.,1989; Masri et al.,1990). Studies from the early 1990s suggested that patients are at risk not only for melanoma but also for developing other cancers, particularly pancreatic cancer (Bergman et al.,1990). The increased risk of pancreatic cancer in these families has so far been observed only in families associated with germline mutations in the p16 gene (Goldstein et al.,1995). A retrospective follow-up study going back to 1830 on 6 FAMMM families associated with p16-Leiden mutations revealed that in some families the mortality due to pancreatic cancer exceeded the mortality associated with melanoma (Hille et al.,1998). The aims of the present study were to evaluate the risk of developing pancreatic and other cancers in FAMMM families registered at the Netherlands Foundation for the Detection of Hereditary Tumours and to discuss possible secondary preventive measures.

MATERIAL AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The FAMMM registry

Data were obtained from the Dutch population-based registry of families with FAMMM. This registry was founded at the Netherlands Foundation for the Detection of Hereditary Tumours in 1989. The aims of the FAMMM Registry are as follows: (i) to promote the identification of families with the FAMMM syndrome, (ii) to implement surveillance programs within these families, and (iii) to guarantee the continuity of lifelong screening by a computerized follow-up system.

The organization and methods of the registry have been published elsewhere (Vasen et al.,1989). In short, pedigree studies are performed by genetic field workers or by clinical genetics centers. The data collected for the registry include personal information and information on type of cancer, age at diagnosis, pathology, and mortality. At present, 130 families have been registered.

Mutation analysis

Genomic DNA from FAMMM family members was isolated from peripheral blood leukocytes according to the method of Miller et al. (1988). The p16-Leiden mutation (19 bp deletion in exon 2 of the CDKN2A gene) was detected after PCR with the primers A1, 5′-AGCCTTCCTTTCCGTCATGC-3′, and A2, 5′-ACCAGCGTGTCCAGGAAG-3′, after electrophoresis through a 2.5% agarose gel plus ethidium bromide (Gruis et al.,1995).

Families were selected for mutation analysis because they had at least one relative with multiple melanoma, at least one relative with pathologically verified melanoma and a positive family history for skin cancer, or at least 2 first-degree relatives with pathologically verified melanoma.

A total of 27 families complied with the selection criteria, and 19 families were found to harbor the p16-Leiden mutation. In the first 6 of the 19 families, a large proportion of patients with melanoma and their first-degree living relatives were tested, while in the remaining 13 families, only 1 or 2 melanoma patients were tested for p16-Leiden mutations.

Risk analysis

For calculation of the age-specific risk of developing pancreatic cancer, Kaplan-Meier survival analysis was used. End points of the analysis were the development of pancreatic cancer, death, or end of the study on 1 January 1995. The study included only family members who died after 1 January 1941. This date was chosen because it is not possible to verify a cancer diagnosis before it. The risk was calculated for the (putative) mutation carriers and their first-degree relatives. As mentioned above, in the first 6 families, a large proportion of the living relatives were tested, while in the remaining 13 families, only 1 or 2 melanoma patients were tested. In the latter families, patients with melanoma were considered to be putative mutation carriers.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The 19 families with a p16-Leiden mutation included a total of 656 relatives. Table I shows the number of patients with melanoma or other tumors in the families with a p16-Leiden mutation and those without a p16-Leiden mutation. Mean ages at diagnosis of the first melanoma identified in families with and those without p16-Leiden mutation were 39 years (range 15–72) and 44 years (12–71), respectively. Families with a p16-Leiden mutation exhibited, on average, 4.5 melanomas per family, while those without a p16-Leiden mutation exhibited 3 melanomas per family.

Table I. PREVALENCE OF CANCER IN 27 FAMMM FAMILIES TESTED FOR p16 MUTATIONS
Cancer siteFamilies with p16 mutation (n = 19)Families without p16 mutation (n = 8)
Melanoma8624 (including 4 eye melanomas)
Pancreas15 
Lung111
Liver5 
Larynx4 
Breast42
Brain31
Other9Morbus Kahler (n = 1)
Prostate cancer (n = 1)

p16-Leiden mutations were identified in 4 (50%) of the 8 families with 1 or 2 melanomas per family, in 6 (75%) of 8 families with 3 or 4 melanomas, in 4 (66%) of 6 families with 5 or 6 melanomas, and in all 5 (100%) families with 7 or more melanomas.

Pancreatic cancer was the most frequent type of cancer in the p16-Leiden families after melanoma, being observed in 7 of 19 families. Two families included 4 cases of pancreatic cancer, 2 families included 2 cases, and the remaining 3 families included 1 case each.

The mean age at diagnosis was 58 years (range 38–77). Detailed information on these cancers identified in families with a mutation is shown in Table II. Table II also includes information on 12 cases of pancreatic cancer in other FAMMM families known at the FAMMM Registry which have not been tested for mutations as they did not fulfill the inclusion criteria. The mean age at diagnosis of pancreatic cancer in the families with a mutation (59 years) was not different from the mean age at diagnosis of cancers (58 years) identified in families that were not tested. Table III shows the cumulative risk of developing pancreatic cancer by age for the (putative) mutation carriers (i.e., proven mutation carriers and patients with a melanoma) and their first-degree relatives.

Table II. CHARACTERISTICS OF PANCREATIC CANCER IN p16-POSITIVE AND OTHER FAMMM FAMILIES
NumberFamily IDSexAge (years)Basis for diagnosisp16 mutation
  • 1

    ND, not determined

14M39Family  report+
24F74Hospital  report+
34M63Physician+
44F64Hospital  report+
510M58Pathology+
610F50Pathology+
73F46Hospital  report+
83F74Hospital  report+
93F49Pathology+
103M71Hospital  report+
1181M46Hospital  report+
1219F77Hospital  report+
1319M50Hospital  report+
1413M66Pathology+
1578M39Hospital  report+
1679F66PathologyND1
17200M62Family  reportND
1877F48Hospital  reportND
1977F55PathologyND
2072F52Family  reportND
2172F80Family  reportND
2272F45PathologyND
2372M42Family  reportND
2424F64PathologyND
2570F53PathologyND
2670M78Hospital  reportND
2770F54Hospital  reportND
Table III. AGE-SPECIFIC RISK OF DEVELOPING PANCREATIC CANCER (%) IN p16-LEIDEN-MUTATED FAMMM FAMILIES
Age (years)Carriers (putative)1First-degree relatives2
  • 1

    In family 7, 19 melanoma patients were considered mutation carriers.

  • 2

    Untested first-degree relatives of proven mutation carriers in the first 6 families and first-degree relatives of melanoma patients in the remaining families.

  • 3

    The expected cumulative risk of pancreatic cancer by age 75 years in the Netherlands is 0.85% for men and 0.53% for women (Visser et al.,1993).

40<1<1
5042
6052
70129
75317  (95%  CI 3–30)13  (95%  CI 2–24)

In addition, a relatively high number of cases of lung cancer was observed (11 cases in the mutation carriers). Lung cancer was diagnosed in 8 families. Three families comprised 2 cases and 5 families included 1 case each. The cumulative risk of lung cancer by age 75 years in male (putative) carriers of a p16-Leiden mutation was 14.3% [95% confidence interval (CI) 1.4–27.2] and in female carriers it was 1.9% (95% CI 0–5.7). The expected cumulative risk of lung cancer by age 75 years in the Netherlands is 8.9% for men and 1.65% for women (Visser et al.,1993). Both pancreatic cancer and lung cancer occurred in 4 of the 19 families.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

A retrospective follow-up study was conducted in families known at the Dutch FAMMM registry. Mutation analysis was performed in families with at least 2 first-degree relatives with a melanoma. Twenty-seven families fulfilled these criteria, and in 19 families a specific 19 bp p16 mutation, referred to as p16-Leiden, was identified. Pancreatic cancer was found only in p16-Leiden-positive families. In an earlier report (Bergman et al.,1990) from our group, pancreatic cancers were observed in 3 of 9 thoroughly investigated FAMMM families.

On the basis of our present results, we estimate that 1 of 6 (17%) p16-Leiden mutation carriers will develop pancreatic cancer by age 75 and ultimately die from this disease. Interestingly, pancreatic cancer was observed in only some (7 of 19 families) of the families with this specific mutation, which suggests that members of families that include cases of pancreatic cancer have an even higher risk of developing this cancer than those in families without pancreatic cancer. Possible explanations for this variation in expression are the presence of modifying genes or the influence of environmental factors (e.g., smoking or nutrition).

As the present study is retrospective, the results might be biased. For example, families with cases of pancreatic cancer might have been selected for DNA analysis just because of the reported association between this cancer and the p16 gene. However, molecular genetic analysis of the families was started before this association was known. In the first 6 families, extensive genetic testing of relatives was performed, while in the remaining families, only 1 or 2 melanoma patients were investigated. All patients with melanoma observed in the latter families were considered to be (putative) mutation carriers. Interestingly, in the first 6 families, 4 patients with melanoma were found not to carry a mutation. This means that melanoma patients in the other 13 families might be non-carriers. As these patients were considered in the calculations to be mutation carriers, the risk of developing pancreatic cancer might be under-estimated.

Pancreatic cancer has also been reported in other inherited tumor syndromes, including hereditary non-polyposis colorectal cancer (Lynch et al.,1985), Peutz-Jeghers syndrome (Giardiello et al.,1987), and familial breast cancer associated with BRCA2 mutations. Also, families with exclusively pancreatic cancer have been reported. It is questionable whether families with site-specific pancreatic cancer have an underlying p16 mutation.

Knowledge of the specific features of pancreatic cancer associated with FAMMM is important for the management of this cancer. Hereditary cancer is generally associated with an unusually young age at diagnosis and the occurrence of multiple tumors. However, the mean age at diagnosis of pancreatic cancer in site-specific pancreatic cancer families known at the National Familial Pancreas Tumor Registry (Hruban et al.,1999) was not different from the age at diagnosis of unselected cases of pancreatic cancer. The average age at diagnosis in both groups was 65 years. In our FAMMM families, the age at diagnosis of pancreatic cancer was slightly lower (59 years).

There is evidence that surveillance of FAMMM families leads to early detection of melanoma. In contrast, it is generally recognized that screening for pancreatic cancer is extremely difficult. Only reports from Japan suggest that screening by abdominal ultrasound of average-risk individuals led to early detection of pancreatic cancer (Ariyama et al.,1998). The effectiveness of screening high-risk groups such as FAMMM families is unknown. The screening protocol suggested in the literature (Lynch et al.,1996; Brentnall et al.,1999) for high-risk families includes annual estimation of alkaline phosphatase, amylase, lipase, carcinoembryonic antigen, and CA19.9. Proposed imaging techniques include abdominal ultrasound, computed tomography, endoscopic retrograde cholangiopancreaticography, endoscopic sonography, and positron emission tomography. In our opinion, surveillance of FAMMM families for pancreatic cancer should be performed only in the setting of a prospective study. In such studies also, the value of new screening methods, such as estimation of K-ras oncogene in the feces or bile, might be assessed. On the basis of the distribution of age at diagnosis of the pancreatic cancers in the present series, we recommend starting such a screening program at an age between 45 and 50 years.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIAL AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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