Increased Risk of Pancreatic Cancer in Melanoma-Prone Kindreds with p16INK4 Mutations
Alisa M. Goldstein, Ph.D., Mary C. Fraser, R.N., M.A., Jeffery P. Struewing, M.D., M.S., Christopher J. Hussussian, M.D., Koustubh Ranade, Ph.D., Deborah P. Zametkin, M.S.N., Laura S. Fontaine, B.S.N., Sara M. Organic, B.A., Nicholas C. Dracopoli, Ph.D., Wallace H. Clark, M.D., and Margaret A. Tucker, M.D.
Background A gene on chromosome 9p, p16INK4, has been implicatedin the pathogenesis of cutaneous malignant melanoma in 19 melanoma-pronefamilies. In 10 of these kindreds mutations that impaired thefunction of the p16INK4 protein (p16M alleles) cosegregatedwith the disease. By contrast, in the other nine kindreds themutation did not alter the function of p16INK4 (p16W alleles).We looked for differences in clinical and genetic epidemiologicfeatures in these two groups of families.
Methods We compared the median ages at diagnosis of melanoma,number of melanomas, thickness of the tumors, and number ofnevi in the kindreds. We estimated prospectively the risks ofmelanoma or other cancers in families followed for 6 to 18 yearsand the risks of other cancers since 1925 (the entire period)by comparing the number of cancer cases observed with the numberexpected.
Results The risk of invasive melanoma was increased by a factorof 75 in kindreds with p16M alleles and a factor of 38 in kindredswith p16W alleles. Although this difference was not significant(P = 0.14), there was a striking difference in the risk of othertumors. In kindreds with p16M alleles, the risk of pancreaticcancer was increased by a factor of 13 in the prospective period(2 cases observed, 0.15 expected; standardized incidence ratio,13.1; 95 percent confidence interval, 1.5 to 47.4) and by afactor of 22 in the entire period (7 cases observed, 0.32 expected;standardized incidence ratio, 21.8; 95 percent confidence interval,8.7 to 44.8). In contrast, we found no cases of pancreatic cancerin kindreds with p16W alleles.
Conclusions The development of pancreatic cancer in kindredsprone to melanoma may require a p16M mutation. Genetic factors,such as the kind of mutation found in p16INK4, may explain theinconsistent occurrence of other cancers in these kindreds.
A low-molecular-weight protein, p16INK4, inhibits the activityof the cyclin D1–cyclin-dependent kinase 4 complex.1 Thiscomplex phosphorylates the retinoblastoma protein, allowingthe cell to pass through the G1 cell-cycle checkpoint. Thus,p16INK4 negatively regulates cell growth by arresting cellsat G1. The inactivation of p16INK4 by deletion or mutation ofthe gene could lead to unchecked cell growth, suggesting thatp16INK4 may be a tumor-suppressor gene.
The p16INK4 gene (also known as MTS1) was localized to chromosome9p21,2,3 a region that has been implicated in melanoma by studiesof linkage, cytogenetics, and loss of heterozygosity.4,5,6,7,8,9The findings of germ-line p16INK4 mutations in some American,European, and Australian melanoma-prone kindreds10,11,12,13(and unpublished data) and of somatic mutations in many melanomacell lines2,3 strongly suggest that p16INK4 is a melanoma tumor-suppressorgene. In addition, functional studies have identified mutationsof p16INK4 that impair the function of its corresponding protein,thus providing a biochemical rationale for the hypothesis thatcertain p16INK4 mutations increase the risk of melanoma.14
In previous work10,15 we sought evidence of linkage of melanomato chromosome 9p and germ-line p16INK4 mutations in 19 kindredswith familial melanoma. Nine kindreds10 plus one that was notdescribed in the reports had p16INK4 mutations that cosegregatedwith melanoma and impaired the function of the p16INK4 proteinin in vitro assays (p16M alleles, in which M designates mutationsthat impaired function).14 These mutations included one nonsense(Arg50Ter), one splice-donor-site (IVS2+1), and three missense(Val118Asp, Gly93Trp, and Arg79Pro) mutations10; one insertionof 24 base pairs; and an uncharacterized mutation that preventsthe transcription of p16INK4 (unpublished data). The other ninekindreds had either no detectable p16INK4 mutations or a missensemutation (Ile41Thr, Asn63Ser, or Ala140Thr) that did not impairthe function of p16INK4 in in vitro assays (p16W alleles, inwhich W designates the wild type or mutations that did not impairfunction). These latter mutations of p16INK4 thus have no apparentlink to melanomas in the nine kindreds with p16W alleles. Inthe present study, we compared the clinical and genetic epidemiologiccharacteristics of two groups of kindreds — one with p16Mand one with p16W alleles.
Methods
Study Population
The study subjects were drawn from 19 families in which therewas a history of invasive melanoma in at least two first-degreerelatives. The kindreds were divided into two groups: 10 kindredswith p16INK4 mutations that cosegregated with disease (p16Malleles) and 9 kindreds with either no detectable p16INK4 mutation(5 kindreds) or a mutation that did not impair p16INK4 function(4 kindreds) (p16W alleles). All kindreds had been evaluatedpreviously for evidence of linkage of familial melanoma to chromosome9p.10,15 Thirteen kindreds have also been evaluated for evidenceof linkage of familial melanoma to chromosome 1p.16,17 Thesefamilies have been followed prospectively for 6 to 18 years.The ways the families were identified varied: some were referredby physicians or other health care professionals, and some wereself-referred. All the families were white, were unrelated,and resided in various regions of the United States.
Before each family was evaluated clinically, the diagnosis ofmelanoma was confirmed by histologic review of tissue from theprimary melanoma when possible or, if this was not available,tissue from metastatic-disease sites. If histologic materialwas no longer available, the diagnosis of melanoma was substantiatedby review of local pathology reports, medical records, or deathcertificates. For each case of invasive melanoma the followinginformation was obtained: the patient's age at diagnosis, thethickness of each tumor (in millimeters), and the total numberof invasive tumors. All diagnoses of nonmelanoma cancers werealso confirmed by review of histologic materials, local pathologyreports, medical records, or death certificates. Clinical examinationsto estimate numbers of nevi and confirm the presence or absenceof dysplastic nevi and melanoma were performed by a single physician.All pathological material was reviewed by one dermatopathologist.
Statistical Analyses
The mean and median ages at the time melanoma was diagnosed,the number of melanomas, and the thickness of the tumors wereestimated for the two groups of families. The medians for thesethree variables were compared with the use of the nonparametricMann–Whitney test as implemented in the BMDP3S computerprogram (nonparametric statistics).18 Because the number oftumors varied from patient to patient, we calculated an averagethickness of the tumors for each patient.
The mean and median number of nevi in the family members weexamined were also estimated for the two groups of families.In addition, we compared the distribution of melanoma and dysplasticor clinically atypical nevi, major precursor lesions of melanoma.15,17For this purpose, we compared the relative proportions of melanomas(including melanoma in situ) and dysplastic nevi in the kindredsin the two groups of families.
To estimate the prospective risk of invasive melanoma or othercancers, we used the computer program of Monson19 to calculatenumbers of person-years of observation according to sex, age,and the interval from the date of the first clinical examinationto the development of melanoma or other cancer, death, or December31, 1994. Tumor-incidence rates specific for sex, age, and calendaryear were obtained from the Surveillance, Epidemiology, andEnd Results (SEER) Program and were multiplied by the totalnumber of person-years to estimate the number of cases of melanomaor other cancers expected if this group had had the same riskof cancers as the general population.20 The statistical methodsused to estimate risk were based on the assumption that thenumber of melanomas and other cancers observed followed a Poissondistribution. Tests of significance and confidence intervalsfor the standardized incidence ratios (the ratio of the numberof observed cases to the number expected) were calculated exactlyon the basis of a Poisson distribution.21 Tests for homogeneitywere performed as implemented in the Epitome computer program.21
We also analyzed the risk of other cancers (excluding melanoma)for the entire risk period (i.e., the retrospective and prospectiveperiods). For this analysis, we calculated the numbers of person-yearsof observation according to sex, age, and the interval fromthe later of two dates — the person's birth date or January1, 1925 (the first year for which back-estimated SEER rateswere available) — to the development of nonmelanoma cancer,death, or December 31, 1994. These results were similar to thosederived from the Connecticut Tumor Registry.
Results
Overall, the median age at which melanoma was diagnosed was34 years (Table 1), which is substantially earlier than in thegeneral population.22 The age at diagnosis was marginally lowerin the kindreds with p16M alleles (P = 0.05). To determine whetherascertainment bias accounted for this difference between groups,we excluded the index patients (the first two patients withmelanoma in each family) from the analysis. The difference inage at diagnosis was no longer significant (27.5 years in thekindreds with p16M alleles vs. 35.5 years in the kindreds withp16W alleles, P = 0.09). In both groups, however, the medianage at which melanoma was diagnosed was at least 18 years lowerthan the median age at which melanoma is diagnosed in the whitepopulation in the united States (median age, 54 years).22 Therewere no significant differences between the two groups in thenumber of melanomas (P = 0.09) or tumor thickness (P = 0.74).Exclusion of the index patients did not alter these results.
Table 1. Clinical Characteristics of 19 Melanoma-Prone Kindreds.
There was no significant difference in the number of nevi betweenthe two groups of kindreds (P = 0.31) (Table 1). Adjustmentfor age had no effect on the results (data not shown). All 19kindreds had dysplastic nevi in addition to melanoma. We thereforecompared the distribution of melanoma and dysplastic nevi inthe kindreds. There was no difference in the relative proportionof family members with melanoma between the kindreds with p16Malleles and the kindreds with p16W alleles (0.60 vs. 0.65, P= 0.54).
Table 2 shows the prospective risk of melanoma and other cancersin the two groups of kindreds. Cancers were considered accordingto organ system rather than individual site (for one or fewercancers) because of the relatively small numbers. The prospectiverisk of melanoma was increased by a factor of 75 in kindredswith p16M alleles (standardized incidence ratio, 74.6; 95 percentconfidence interval, 45.6 to 115.2) and a factor of 38 in kindredswith p16W alleles (standardized incidence ratio, 38.1; 95 percentconfidence interval, 13.9 to 82.9). This difference was notstatistically significant (P = 0.14). However, there was a strikingdifference in the risk of other tumors between the two groups.The prospective risk of pancreatic cancer was increased by afactor of 13 (standardized incidence ratio, 13.1; 95 percentconfidence interval, 1.5 to 47.4) in the kindreds with p16Malleles. The two observed cases of pancreatic cancer were indifferent families. In both cases there was a previous diagnosisof invasive melanoma or melanoma in situ. There were no casesof pancreatic cancer among the kindreds with p16W alleles.
Table 2. Prospective Risk of Cancer in Bloodline Members of Melanoma-Prone Kindreds with p16M or p16W Alleles.
Table 3 shows the risks of other cancers in the two groups ofkindreds during the entire risk period. Since families wereenrolled in the study on the basis of a history of melanoma,melanomas were excluded from this analysis. However, we wouldexpect the assessment of other cancers to be similar in theprospective and entire (i.e., retrospective plus prospective)risk periods if families were not selected because they hadother cancers. Overall, there was no excess of cancer in eithergroup. However, the risk of digestive-system cancers was increasedby a factor of 3 in the kindreds with p16M alleles because ofthe excess of pancreatic cancer (standardized incidence ratio,21.8; 95 percent confidence interval, 8.7 to 44.8) in kindredswith p16M alleles. In addition, there was a significant differencein the standardized incidence ratio for pancreatic cancer betweenthe two groups of kindreds (P = 0.02). The seven cases of pancreaticcancer occurred in four different families with p16M alleles,three of which had two cases of pancreatic cancer each (Table 4).Three patients had also had invasive melanoma or melanomain situ. One of the patients with pancreatic cancer had a p16INK4mutation; two were obligate carriers of a mutation. The p16INK4status of the other four patients could not be determined. Therewas no relation between specific p16INK4 mutations and the riskof pancreatic cancer; each kindred with pancreatic cancer hada different p16INK4 mutation.10 Thus, overall, 4 of the 10 kindredswith p16M alleles had at least one family member each with pancreaticcancer, as compared with none of the 9 kindreds with p16W alleles.
Table 4. p16INK4 Mutations in Melanoma-Prone Kindreds with Pancreatic Cancer According to the Number of Bloodline Relatives with Melanoma, Pancreatic Cancer, or Both.
Discussion
We evaluated 10 melanoma-prone kindreds with p16M alleles and9 with p16W alleles to determine whether there were differencesin clinical features and the risk of various cancers. Althoughthe difference was not significant, kindreds with p16M alleleshad a lower median age when melanoma was diagnosed than kindredswith p16W alleles. In both groups, however, the median age atdiagnosis was substantially lower than that in the general U.S.population. There were no significant differences in the numberof melanomas or in tumor thickness in the two groups, nor werethere differences in the number of nevi or in the proportionsof melanoma and dysplastic nevi. The prospective risk of melanomawas increased by a factor of 75 in kindreds with p16M allelesand a factor of 38 in kindreds with p16W alleles — a differencethat was not significant. By contrast, the risk of pancreaticcancer was significantly increased only in kindreds with p16Malleles.
Several researchers have investigated whether familial susceptibilityto melanoma increases the risk of other cancers independentlyof other known familial cancer syndromes (e.g., Li–Fraumenisyndrome23). The present 19 kindreds were part of a prospectivefollow-up study of 23 melanoma-prone families in the UnitedStates that found no significant excess of cancers in thesefamilies other than melanoma.24 Kopf et al.25 also observedthat patients with familial melanoma had fewer cancers of othertypes than those with sporadic melanoma, and Swerdlow et al.,26who examined the risk of second primary cancer in all patientswith cutaneous melanoma (total, 12,460) in Denmark from 1943to 1989 (follow-up, 88,667 person-years), found no increasedrisk of pancreatic cancer in these patients.
In contrast, Lynch et al.27 described a large kindred with familialatypical multiple-mole melanoma with an increased risk of severalother cancers, including intraocular melanoma and carcinomaof the lung, skin, larynx, and breast. Since this study waslimited to a single kindred, it is possible that the reportedexcess may have represented chance cosegregation of rare cancersrather than an increased risk of other cancers in melanoma-pronefamilies. Subsequently, Bergman et al.28 observed an increasedfrequency of gastrointestinal tract neoplasms, particularlycarcinoma of the pancreas, in some Dutch melanoma-prone kindreds.Our finding that the risk of pancreatic cancer was increasedonly in melanoma-prone kindreds with p16M alleles may partlyexplain these variations in familial melanoma.
The finding of an increased risk of pancreatic cancer was basedon only two prospective cases and seven total cases and thusrequires corroboration before this information can be appliedin a clinical setting. However, the finding of multiple casesof pancreatic cancer in three of the four kindreds with pancreaticcancer suggests that health care professionals should carefullycheck the family history of melanoma-prone kindreds.
Abnormalities of p16INK4 have been linked directly to pancreaticadenocarcinoma. Caldas et al.29 found frequent somatic mutationsand homozygous deletions of the p16INK4 gene in pancreatic carcinomas.They observed allelic deletions of chromosome 9p21-p22, theregion that harbors p16INK4, in 85 percent (22 of 26) of informativetumors. In addition, Caldas et al. examined 37 pancreatic carcinomas(27 xenografts and 10 cell lines) and found homozygous deletionsof the p16INK4 gene in 15 (41 percent) and sequence changesin 14 (38 percent).29 These results suggest that abnormal regulationof cyclin-dependent kinases may have an important role in thebiology of pancreatic carcinoma.
Mutations in p16INK4 have been detected in only one third toone half of the melanoma-prone kindreds examined to date10,11,12,13(and unpublished data). Nevertheless, in a small number of kindredswithout detectable p16INK4 mutations there was strong evidenceof linkage of familial melanoma to chromosome 9p21-p22.9,10,11,12,13,15,30,31These kindreds may have undetected p16INK4 mutations, or theremay be another gene relevant to melanoma in this chromosomalregion. It is also possible that the melanoma in families withoutp16INK4 mutations may represent chance aggregations of smallclusters of cases. Although two of the kindreds with p16W alleleshad only two family members with melanoma, the average numberof persons with melanoma (invasive and in situ) was similarin the kindreds with p16M and p16W alleles (5.8 vs. 5.2, respectively),suggesting that the majority of cases of melanoma in kindredswith p16W alleles do not result from chance aggregations ofsmall clusters of cases.
One kindred (Family 373) had a missense mutation (Asn63Ser)that cosegregated with the combined trait of melanoma and dysplasticnevi.10 However, functional studies in in vitro assays14 suggestedthat this mutation had little ability to impair the functionof p16INK4. Thus, this kindred was included in the group withp16W alleles. Neither the exclusion of this kindred from thegroup with p16W alleles nor its inclusion in the group withp16M alleles had much effect on the results (data not shown).
In summary, previous examinations of familial melanoma haveinconsistently shown relations between melanoma and pancreaticcancer. This inconsistency may be due to pancreatic cancer'sbeing associated only with familial melanoma involving p16Mmutations. Thus, information about genetic factors, such asp16INK4, may help explain the inconsistent occurrence of othercancers in kindreds with familial melanoma.
We are indebted to the participating families, whose generosityand cooperation have made this study possible, and to KevinMeagher for analytical support.
Source Information
From the Genetic Epidemiology Branch, National Cancer Institute, Bethesda, Md. (a.M.G., M.C.F., J.P.S., S.M.O., M.A.T.); the Department of Nursing, Warren G. Magnuson Clinical Center, Bethesda, Md. (M.C.F.); the National Center for Human genome Research, National Institutes of Health, Bethesda, md. (J.P.S., C.J.H., K.R., N.C.D.); the Department of Surgery, Washington University School of Medicine, St. Louis (C.J.H.); Westat, Inc., Rockville, Md. (D.P.Z.); Battelle/SRA, Rockville, Md. (L.S.F.); Sequana Therapeutics, Inc., La Jolla, Calif. (N.C.D.); the Pigmented Lesion Study Group and Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia (W.H.C.); and the Department of Pathology, Beth Israel Hospital, Harvard Medical School, Boston (W.H.C.).
Address reprint requests to Dr. Goldstein at Genetic Epidemiology Branch, Executive Plaza North, Rm. 439, 6130 Executive Blvd., MSC 7372, Bethesda, MD 20892-7372.
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Familial Melanoma and Pancreatic Cancer
Ciotti P., Strigini P., Bianchi-Scarrà G., Wright F. A., Thomas R. G., Bergman W., Gruis N., Goldstein A. M., Tucker M. A., Whelan A. J., Bartsch D., Goodfellow P. J.
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N Engl J Med 1996;
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Correspondence
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