Wilma Bergman

Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16‐Leiden)

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.

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence

The CDKN2A tumour suppressor locus encodes two distinct proteins, p16INK4a and p14ARF, both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma‐prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16INK4a deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14ARF. Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage‐independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.

Patients’ illness perceptions and coping as predictors of functional status in psoriasis: a 1‐year follow‐up

In a longitudinal study (two measurements with a 1‐year interval), 69 patients with psoriasis completed the Illness Perception Questionnaire, the Medical Outcomes Study SF‐20 Health Survey, and the Hospital Anxiety and Depression Scale. Data on coping (Utrecht Coping List) and severity of illness (body surface scores) were also collected. The results of regression analyses indicated that a strong illness identity was associated with more visits to the outpatient clinic, and worse outcome on physical health, social functioning, mental health, health perceptions and depression. Strong beliefs that the disease is controllable/curable and that the disease has disabling consequences were also related to more clinic visits and more negative perceived health, respectively. Patients who initially engaged in coping characterized by more expression of emotions, seeking more social support, seeking more distraction, and less passive coping were prescribed a lower number of different therapies, were less anxious, less depressed, and had a better physical health 1 year later. These results have implications for the management of patients with psoriasis, which reinforces current views on integrating psychosocial aspects into clinical care.

Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls

Background Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude. Methods We performed a pooled analysis of 15 case–control studies (5700 melanoma cases and 7216 controls), correlating patterns of sun exposure, sunburn and solar keratoses (three studies) with melanoma risk. Pooled odds ratios (pORs) and 95% Bayesian confidence intervals (CIs) were estimated using Bayesian unconditional polytomous logistic random-coefficients models. Results Recreational sun exposure was a risk factor for melanoma on the trunk (pOR = 1.7; 95% CI: 1.4–2.2) and limbs (pOR = 1.4; 95% CI: 1.1–1.7), but not head and neck (pOR = 1.1; 95% CI: 0.8–1.4), across latitudes. Occupational sun exposure was associated with risk of melanoma on the head and neck at low latitudes (pOR = 1.7; 95% CI: 1.0–3.0). Total sun exposure was associated with increased risk of melanoma on the limbs at low latitudes (pOR = 1.5; 95% CI: 1.0–2.2), but not at other body sites or other latitudes. The pORs for sunburn in childhood were 1.5 (95% CI: 1.3–1.7), 1.5 (95% CI: 1.3–1.7) and 1.4 (95% CI: 1.1–1.7) for melanoma on the trunk, limbs, and head and neck, respectively, showing little variation across latitudes. The presence of head and neck solar keratoses was associated with increased risk of melanoma on the head and neck (pOR = 4.0; 95% CI: 1.7–9.1) and limbs (pOR = 4.0; 95% CI: 1.9–8.4). Conclusion Melanoma risk at different body sites is associated with different amounts and patterns of sun exposure. Recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes, whereas measures of occupational and total sun exposure appear to predict melanoma predominately at low latitudes.

Genome-wide association study identifies three new melanoma susceptibility loci

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10−3: an SNP in ATM (rs1801516, overall P = 3.4 × 10−9), an SNP in MX2 (rs45430, P = 2.9 × 10−9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10−10). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10−7 under a fixed-effects model and P = 1.2 × 10−3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Localization of a Novel Melanoma Susceptibility Locus to 1p22

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.

Increased Risk of Cancer Other Than Melanoma in CDKN2A Founder Mutation (p16-Leiden)-Positive Melanoma Families

Purpose: We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for the same CDKN2A mutation. Experimental Design: We studied family members of 22 families positive for the p16-Leiden founder mutation who had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person and their relatives. Results: Our analysis shows a relative risk (RR) of cancer other than melanoma and nonmelanoma skin cancer of 4.4 [95% confidence interval (95% CI), 3.3-5.6], predominantly attributable to the increased risk for pancreatic cancer (RR, 46.6; 95% CI, 24.7-76.4), but also for other cancers. We provide substantial proof for pancreatic cancer being a key component of the p16-Leiden phenotype. Inclusion of this cancer in a penetrance analysis leads to an estimated RR of pancreatic cancer for mutation carriers of 47.8 (95% CI, 28.4-74.7). Conclusions: This study shows clear evidence of increased risk of cancers other than melanoma in CDKN2A families carrying the p16-Leiden mutation. Further research is necessary to determine if similar risks apply to families with CDKN2A mutations other than p16-Leiden.

Magnetic Resonance Imaging Surveillance Detects Early-Stage Pancreatic Cancer in Carriers of a p16-Leiden Mutation

BACKGROUND & AIMS Surveillance of high-risk groups for pancreatic cancer might increase early detection and treatment outcomes. Individuals with germline mutations in p16-Leiden have a lifetime risk of 15% to 20% of developing pancreatic cancer. We assessed the feasibility of detecting pancreatic cancer at an early stage and investigated the outcomes of patients with neoplastic lesions. METHODS Individuals with germline mutations in p16-Leiden (N = 79; 31 male; mean age, 56 years; range, 39-72 years) were offered annual surveillance by magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP). Those found to have neoplastic lesions were offered options for surgery or intensive follow-up. Individuals found to have possible neoplastic lesions were examined again by MRI/MRCP within 2 to 4 months. RESULTS After a median follow-up period of 4 years (range, 0-10 years), pancreatic cancer was diagnosed in 7 patients (9%). The mean age at diagnosis was 59 years (range, 49-72 years). Three of the tumors were present at the first examination, and 4 were detected after a negative result in the initial examination. All 7 patients had a resectable lesion; 5 underwent surgery, 3 had an R0 resection, and 2 had lymph node metastases. Possible precursor lesions (ie, duct ectasias, based on MRCP) were found in 9 individuals (11%). CONCLUSIONS MRI/MRCP detects small, solid pancreatic tumors and small duct ectasias. Although surveillance increases the rate of resectability, carriers of a p16-Leiden mutation develop aggressive tumors.

CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families.

Combined multi-point linkage analysis in seven Dutch families with FAMMM syndrome confirmed the location of a melanoma susceptibility (MLM) gene in the 9p21 area. The occurrence of a shared high-risk haplotype in six of the families strongly suggests a founder effect in the Leiden region. No indication for locus heterogeneity was observed. Recently, the CDKN2 (p16) gene, an important regulator of the cell cycle, was isolated from the 9p21 region. A 19-bp germline deletion in the CDKN2 gene was detected in the high-risk haplotype, suggesting CDKN2 to be identical to MLM. Loss of heterozygosity studies in melanoma and pancreatic carcinoma from gene carriers strongly support the view that CDKN2 is a general tumour suppressor gene predisposing not only to melanoma but also to other malignancies. Interestingly, the occurrence of apparent clinical FAMMM cases with melanoma but without the high-risk deletion haplotype suggests the necessity of additional (naevus) genes to explain the complete FAMMM phenotype.