Familial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family

doi:10.1016/j.jaad.2012.05.014

Journal of the American Academy of Dermatology

Volume 67, Issue 6, December 2012, Pages 1257-1264.e2

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https://doi.org/10.1016/j.jaad.2012.05.014 Get rights and content

Background

Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied.

Objective

We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family).

Methods

We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer.

Results

The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families.

Limitations

The study was not population based.

Conclusions

This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.

Section snippets

Study design and data collection

Families with at least 2 patients with CM were recruited between 1995 and 2010 through a national network of French dermatology departments and oncogenetic clinics as part of the MELARISK collection (as described in more detail in Chaudru et al¹⁴). Eligible probands were defined as white-skinned individuals with histologically confirmed melanoma. Families referred for CDKN2A mutation testing had to include at least 2 confirmed melanoma cases. Written informed consent was obtained from all

Descriptive characteristics of the sample

A total of 483 families including at least 2 first-degree relatives affected with CM and having been tested for CDKN2A mutations were available for this study (Table I). This sample included 387 families (80%) with only 2 patients with CM (F2 families) and 96 families (20%) with 3 or more patients with CM (F3+ families). The percentage of families with a median age at diagnosis younger than 50 years was 56% in the total sample. This percentage (54% in F2 and 63% in F3+) was not statistically

Discussion

To our knowledge, this study of a large series of 483 French families with at least 2 patients with confirmed cutaneous melanoma among first-degree relatives of the index case is the first to explore associations between 3 clinical factors and the presence of a CDKN2A mutation in a family according to the extent of CM family clustering (2 vs ≥3 CM cases, F2 and F3+ families, respectively). In the F2 families, the factors significantly associated with CDKN2A mutations were early age at CM

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CDKN2A-positive melanoma patient treated with combination immunotherapy – A case report
2022, Advances in Cancer Biology - Metastasis
Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.
Special Clinical Situations
2017, Cutaneous Melanoma: a Pocket Guide for Diagnosis and Management
The traditional “dichotomic” (benign vs. malignant) approach to the diagnosis of melanocytic skin neoplasms is increasingly becoming less popular. Definitional features for a “gray zone” (in between the benign “white zone” and the malignant “black zone”) are as follows: (1) an “intermediate morphology,” ascribed to either deceptively bland melanomas or morphologically “atypical” but benign nevi; (2) an “intermediate biology,” referred to melanocytic tumors (“melanocytomas”) showing a high rate of regional node involvement but a very low rate of distant metastases. The histopathological report of these tumors should always reflect the diagnostic uncertainty with a “provisional diagnosis” based on the following categories: (1) atypical (junctional/compound/dermal) melanocytic nevus, for a neoplasm that is felt to be most likely benign; (2) severely atypical (junctional/thin compound/thick compound/dermal based) melanocytic proliferation for a neoplasm that is possibly/probably malignant. Recommendations about the management should be set up through a multidisciplinary team meeting.
Familial melanoma and multiple primary melanoma are suggestive of hereditary melanoma predisposition. CDKN2A is the major high-penetrance susceptibility gene to date and germline mutations are identified in 20%–40% of melanoma families, with the frequency varying between different geographical regions. A positive CDKN2A mutation status has been associated with a high number of affected family members, multiple primary melanomas, pancreatic cancer, and early age of melanoma onset. Mutations in the CDK4, BAP1, TET, POT1, ACD, TERF2IP, and MITF genes are rare, overall contributing to explain a further 10% of familial clustering of melanoma. The underlying genetic susceptibility remains indeed unexplained for half of melanoma families. Genetic testing for melanoma in clinical practice is controversial. Patients with hereditary predisposition should be counseled focusing primarily on recommendations on appropriate lifestyle, encouraging skin self-examination and regular dermatological screening. Finally, familial melanoma-associated genes have been also shown to be relevant for other cancers with implications for surveillance in mutation carriers.
Melanoma is the most common malignancy encountered during pregnancy, accounting for 31% of all malignancies diagnosed in pregnant women. In Australia, the crude incidence of pregnancy-associated melanoma increased from 37.1 per 100,000 maternities in 1994 to 51.8 per 100,000 maternities in 2008. No association between women’s parity and melanoma has been reported. Case reports with unfavorable prognosis have been published and still emerge. However, to-date reviews have not been able to conclude whether pregnancy influences the prognosis of melanoma. Within the past couple of years, two large epidemiological cohort studies have been published. The first, from the United Kingdom, reported on a significantly increased risk, while the second one, from Sweden, was not able to document such a correlation.
Melanoma is extremely rare in the pediatric age group, especially in children before puberty. It is reported to be more frequently of the nodular type and amelanotic; however, no clear-cut clinical and dermoscopic features have been described.
One important risk factor is represented by congenital nevi. Giant congenital nevi, in particular, harbor the higher risk of development of melanoma and neurocutaneous melanocytosis, requiring a multidisciplinary approach.
Controversies exist in the diagnosis and treatment of atypical Spitz tumor, a spitzoid melanocytic lesion with uncertain malignant potential.
Staging and follow-up of melanoma in children do not differ from the current practice in adults. No data are currently available about the efficacy of targeted and immunotherapy in melanoma in children. Recent evidence suggests the lack of prognostic value for sentinel lymph node biopsy in atypical Spitz tumors.
Discovery of lymph node or visceral malignant invasion by melanoma cells without clear previous history of cutaneous, ocular, or mucosal melanoma is not an uncommon situation. In such a case the four possible explanations for this phenomenon are the following: neglected or left undiagnosed primary tumor or misdiagnosed primary tumor (Hutchinson’s melanotic whitlow), fully or almost fully regressed primary tumor, metastatic spread from a visceral (occult) primary tumor (eye, sinuses, gastrointestinal tract, meninges, etc.), and hypothetical primary melanoma (in unique) of the lymph node of the affected organ.
Role of CDKN2A Mutations and Other Relevant Genes in Melanoma Predisposition
2016, Brain Metastases from Primary Tumors: Epidemiology, Biology, and Therapy of Melanoma and Other Cancers
Melanoma is the most aggressive type of skin cancer and occurs both sporadically and in a familial context. Currently, about half of the known melanoma families have unknown etiology, and few genes are associated with melanoma predisposition. Melanoma susceptibility genes are related to cell cycle, DNA damage repair, pigmentation traits, and telomere-regulating pathways. Here, we present an overview of the known melanoma susceptibility genes, and the germline mutations of which that have been found to segregate within melanoma families, highlighting the central role of the CDKN2A gene. We provide a brief history on melanoma predisposition and detail the more common mutations that have been found worldwide over the past 5 years. Additionally, we describe candidate melanoma genes that have less conclusive evidence derived from family reports and genome-wide association studies. Finally, we comment on the importance of newly developed DNA sequencing technologies and the field of epigenetics in increasing our knowledge of melanoma predisposition.
Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup
2016, Journal of the American Academy of Dermatology
Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral.
We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history.
In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor.
CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether.
The study was hospital based, not population based. Rare novel susceptibility genes were not tested.
Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.
The aggregation of early-onset melanoma in young Western Australian families
2015, Cancer Epidemiology
Citation Excerpt :
The selected cancers were melanoma, breast, prostate, colorectal, lung, thyroid, brain, lip/gum/mouth, cervical, testicular and kidney cancers. One of the most widely reported co-aggregations with melanoma is pancreatic cancer [9,10,12,21–23,33] and it was therefore also included, despite occurring at a frequency of less than 2.0% in the sample. Other cancers previously found to aggregate with melanoma to a lesser extent, such as non-Hodgkin's lymphoma, occurred at frequencies of less than 1.0% in the sample.
Few studies have examined the familial aggregation of melanoma or its co-aggregation with other cancers using whole-population based designs. This study aimed to investigate aggregation patterns in young Western Australian families, using population-based linked health data to identify individuals born in Western Australia between 1974 and 2007, their known relatives, and all incident cancer diagnoses within the resulting 1,506,961 individuals.
Cox proportional hazards regression models were used to compare the risk of melanoma for first-degree relatives of melanoma cases to that for first-degree relatives of controls, with bootstrapping used to account for correlations within families. The risk of (i) developing melanoma based on the number of first-degree relatives with other cancers, and (ii) developing non-melanoma cancers based on the number of first-degree relatives diagnosed with melanoma was also investigated.
First-degree relatives of melanoma cases had a significantly greater incidence of melanoma than first-degree relatives of individuals not affected with melanoma (Hazard Ratio (HR) = 3.58, 95% bootstrap confidence interval (CI): 2.43–5.43). Sensitivity analyses produced a higher hazard ratio estimate when restricted to melanoma cases diagnosed before 40 years of age (HR = 3.77, bootstrap 95% CI: 2.49–6.39) and a lower estimate when only later-onset cases (>40 years) were considered (HR = 2.45, bootstrap 95% CI: 1.23–4.82). No significant evidence was found for co-aggregation between melanoma and any other cancers.
Results indicated a strong familial basis of melanoma, with the higher than expected hazard ratio observed likely to reflect early-age at onset cases in this young cohort, supported by the results of the sensitivity analyses. Exploratory analyses suggested that the determinants of melanoma causing the observed aggregation within families may be independent of other malignancies, although these analyses were limited by the young age of the sample. Determining familial aggregation patterns will provide valuable knowledge regarding improved clinical risk prediction and the underlying biological mechanisms of melanoma and other cancers.
Recommendations for genetic testing and management of individuals genetically at-risk of cutaneous melanoma
2015, Annales de Dermatologie et de Venereologie
Le mélanome cutané est une maladie multifactorielle résultant des effets et interactions de facteurs environnementaux et génétiques. Plusieurs gènes de prédisposition ont été identifiés ces dernières années ; il s’agit de gènes conférant un risque élevé (CDKN2A, CDK4 et BAP1) ou un risque intermédiaire (MITF et MC1R). L’objet de ce travail d’experts était de définir les situations cliniques incontournables justifiant la prescription d’analyses génétiques, d’exposer le déroulement de ces analyses et de proposer des recommandations de prise en charge des personnes à risque. Du fait des contraintes réglementaires, il est préférable de travailler en tandem « dermatologue–généticien ». Les situations cliniques retenues sont la présence d’au moins deux cas de mélanomes cutanés invasifs, vérifiés histologiquement, diagnostiqués avant 75 ans chez deux apparentés au premier ou au deuxième degré, ou chez le même individu. L’association, chez une même personne ou dans une branche parentale, d’un mélanome cutané invasif à un mélanome oculaire, un cancer du pancréas, un cancer du rein, un mésothéliome ou une tumeur du système nerveux central représente également une indication d’analyse génétique. Les propositions de prise en charge reposent sur une photoprotection bien conduite et une surveillance dermatologique modulée selon le statut génétique. De plus, selon le gène en cause et les antécédents familiaux, il existe des risques tumoraux associés nécessitant une prise en charge spécifique (mélanome oculaire, cancer du pancréas…). Du fait des progrès rapides dans le domaine de la génétique, ces recommandations sont susceptibles d’évoluer rapidement.
Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly.

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: Supported by Institut National de la Santé et de la Recherche Médicale (including an INSERM Research Fellowship for hospital-based scientists to Dr Bressac-de Paillerets), Université Paris Diderot, and the National Institutes of Health RO1 CA-83115 (Dr Demenais); Programme Hospitalier de Recherche Clinique, PHRC 2007-AOM-07-195 (Drs Demenais and Avril); and Institut National du Cancer.

: French melanoma oncogenetic network coordinated by Dr Bressac-de Paillerets and Institut National du Cancer (French melanoma oncogenetic network coordinated by Dr Bressac-de Paillerets).

: Drs Maubec, Chaudru, Bressac-de Paillerets, Avril, and Demenais contributed equally to this article.

: Conflicts of interest: None declared.

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Original articleFamilial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family

Background

Objective

Methods

Results

Limitations

Conclusions

Section snippets

Study design and data collection

Descriptive characteristics of the sample

Discussion

Cell

J Invest Dermatol

J Am Acad Dermatol

GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC CancerBase No. 10

Germline CDKN2A mutations in childhood melanoma

J Natl Cancer Inst

The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study

Cancer Epidemiol Biomarkers Prev

Selection criteria for genetic assessment of patients with familial melanoma

J Am Acad Dermatol

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

Cancer Res

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

J Med Genet

A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4

Nature

Geographical variation in the penetrance of CDKN2A mutations for melanoma

J Natl Cancer Inst

Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample

J Natl Cancer Inst

Genetic susceptibility in familial melanoma from northeastern Italy

J Med Genet

Germline mutation and large deletion analysis of the CDKN2A and ARF genes in families with multiple melanoma or an aggregation of malignant melanoma and breast cancer

Int J Cancer

Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families

J Natl Cancer Inst

Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma

J Med Genet

Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients

Hum Mutat

Original article
Familial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family