Familial Atypical Multiple Mole Melanoma Research Articles

Pancreatic cancer screening: state of the art

Pancreatic cancer is a devastating disease with a median survival of approximately 6 months after diagnosis. Many factors are associated with a worse outcome; examples include late diagnosis, low resection rate, aggressive tumor behavior and a lack of an effective chemotherapy regimen. Owing to the low prevalence of pancreatic cancer relative to the diagnostic accuracy of present detection methods and the absence of promising treatment modalities, even in early stages, it is currently neither advisable nor cost effective to screen the general population. Efforts are focused on early screening of selected high-risk-cohorts, who account for approximately 10% of patients with pancreatic cancer. These include patients with chronic pancreatitis, individuals with a family history of pancreatic cancer, patients with hereditary pancreatitis, Peutz–Jeghers syndrome, cystic fibrosis or familial atypical multiple mole melanoma. At present, a multimodal-screening approach of endoscopic ultrasound, computed tomography and endoscopic retrograde cholangiopancreatography appears to be the most effective method to screen for pancreatic cancer in high-risk patients. Continued efforts are needed to elucidate effective testing to identify patients with nonhereditary risk factors who will benefit from screening protocols. A combined approach of serum markers, genetic markers and specific imaging studies may prove to be the future of pancreatic screening.

Skin self-examination of persons from families with familial atypical multiple mole melanoma (FAMMM)

Objective Early detection of melanomas might increase survival chance. Patients can usually see primary lesions while inspecting their skin. Skin self-examination (SSE) is therefore the recommended pre-screening method. To maximize the likelihood that SSE will be performed, it is important to distinguish those factors that increase the chance of performance. The aim is to examine motivational differences between (a) melanoma-prone persons who perform SSE once every 2–3 months, and (b) melanoma-prone persons with a lower SSE frequency. Methods A survey to assess socio-demographic factors, attitude, social influence, self-efficacy and intention to perform SSE. Results Members ( n = 71) of 18 familial atypical multiple mole melanoma (FAMMM) families participated; 70% performed SSE at least once every 2–3 months. Adequate performers were more likely to have a partner, had a more positive attitude toward SSE, perceived SSE as less difficult to perform and had a stronger intention to perform SSE compared to poor performers. Logistic regression indicated attitude as the only reliable predictor of SSE performance. Conclusion We found that about one third of our genetically predisposed population did not report an adequate frequency of performing SSE. Practice implications Deficiencies in SSE practices in a genetically predisposed population are indicated.

Early Detection of Pancreatic Cancer: Why, who, and how to Screen

Pancreatic cancer represents the fourth-leading cause of cancer death in the United States, with a dismal 5-year survival rate of less than 5%. Despite advancements in screening and early detection of other cancers such as breast and colon cancer, no reliable screening test exists for pancreatic cancer. Subsequently, the majority of patients present with advanced-stage disease leading to a poor prognosis. Because of the relatively low incidence, current efforts are focused on early detection and screening only in patients at high risk for the development of the disease. We discuss the practical considerations encountered when determining if an individual should be screened for pancreatic cancer. The current literature was reviewed regarding risk factors, genetic syndromes, screening modalities, and screening studies of pancreatic cancer. The current high-risk pancreatic screening program at our institute is also summarized. Current efforts to detect pancreatic cancer at a curative phase are focused on screening individuals at high risk for the development of this disease. They include kindreds with two or more first-degree relatives affected with this disease and those with known hereditary pancreatic cancer syndromes. Hereditary pancreatic cancer syndromes include Peutz-Jeghers syndrome, familial breast cancer syndrome, and familial atypical multiple mole melanoma syndrome. Of all the screening modalities available, endoscopic ultrasound is the most sensitive and specific screening tool to evaluate the pancreas and has been proven to detect early precancerous and cancerous changes in clinical studies. Early detection and screening for pancreatic cancer in the current state should be limited to high-risk patients, although hereditary/familial factors account for only 10% of patients with pancreatic cancer. Continued efforts are needed to discover effective test to identify patients with nonhereditary risk factors who will benefit from screening and also to develop less invasive and more cost-effective screening modalities aimed at controlling pancreatic cancer.

Hereditäres Pankreaskarzinom

An inherited predisposition to pancreatic cancer (PC) is prevalent in about 3% of PC cases and is currently believed to occur in three distinct clinical settings, (1) hereditary tumour predisposition syndromes with an increased risk of PC such as Peutz-Jeghers syndrome and familial atypical multiple mole melanoma, (2) hereditary pancreatitis and cystic fibrosis, in which genetically determined early-age changes of the pancreas can predispose to the development of PC, and (3) familial pancreatic cancer syndrome (FPC). According to a recent consensus conference, high-risk individuals from PC-prone families should be enrolled in board-approved, prospective, controlled screening programs at expert centres. Based on the available data, prophylactic pancreatectomy is not indicated, since the underlying causative gene defect of the FPC syndrome is still unknown and the penetrance of PC in other tumour predisposition syndromes is either low or yet undetermined. In case of the diagnosis of a PC or high-grade precursor lesions, a prophylactic extension of the resection can be considered, since patients with hereditary PC often develop multifocal pancreatic lesions.

Survival from cancer of the pancreas in England and Wales up to 2001.

Survival from cancer of the pancreas in England and Wales up to 2001.

Pancreatic cancer and the FAMMM syndrome

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.

Head and neck squamous cell cancer as part of the germline p16/INK4a mutation-induced FAMMM syndrome

6052 Background: p16/INK4a constitutes an important cancer susceptibility locus. Germline mutations at this locus have been implicated in several human cancer syndromes, including familial atypical multiple mole melanoma (FAMMM) syndrome, FAMMM-pancreatic cancer (FAMMM-PC) syndrome, and more recently, in familial head and neck cancer syndrome. Methods: We present an individual with a family history of both pancreatic cancer and melanoma, who developed squamous cell carcinoma of the tongue at 21 years old, multiple melanomas, a second squamous cell cancer of the tongue at 40 years old, and ultimately a pancreatic cancer. Results: We identify a germline mutation in INK4a that leads to a substitution of tryptophan for glycine in the Ankyrin III domain of the p16 protein (G101W). We demonstrate loss of heterozygosity at the INK4a locus and lack of p16 expression in the second head and neck squamous cell cancer (HNSCC) tissue. Based on these and on previously published data, we propose that HNSCC resulting from an INK4a germline mutation is a variant of the FAMMM/FAMMM-PC syndrome. Further studies will determine whether there is genotype-phenotype correlation between these syndrome variants. Conclusions: We conclude that young individuals who develop HNSCC should be considered at high-risk for other cancers, including pancreatic cancer and melanoma. They should be advised to avoid cigarette smoking and should be considered for pancreas cancer screening. No significant financial relationships to disclose.

Prophylaktische Chirurgie des Pankreas

The goal of prophylactic surgery is to prevent malignant growth in patients with hereditary tumor predisposition. The pancreas presents as particularly challenging, due to the difficulty of operation and comparatively high risk of morbidity and even mortality. In addition, partial operative procedures and, more significantly, total resection lead to exocrine pancreas insufficiency and secondary diabetes, with grave consequences for the patient. Hereditary tumor predisposition syndromes that can result in pancreaticoduodenal endocrine tumors (PET) include multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau syndrome. As penetrance is maximally 70-80% and the 10-year survival rate over 80%, prophylactic pancreatic resection without evidence of a tumor is not indicated. However, prophylactic extension of a resection would be advised, should a PET be diagnosed. Patients predisposed to developing ductal pancreatic carcinoma (PC) are at risk of familial pancreatic cancer syndrome (FPC), hereditary pancreatitis, and other hereditary tumor predisposition syndromes such as Peutz-Jeghers syndrome and familial atypical multiple mole-melanoma syndrome. As the gene defect responsible for FPC has yet to be identified and the penetrance of PC in the other tumor predisposition syndromes is low or unknown, a prophylactic pancreatectomy based on today's knowledge is not indicated. Prophylactic extension of the resection is advisable should PC or high-grade PanIN lesions be diagnosed, as these patients often present with multifocal dysplasia and even carcinoma.

Inherited predisposition to cancer: a historical overview.

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries.

FAMMM Syndrome

Familial atypical multiple mole melanoma (FAMMM) syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Pathogenesis of this syndrome has not been fully investigated. Across multiple studies, germline mutations in the INK4a antioncogene encoding p16 protein were found on average in approximately 40% of the FAMMM syndrome. Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer. Melanoma can develop from numerous atypical moles as well as de novo. A proper diagnosis of the syndrome and early application of prophylactics decreases the risk of neoplastic transformation of melanocytes.

FAMMM syndrome: pathogenesis and management.

Familial atypical multiple mole melanoma (FAMMM) syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Pathogenesis of this syndrome has not been fully investigated. Across multiple studies, germline mutations in the INK4a antioncogene encoding p16 protein were found on average in approximately 40% of the FAMMM syndrome. Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer. Melanoma can develop from numerous atypical moles as well as de novo. A proper diagnosis of the syndrome and early application of prophylactics decreases the risk of neoplastic transformation of melanocytes.

Familial sarcoma: challenging pedigrees.

Partially due to the rare occurrence of soft tissue and osteogenic sarcomas in the general population, scant attention has been given to their hereditary etiology. Their overall poor prognosis might be ameliorated through an understanding of their environmental and hereditary causal factors, and/or their interactions, thereby contributing to earlier diagnosis and even the development of molecularly based targeted therapy. The authors selected 10 sarcoma-prone families from their extensive hereditary cancer-prone family resource and focused on their challenging diagnostic, surveillance, and management features. The family study protocol included the compilation of a detailed family history of malignant disease of all anatomic sites and the collection of all available primary medical and pathology documents for verification. Genetic counseling was provided before DNA collection and at disclosure of results. These families displayed marked phenotypic and genotypic heterogeneity. In one of these families, 16 relatives had sarcomas, with 2 of the 16 each having 2 metachronous sarcomas; to our knowledge, this represents the greatest number of sarcomas reported in any family described to date. Two familial atypical multiple-mole melanoma syndrome kindreds with the CDKN2A mutation showed the association of sarcoma with malignant melanoma, whereas one family had several pancreatic carcinomas. Other families with sarcoma had hereditary nonpolyposis colorectal carcinoma with MSH2 mutation, hereditary breast carcinoma with BRCA1 mutation, and p53 mutation in a Li-Fraumeni syndrome. Sarcoma-prone families reported in the current study were selected carefully to depict clinicopathology and compliance features, the understanding of which could elucidate the etiologic role of genetic factors in concert with the phenotypic and genotypic heterogeneity encountered in such families. The lack of a population-based data set for these families posed a limitation.

Pancreatic diseases.

Pancreatic diseases.

The genetics of pancreatic cancer

The genetic basis for invasive and preoneoplastic neoplasms of the exocrine and endocrine pancreas has been the subject of a number of investigations in recent years. The purpose of this paper was to briefly review and summarize the pertinent findings. High frequency changes associated with pancreatic adenocarcinomas include mutations of the k-ras oncogene, and inactivating alterations of the p53, p16, and DPC4 tumor suppressor genes. Hereditary syndromes that have a known predisposition for pancreatic adenocarcinoma development include hereditary pancreatitis, familial atypical multiple mole melanoma (FAMM) syndrome, Peutz-Jeghers syndrome, familial breast cancer (BRCA-2), hereditary nonpolyposis colorectal cancer syndrome (HNPCC), and Li-Fraumeni syndrome. The underlying genetic defects have been identified and are currently being studied. Germline mutations of the men-1 gene are responsible for the MEN-1 syndrome, known to be associated with pancreatic endocrine tumors. It appears that somatic mutations of the gene are present in at least a subset of sporadic tumors. In addition, alterations in the Rb/p16 pathway appear to be commonly associated with pancreatic endocrine tumors. Further characterization of pancreatic tumors will result in a better understanding of the cellular pathways involved in pancreatic tumorigenesis and holds promise to identify targets for novel diagnostic and therapeutic strategies.

Characterization of the neoplastic phenotype in the familial atypical multiple-mole melanoma-pancreatic carcinoma syndrome.

Previous studies suggest that the familial atypical multiple-mole melanoma (FAMMM) syndrome may predispose affected families to nonmelanoma carcinomas, including adenocarcinoma of the pancreas. It has been found that many of these families harbor mutations in the CDKN2A gene on chromosome 9p21. The phenotypic expression of CDKN2A mutations in these families has not been characterized fully. The authors studied eight families that appeared to inherit multiple nevi, cutaneous melanomas, and pancreatic carcinomas in association with a CDKN2A germline mutation. The expression of disease within these families was examined, and segregation ratios were estimated to assess the patterns of inheritance according to various definitions of phenotype. Either multiple nevi or pancreatic carcinoma was diagnosed in 53% of first-degree relatives of the probands. The offspring of parents affected with multiple nevi, melanoma, or pancreatic carcinoma were significantly more likely to be affected themselves compared with the offspring of unaffected parents (48.9% vs. 16.7%; P = 0.004). The current results provide additional evidence that multiple nevi, melanoma, or pancreatic carcinoma may be inherited as autosomal-dominant traits in families known to harbor CDKN2A mutations. Other malignancies may be a part of the phenotype in these families, although this hypothesis requires additional study.

Familial pancreatic cancer.

Screening advocated

Epidemiology of pancreatic cancer: an overview

Introduction: The incidence of pancreatic cancer worldwide appears to correlate with increasing age, and it is slightly more common among men and Jewish people. There is evidence that the incidence rate is higher among blacks than among whites. Methods: The published literature was reviewed for preparation of an overview on epidemiology of pancreatic cancer. Results: A possible role of diabetes in the etiology of pancreatic cancer has been suggested by different epidemiological studies. Several investigations indicate that a history of pancreatitis may increase the risk of pancreas cancer, and it appears that people with a history of pernicious anemia or partial gastrectomy for ulcer as well as cholecystectomy may be at higher risk. Individuals with familial adenomatous polyposis (FAP) also have a high risk of developing this cancer. Pancreatic cancer is seen in some breast cancer families with BRCA1 and BRCA2 mutations. Epidemiological studies have confirmed that relatives of individuals with pancreatic cancer have an increased risk of this malignancy. Affected family members of the familial atypical multiple-mole melanoma (FAMMM) as well as those with a positive family history of ataxia-telangiectasia (AT) have much higher risk of developing pancreatic cancer, compared with the general population. A positive association has been reported between pancreatic cancer risk and dietary intake such as fat and oil, meat, and dairy products, as well as with high intake of energy, fried foods, carbohydrates, cholesterol, and salt. The risk is found to decrease with increased consumption of fresh fruits and vegetables, fiber, natural foods, and Vitamin C. Cigarette smoking has shown the strongest positive association with risk of pancreatic cancer. Conclusion: Some diseases and medical conditions such as diabetes, chronic pancreatitis, AP, family aggregation of pancreatic cancer, FAMMM, AT, as well as nutrition and lifestyle factors, like smoking may play important role in the etiology of pancreatic cancer.

Evidence for a major gene influencing risk of pancreatic cancer.

Family history of pancreatic cancer, the fifth leading cause of cancer death in the United States, confers a 1.5-13-fold higher risk of developing pancreatic cancer. Pancreatic cancer is associated with several genetic syndromes, including hereditary breast cancer (BRCA2), familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer (HNPCC). However, these syndromes explain little of the observed familial aggregation of pancreatic cancer. We performed complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994 and December 31, 1999. We tested for the presence of a major gene controlling either the "age-at-onset of pancreatic cancer" of "susceptibility to pancreatic cancer," and incorporated smoking data on kindred members as a covariate. We found evidence for involvement of a major gene in the etiology of pancreatic cancer. Whether inheritance was modeled as "age-at-onset" or "susceptibility," nongenetic transmission models were strongly rejected. However, modeling "age-at-onset" provided a better fit to the observed data than did modeling "susceptibility." The most parsimonious models included autosomal-dominant inheritance of a rare allele. Under the age-at-onset model, approximately 0.7% of the population appears to be at high risk of developing pancreatic cancer due to this putative gene, whereas 0.4% of the population is at high risk under the susceptibility model. Inclusion of smoking as a covariate did not significantly improve the fit of these models. This hospital-based segregation analysis of pancreatic cancer found evidence supporting the role of a rare major gene influencing risk of pancreatic cancer.

Familial Pancreatic Cancer

The dismal prognosis of ductal pancreatic adenocarcinoma is mainly attributable to advanced tumor stages at the time of diagnosis. Meanwhile, familial pancreatic cancer is an established hereditary tumor entity that is responsible for approximately 3% of pancreatic cancer (PC) cases. Therefore, analysis of the family history may help to identify individuals at increased risk of developing PC. These include members of families with a history of PC as well as those of families with distinct hereditary cancer syndromes such as Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer. In future, the identification of germline mutations in genes predisposing to PC, together with the analysis of exogenous risk factors, could be used for a more precise risk assessment for the development of PC. This may allow the application of invasive screening methods for the identification of early PC or, even better, its precursor lesions in high-risk individuals, providing the option of timely curative pancreatectomy.

Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.

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. 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. 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. 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.