Hereditary Malignant Melanoma

Ramon M. Fusaro, Henry T. Lynch, Ramon M. Fusaro, Henry T. Lynch

• Publisher: CRC Press
• Year: 2019
• Print ISBN:
  9780415604284
• eBook ISBN:
  9781000013009
• Edition: 1
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

First published in 1991: The book focuses only on hereditary malignant melanoma. The epidemic of cutaneous melanoma which is now occurring in the sun belt areas of the world is due partly to a susceptible subgroup of Caucasians who have immigrated there.

Chapter 1

HEREDITARY MALIGNANT MELANOMA AND THE FAMMM SYNDROME

Henry T. Lynch, Ramon M. Fusaro, Lavonne Johnsen, and Jane F. Lynch

TABLE OF CONTENTS

I.	Introduction
II.	How Does Sunlight Interact with Host Factors in Melanoma Carcinogenesis?
III.	Unifying Etiology Hypothesis
	A.	Albinism
	B.	Xeroderma Pigmentosum
	C.	Giant Pigmented Nevus
	D.	Retinoblastoma
IV.	Hereditary Intraocular Malignant Melanoma
V.	Problem Areas in Cancer Genetics
VI.	Historical Aspects of Hereditary CMM
VII.	Terminology
VIII.	Prototype Clinical/Genetic Model of the FAMMM
IX.	FAMMM Kindreds and Segregation Analysis
X.	Polygenic Inheritance and the FAMMM
XI.	Extra-Melanotic Cancer and the FAMMM
XII.	Cytogenetic and Gene Linkage Studies and the FAMMM
XIII.	Discussion
References

I. INTRODUCTION

Cutaneous malignant melanoma (CMM) in the U.S. is now increasing in occurrence at a rate second only to lung cancer in women. By the year 2000 A.D., it is estimated that 1 in 100 Caucasians will develop CMM during their lifetime.¹ The cause for this change within the last 3 to 4 decades is multifold: (1) the presence of a genetically susceptible Caucasian population with probable multiple inheritable traits which have been present for eons but are only now being quantitatively activated by geographic, environmental, and social factors; (2) the increasing number of Caucasians who are moving into the sunny climates around the globe (e.g., southern U.S. or Australia); (3) increase in leisure time available for outdoor recreational activity during prime sunlight hours because of affluence and a shorter work week; (4) the wearing of minimal clothing during these activities so that maximum athletic function can be accomplished (little attention is given by manufacturer to protect wearer from exposure to sunlight); (5) exposure to sunlight starting at an early age (the first decade) and continuing well into middle adult life; (6) the history of repeated moderate to severe “sunburns,” prepubertally; (7) the successful indoctrination of the public by commercial enterprises on the value of prolonged outdoor recreational activities; (8) failure of the medical and paramedical professions to successfully educate the public on the long-term effects of excessive sunlight exposure and need for reduction of outdoor recreational activities during the midday period; and (9) failure of public to use sun screen effectively. These events have led to an increase in sunlight exposure by the general public that is a relatively new, unprecedented experience for Caucasians.

In light of these facts, it is extremely important to realize that all individuals who are excessively exposed are not equal with respect to cancer susceptibility from solar radiation. Some are more susceptible to CMM than others. These differences in susceptibility to CMM result primarily from host factor variation. Those genotypic factors which endow many in our population with fair complexion, blond or red hair, freckles, blue eyes, and poor tanning ability are also extremely important etiologic factors, particularly when they interact with solar radiation. Collectively, these help to explain the enormous upswing in CMM. A less frequent but potentially devastating etiologic factor to specific families is that of Mendelian inheritance of a single deleterious CMM-predisposing gene. Families in which these CMM-prone genes segregate in accord with Mendelian inheritance patterns include the autosomal recessive disorders of albinism and xeroderma pigmentosum. The newly discovered, autosomal dominantly inherited, familial atypical multiple mole melanoma (FAMMM) syndrome (or hereditary dysplastic nevus syndrome [HDNS]) is by far the most common hereditary CMM-predisposing disorder. Collectively, these genetic disorders provide tremendously interesting models for the study of melanoma’s carcinogenesis, as well as its control. Multifactorial factors, as in pigmentation and complexion, and Mendelian inherited predisposing genes will provide the major subject matter for this book.

II. HOW DOES SUNLIGHT INTERACT WITH HOST FACTORS IN MELANOMA CARCINOGENESIS?

Surprisingly, there has been limited investigation of the etiologic role of environmental interaction with host factors in CMM, inclusive of the FAMMM. For example, in spite of the prodigious evidence for the significance of solar radiation exposure in the etiology of CMM, we are not aware of any definitive clinical evidence showing the effect of sunlight exposure on atypical nevi (AN) or CMM in the FAMMM.

A study of keen interest toward the understanding of the genetic epidemiology of CMM is that of Roser et al.² This investigation pertained to the manner in which genetically enhanced susceptibility to ultraviolet (UV) radiation may play a crucial etiologic role in the evolution of CMM at the laboratory level. These researchers studied skin fibroblasts from 26 patients with CMM and controls. They utilized the micronucleus (MN) test and sister chromatid exchange (SCE) following UV radiation. SCE and MN formation were then employed as investigational parameters for the detection of UV-induced genotoxic damage in the individual cell strains. Results disclosed “...that the UV-induced level of MN was significantly increased in CMM patients (p = 0.0005), being most pronounced in the familial cases (p = 0.001), but there wasn’t any difference between familial and nonfamilial cases. The present findings indicate that genetic predisposition contributes to the development of CMM in a subset of CMM patients and may be due to an enhanced susceptibility to UV light.” This methodological approach needs to be pursued in well-defined FAMMM kindreds.

FIGURE 1. The FAMMM syndrome, unifying etiologic hypothesis. FAMMM = familial atypical multiple mole melanoma syndrome (suffixes indicate heterogeneous forms); XDP = xeroderma pigmentosum; IOM = intraocular malignant melanoma, site specific; CMM = cutaneous malignant melanoma. (Reprinted from Lynch, H. T. and Fusaro, R. M., Cancer Genet. Cytogenet., 20, 301, 1986. With permission.)

III. UNIFYING ETIOLOGY HYPOTHESIS

Lynch and Fusaro³ proposed a unifying etiologic hypothesis for the etiology of malignant melanoma (see Figure 1). This hypothesis emphasized the occurrence of malignant melanoma as resulting from the interactions of genetics and environment. The hypothesis embraced basic genetic principles of reduced gene penetrance, variable expressivity of the phenotype, and genetic heterogeneity.^4,7 Primary genetic perturbations such as position effects and modifying genes, as well as extragenetic environmental interactions, in concert with such factors as activated oncogenes, may bear directly on melanoma carcinogenesis.⁴ Clearly, we are exceedingly low on the learning curve with respect to the identification of the role of primary genetic factors in malignant melanoma. This problem is hampered in a major way by the limited genetic knowledge of many physicians who attend these genetically high risk patients. The problem is seriously confounded: (1) by the fact that the family history is rarely developed in sufficient depth to enable an hereditary cancer syndrome diagnosis; and (2) by variations in clinical expression of phenotype, which may be extant and thereby require detailed clinical and genetic analysis of the patients and their family members.

The following CMM-predisposing disorders, while rare, are nevertheless pertinent to the understanding of the genetics of malignant melanoma, in the context of this hypothesis.

A. ALBINISM

Albinism is a genetic spectrum of disease involving different aspects of the metabolism and distribution of melanin in the skin, hair, and eyes. The term albinism is limited to those congenital universal hypomelanoses that involve the skin and eye (oculocutaneous albinism [OCA]) and the eye alone (ocular albinism [OA]). There are ten types of OCA: (1) tyrosinase-negative (ty-neg) OCA, (2) tyrosinase-positive (ty-pos) OCA, (3) yellow mutant OCA (YMA) (4) plastinum OCA (pt-OCA), (5) Hermansky-Pudlak syndrome (HPS), (6) brown OCA (BA), (7) rufous OCA (RA), (8) Cross-McKusick-Breen syndrome (CMBS), (9) black locks-albinism-deafness syndrome (BADS), and (10) Chediak-Higashi syndrome. The cutaneous findings are an absence or decrease in melanin pigmentation of the skin and hair. The eyes show the same pigmentation changes, but in addition, there is nystagmus, photophobia, and decreased visual acuity. All of these are inherited in an autosomal recessive pattern. At the other end of the genetic spectrum of OCA are the dominant forms with cutaneous hypomelanoses: (1) autosomal dominant OCA and (2) oculocutaneous albinoidism. In addition, there is albinism limited to the eye — ocular albinism. The skin is usually normal in color. There are five types of ocular albinism with only ocular pigmentation abnormalities: (1) X-linked type (Nettleship o...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Chapter 1 Hereditary Malignant Melanoma and the FAMMM Syndrome
• Chapter 2 The Cutaneous Manifestations of the Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome
• Chapter 3 The FAMMM Syndrome in the Netherlands
• Chapter 4 Ocular Melanoma Associated with the Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome
• Chapter 5 Histopathological Criteria Required for the Diagnosis of Familial Dysplastic Nevi
• Chapter 6 HLA and Malignant Melanoma
• Chapter 7 Molecular Genetic Analyses of Functional Melanoma-Associated Antigens
• Chapter 8 ECF-Receptor Gene, X-src Oncogene and Inositol Lipid Turnover in Key Processes Preceding Melanoma in the Xiphophorus Model
• Epilogue
• Index