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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.

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Oncologists who are aware of the progress in hereditary cancer syndrome diagnosis, and, in particular, of how this effort may be effectively facilitated through a comprehensive family history in concert with molecular genetic studies, are in the envious position of designing highly targeted screening and management programs for the membership of these cancer-prone families. The Lynch syndrome is discussed as a clinical model wherein the presence of mismatch repair mutations provides a high level of diagnostic certainty for the initiation of targeted cancer screening and management. The familial atypical multiple mole melanoma–pancreatic cancer (FAMMM–PC) syndrome, on the other hand, provides another model with cancer-control potential. Given its phenotypic features of multiple atypical nevi, high total body mole count and cutaneous malignant melanoma, coupled with the integral association of PC in a subset of FAMMM kindreds with the CDKN2Agermline mutation, this may result in a perhaps lower level of diagnostic certainty when compared with the Lynch syndrome. This knowledge may impact upon progress in the earlier diagnosis of melanoma and provide an impetus for creative diagnostic methods in PC, a disease that, at this time, demonstrates a mortality rate virtually identical to its incidence rate.

Unprotected sunlight exposure is a risk factor for a variety of cutaneous cancers. Topically used dihydroxyacetone (DHA) creates, via Maillard reaction, chemically fixed keratin sunscreen in the stratum corneum with significant protection against UVA/Soret radiation. When used in conjunction with naphthoquinones a naphthoquinone-modified DHA Maillard reaction is produced that provides protection across the UVB/UVA/Soret spectra lasting up to 1 week, resisting sweating and contact removal. The aim of this study was to examine a simplified version of this formulation for effect on UV transmission and to determine if penetration levels merit toxicity concerns. Permeability was demonstrated for freshly prepared DHA (30 mg/mL) and lawsone (0.035 mg/mL) alone and in combination using a side-by-side diffusion apparatus at 37°C over 48 h across shed snake skin and dermatomed pig skin. These samples were then examined for effectiveness and safety. Concentrations were determined by HPLC and UPLC monitored from 250-500 nm. Lawsone flux significantly decreased across pig skin (20.8 (± 4.8) and 0.09 (± 0.1) mg/cm(2) h without and with DHA, respectively) but did not change across shed snake skin in the presence of DHA. Significantly reduced lawsone concentration was noted in donor chambers of combined solutions. Damage was not observed in any skins. Darker coloration with greater UV absorbance was observed in skins exposed to the combined solution versus individual solutions. This study confirmed that combined DHA and lawsone provided effective blocking of ultraviolet light through products bound in keratinized tissue. DHA permeation levels in pig skin suggest further in vitro and in vivo study is required to determine the safety of this system.

Approximately 5% to 10% of patients with pancreatic cancer have one or more first-degree relatives with this disease. A subset of these individuals have a hereditary form of pancreatic cancer designated by association with such hereditary disorders as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, hereditary pancreatitis, or familial atypical multiple mole melanoma (FAMMM) syndrome. A subset of those FAMMM kindred with the CDKN2A (p16) germline mutation that expresses both pancreatic cancer and malignant melanoma may constitute a new hereditary pancreatic cancer-prone syndrome.

The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%–10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer–malignant melanoma in which p16 ( CDKN2 ) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non–cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage. GASTROENTEROLOGY 2000;119:1756-1760

Research into the epidemiology of the melanoma-prone FAMMM syndrome, molecular genetics of the occurrences of melanoma, the photobiology of DNA damage/repair, diagnostic epiluminescence, microscopic/imaging techniques, and a new concept of photoprotection have altered melanoma strategies in surveillance and prevention. Molecular genetic research has implicated the importance of hereditary aspects of melanoma and associated malignancies. High-risk pedigrees can be identified through an informatic analysis of the occurrence patterns of melanoma and systemic cancers in kindreds. All ultraviolet radiation results in cutaneous DNA damage and in high-risk individuals may cause melanoma. We may reverse the epidemic trend in melanoma occurrences in these high-risk pedigrees if we are willing to change our cultural approach to sunlight exposure with restrictive sunlight behavior, wearing of ultraviolet protective clothes, the use of broad-spectrum ultraviolet protection from nightly topical dihydroxyacetone coupled with daytime UVB sunscreens, and periodic surveillance.

The role of primary genetic factors in the etiology of cancer has become of intense interest to the research and clinical community. This interest has been heightened by recent discoveries that germ-line mutations such as BRCA1 and BRCA2 in hereditary breast cancer are responsible for an increasing percentage of common solid tumors. A potpourri of proto-oncogenes and tumor-suppressor genes has been identified in hereditary as well as certain common sporadic and rare cancer types, and new cancer genes will likely be discovered every month to account for the 5 to 10% of the cases of cancer that can be attributed to primary genetic factors. Molecular mechanisms in the pathogenesis of hereditary cancer can result in more-targeted cancer-control measures. At least four mutator genes (MHS2, MLH1, PMS1 and PMS2) appear to account for 70–80% of hereditary nonpolypoid colorectal cancer (HNPCC). When one of these germ-line mutations is present in an HNPCC family, the physician is then able to determine the patient's lifetime cancer destiny with an accuracy of about 90% (limited only by the penetrance of the gene). This will enable highly targeted surveillance to be initiated early, such as colonoscopy beginning at ages 20 to 25 or prophylactic subtotal colectomy. Also, in multiple endocrine neoplasia syndromes (MEN 2A and 2B), the identification of the culprit RET proto-oncogene now enables a secure diagnosis and permits testing of children who might benefit from prophylactic total thyroidectomy. Central to translation of these momentous molecular genetic discoveries into patient care is the necessity of determining who requires DNA testing. The cancer family history is the linchpin in making this decision.

The identification of an increasing variety of "cancer genes," thereby signifying the cancer destiny of patients from hereditary cancer families, offer numerous opportunities for cancer surveillance and management, including prophylactic surgery in selected circumstances. This new science and technology has emerged at a rapid pace, making it difficult for many physicians to grasp its full impact. This article reviews the genetics and molecular genetics of cancer and updates its genetic counseling implications. Several hereditary cancer syndromes are reviewed as cancer genetic models, including multiple endocrine neoplasia types 2A and 2B, neurofibromatosis, familial pancreatic carcinoma, familial atypical multiple mole melanoma syndrome, and von Hippel-Lindau disease. Special attention is given to the distinctive pathology features that may appear in certain hereditary cancer syndromes, with hereditary nonpolyposis colorectal carcinoma discussed as a prototypic model. Genetic testing issues including variable positions relevant to whether and/or when to test and whom to test, as well as the position of the American Society of Clinical Oncology, are also discussed. Cancer 1997; 80:523-32. © 1997 American Cancer Society.

BACKGROUND. Hereditary cancer accounts for 5-10% of the estimated 1.38 million cancer cases in 1997 and requires an approach to cancer prevention that is distinct from its sporadic counterpart based on its differing natural history. The laboratory advances in the molecular biology of hereditary cancer have recently resulted in the development of specialized hereditary cancer clinics with both broad and syndrome specific hereditary cancer assessment capabilities. A key question is how well these clinics can accomplish this new mission. METHODS. A total of 58 people underwent hereditary cancer risk assessment in the Creighton University Hereditary Cancer Prevention Clinic from September of 1995 to September of 1996. Assessment included construction of a detailed pedigree and a cancer-directed medical history and physical examination. Cancer education, genetic counseling, the option of DNA testing when appropriate, and cancer prevention recommendations based on cancer risk were provided. RESULTS. The 58 patients were comprised of 51 females (88%) and 7 males (12%) predominantly from the Omaha, Nebraska geographic region. Forty patients (69%) were cancer unaffected whereas 18 (31%) were cancer affected; patient age ranged from 6 to 70 years with a mean age of 40 years. Thirty (52%) of the patient families were diagnosed with a hereditary cancer syndrome, 24 (41%) were diagnosed with familial cancer risk, and 4 (7%) were diagnosed with sporadic cancer risk. Of the 30 families with hereditary cancer syndromes, only 4 (13%) individuals have so far undergone DNA testing due to a variety of emotional, financial, insurance, and technical barriers. CONCLUSIONS. The authors have successfully implemented a clinically applicable hereditary cancer prevention program based on their expertise in hereditary cancer risk assessment that offers DNA testing through a commercial laboratory to patients diagnosed with hereditary cancer syndromes. However, a number of barriers to DNA evaluations exist that will require discussion among the medical, legislative, insurance, and lay communities in addition to further research in hereditary cancer risk assessment, genetic counseling, and cancer prevention strategies.

Background: Hereditary polymorphic light eruption (HPLE) occurs uniquely in the American Indian and Inuit and exhibits autosomal dominant transmission. Because the cutaneous expression of HPLE resembles that of polymorphic light eruption (PLE) and because many non-Indians in the United States have American Indian heritage, some instances of PLE may actually be HPLE. Objective: Our purpose was to determine whether non-Indian patients with PLE have characteristics suggestive of HPLE. Methods: We surveyed in Nebraska 25 European-Caucasian and 36 African-American patients with PLE for American Indian heritage and photosensitive relatives. Nonphotosensitive subjects (52 Caucasians and 40 African Americans) were surveyed for American Indian heritage. Results: American Indian heritage occurred in 11 Caucasian patients (44%); of those, seven (64%) had photosensitive relatives. Likewise, 29 African Americans (81%) had American Indian heritage; 19 (66%) of those had photosensitive relatives. American Indian heritage occurred in 10 Caucasian control subjects (19%) and in 34 African-American control subjects (85%). Conclusion: If American Indian heritage and a family history of photosensitivity are definitive for HPLE, seven (28%) of our Caucasian patients and 19 (53%) of our African-American patients have HPLE rather than PLE. We urge physicians who suspect PLE in non-Indians to ask about American Indian heritage and photosensitive relatives and to screen their present patients with PLE for such characteristics.

Our study involved two extended familial atypical multiple mole melanoma (FAMMM) kindreds wherein a sufficient number of informative, high genetic risk, and affected patients enabled collection of pertinent tissue samples (normal skin/fibroblasts and atypical nevi/melanocytes) for cytogenetic analysis, and peripheral blood lymphocytes for DNA usage for linkage studies. We observed marked chromosome instability, as evidence by increased frequencies of cells with chromosomal rearrangements (translocations, deletions, and inversions) in cell cultures from atypical nevi and normal skin. There was no evidence of linkage of the FAMMM disease locus to any of the markers for the short arm of chromosome 1p in these two families. Well-characterized FAMMM kindreds provide an opportunity for biomarker investigations for elucidating heterogeneity and, ultimately, improving cancer control.

This survey of physicians covered their attitudes toward, knowledge of, and diligence in the integration of family history and its application to the care of patients with multiple atypical nevi. The respondents recognized the importance of a personal or family history of malignant melanoma and a medical genealogical investigation of the kindred, but they gave little attention to pursuing an in‐depth genetic investigation of their patients’ kindred. The data suggest that curricula in medical schools need to include not only the clinical expressions of genetic disorders but must emphasize the physicians’ behavior skills pursuing genealogical investigative techniques in the preventive health care of patients and their kindred with hereditary cancers.

T he field of precursor lesions to melanoma is subject to ongoing debate and evolving insights. Regarding congenital melanocytic nevi there is controversy about the management of these lesions. It has become apparent that patients with giant (“bathing trunk-type”) congenital nevi have an increased incidence of malignant melanoma developing in their lesions. Prophylactic excision is generally accepted treatment and these lesions should be removed in early childhood; however, the subject of debate has been enlarged to include all congenital nevi, including those of the “small” type. It is unclear to what extent melanoma develops in smaller congenital nevi and dermatologists disagree on the therapy of smaller lesions. The intensity of the controversy appears to be inversely proportional to the size of the nevus. Regarding dysplastic nevi there is controversy about diagnostic definitions both clinically and histologically. Some even deny the existence of dysplastic nevi! The Familial Atypical Multiple-Mole Melanoma (FAMMM) syndrome also has its contentions with regard to the genetic mechanism: Is a dominant gene localized on chromosome lp involved in all FAMMM families? Furthermore, the complete spectrum of the FAMMM syndrome including the occurrence of systemic cancer(s) and ocular melanoma is still debated. This review focuses on the aforementioned controversies in the field of precursor lesions to melanoma. Early detection of malignant melanoma reduces its morbidity and mortality. The most important method to achieve this is by professional and public education about the signs and symptoms of early melanoma and preven

We report here preliminary pilot study data of the effect of sunless tanning spray with 9% [Correction added after online publication (August 24th, 2009): The concentration of Dihydroxyacetone used in the study was 9% and not 3% as previously stated] dihydroxyacetone (DHA) on 25-hydroxyvitamin D [25(OH)D] serum levels in subjects exposed to controlled amounts of UV-B radiation during April/May in Omaha, NE, 41 degrees N latitude. We found that DHA-induced melanoidins in skin act as a topical sunscreen attenuating the formation of 25(OH)D.

There are no premonitory physical signs or biomarkers which can identify the genotypic status in Lynch syndrome II. Diagnosis is therefore dependent on the pedigree, with attention to cancer of all anatomic sites, inclusive of those cardinal features of its natural history. The tumor spectrum in Lynch syndrome II has continued to expand commensurately with increasing interest in this disorder. We report a family showing the constant cancer features of this syndrome but, in addition, occurrences of carcinoma of the bile duct, urologic system, and extremely early-onset carcinoma of the pancreas, in patients in the direct genetic lineage who were considered to be candidates for having inherited the deleterious genotype. Diagnosis of Lynch syndrome II is crucial in targeting its surveillance and management.

The FAMMM syndrome consists of the familial occurrence of cutaneous malignant melanoma and atypical nevi (dysplastic nevi), and is inherited as an autosomal dominant trait. Conflicting results have been reported on the question of whether the syndrome includes increased susceptibility to non-melanoma cancers. We have studied cancer of all anatomic sites and histologies in nine FAMMM families which were ascertained in a pigmented lesions clinic in the Netherlands. We evaluated two hypotheses: that the number of systemic cancers observed in the families was excessive, compared to expected incidence, based on Dutch incidence data, and that there was variation (or heterogeneity) among families in the frequency of systemic cancer. A significant excess of systemic cancer (especially digestive tract cancer) was observed. Significant heterogeneity was also found among the families; three of the nine families had marked excess in numbers of systemic cancers, and the remaining families had normal numbers of cancers among the known FAMMM gene carriers and their first degree relatives. Thus, we provide evidence of increased susceptibility to systemic cancer occurring in conjunction with the FAMMM syndrome in a subset of this resource.

During seven months of a clinical trial in spring, summer, and fall, 30 UVA/B/Soret band-photosensitive patients used sequential topical applications of dihydroxyacetone (DHA) followed by naphthoquinone only at bedtime and received excellent photoprotection without a single therapeutic failure or loss of any patient to follow-up. Eighteen of the 30 patients extended the limits of their photoprotection repeatedly over a seven-month period to tolerate without sunburns six to eight hours of midday sunlight under all kinds of occupational and recreational environmental conditions. Previously, the use of 3% DHA topically in earlier studies gave only a sun protection factor (SPF) of 3. In this reanalysis of the original notes of a previous clinical study of the melanoidins produced by DHA followed by naphthoquinone in the keratin layers of the epidermis of minimally pigmented Caucasian photosensitive patients, it is determined that these patients received a minimal UVB photoprotection of SPF 18 or more. This represents at least a sixfold amplification of the UVB photo-protective effect over the use of only dihydroxyacetone in the Maillard reaction.

Dihydroxyacetone (DHA) undergoes the Maillard reaction with skin surface protein to produce a durable brown color. This pigment protects persons sensitive to ultraviolet and visible radiation. Interest in photosensitivity encouraged us to examine browning activities of DHA and other hydroxycarbonyl compounds. Our observations provide clues of general interest in understanding the Maillard reaction. Although DHA has been used in the popular sunless tanning preparations for over 30 years, a more effective substitute has not been developed.

Coding mutations of the CDKN2A gene on chromosome 9p21 cosegregate with 25-60% of familial melanoma cases, but there remains a number of 9p21-linked kindreds that lack germline coding mutations of CDKN2A. We sequenced CDKN2A exons 1alpha, 2, 3, and the adjacent intronic regions in 167 melanoma-prone families (at least two affected first-degree relatives), and detected four splice site variations, three of which cosegregate with the disease. RT-PCR experiments verified that these three variants, including an AGgt to ATgt mutation that demonstrates a founder effect, do affect splicing. While an exon 1alpha splice donor site mutation incompletely abolishes splicing, the correctly spliced mRNA yields a protein (Q50P) that cannot effectively interact with CDK4. We also performed RT-PCR on mRNA from 16 melanoma-prone kindreds to search for cryptic splice sites deep within introns, but identified no splice variants. Meanwhile, we screened 139 affected families using allele-specific PCR for the recently discovered IVS2-105A>G mutation, but found only one family that possesses this alteration. We conclude that splice site mutations do predispose to disease in a subset of melanoma-prone kindreds. Characterization of additional splice site variants and other noncoding alterations of CDKN2A should allow us to detect a wider range of mutations in at-risk patients.

The incidence and the mortality rates for pancreatic cancer are the same, indicating its dismal outlook. Its natural history remains elusive. Cigarette smoking appears to be the most significant environmental culprit. Hereditary factors may account for approximately 5% of the total pancreatic cancer burden. However, when its extant heterogeneity and the reduced penetrance of causal germline mutations are considered, the hereditary incidence may significantly exceed this estimate. Even when endoscopic ultrasound (EUS), the gold standard for pancreatic cancer screening, is utilized, early detection with surgical cure has rarely been accomplished. Needed to ameliorate this problem is research into genetic and environmental risk factors and their interaction. The identification of tumor biomarkers which signal early pathogenetic events, thereby enabling pancreatic cancer to be diagnosed at its earliest possible stage before it has spread to regional lymph nodes or to more distant sites, will improve the outlook. We discuss our research approaches to this problem. Members of families with the p16 germline mutation will undergo EUS coupled with the collection of pancreatic juice for the study of a possible gradient for telomerase activity, K- ras mutations, and cytology. If changes in these putative biomarkers are observed, endoscopic retrograde cholangiopancreatography (ERCP) would be the next diagnostic step. We conclude with a discussion of ethical concerns about this research.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. Cancer 2002;94:84–96. © 2002 American Cancer Society.

The Muir-Torre syndrome (MTS) is characterized by an autosomal dominant predilection to sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas, in concert with the cancer phenotype of hereditary nonpolyposis colorectal cancer (HNPCC). Proof that patients showing a familial aggregation of MTS's cutaneous signs in combination with a specific pattern of visceral cancers which are consonant with an HNPCC diagnosis has been buttressed by the discovery of hMSH2 and hMLH1 germ-line mutations in such families. Our purpose in this investigation was to determine the germ-line mutation in a Gypsy family with MTS in concert with HNPCC cancer features, and to provide genetic counseling. An added objective for this paper is to review the literature on MTS.We describe a Gypsy family with MTS in concert with HNPCC cancer features, as well as the molecular genetic and genetic counseling procedures used in the interest of improved compliance with cancer control recommendations. We review the clinical phenotype, natural history, and molecular genetics involved in the MTS variant HNPCC.An hMSH2 germ-line mutation was identified as the culprit germ-line mutation in this family.The presence of the hMSH2 germ-line mutation in this family provides powerful predictability of colorectal and other HNPCC integral cancers. The gastroenterologist must assume an important role in the diagnosis and management of MTS.

Computer-based data mining methodology applied to family history clinical data can algorithmically create highly accurate, clinically oriented hereditary disease pattern recognizers. For the example of hereditary colon cancer, the data mining's selection of relevant factors to assess for hereditary colon cancer was statistically significant (P < 0.05). All final recognizer-formulated patterns of hereditary colon cancer were independently confirmed by a clinical expert. Applied to previously analyzed family histories, the recognizer identified the definitive hereditary histories, correctly responded negatively to the putative hereditary histories, and correctly responded negatively to empirically elevated colon cancer risk situations. This capability facilitates patient selection for DNA studies in search of gene mutations. When genetic mutations are included as parameters in a patient database for a genetic disease, the process yields an expert system which characterizes variations in clinical disease presentations in terms of genetic mutations. Such information can greatly improve the efficiency of gene testing.

Cutaneous lesions consonant with Muir-Torre syndrome strongly suggest hereditary non-polyposis colorectal cancer (HNPCC). Ponti et al. discuss the importance of combining molecular genetic features of the sebaceous neoplasms, including microsatellite instability and immunohistochemistry, with family history, to determine the likelihood of HNPCC. Proof of diagnosis is identification of one of the mismatch repair germline mutations.

A first-degree relative with pancreatic cancer is found in 5% to 10% of patients with pancreatic carcinomas, suggesting an inherited predisposition for this neoplasm. The recently identified DPC4 tumor suppressor gene is a strong candidate for the gene responsible for the familial form of pancreatic carcinoma. DPC4 was identified in a consensus area of homozygous deletion in pancreatic carcinomas, and it is biallelically inactivated in approximately 50% of sporadic pancreatic carcinomas. The coding sequence of this gene is 1660 nucleotides in length, covering 11 exons. We describe optimized primers and conditions used in polymerase chain reaction and cycle sequencing of the entire DPC4 coding sequence of 25 individuals (eight with pancreatic carcinoma) from 11 kindreds with a familial aggregation of pancreatic carcinoma. No mutations in the coding sequences of the DPC4 gene were found; hence, it appears that germline mutations in DPC4 cannot account for many of the familial aggregations of pancreatic carcinoma.

3. Sutton RL. Diseases of the skin, 2nd ed. St. Louis: C.V. Mosby; 1917. 4. Stelwagon HW. Treatise on diseases of the skin. Philadelphia and London: W.B. Saunders; 1902. 5. Schade H, Marchionini A. The acid mantle of the skin [in German]. Klin Wochenshr 1928;7:12-4. 6. Rippke F, Schreiner V, Schwanitz HJ. The acidic milieu of the horny layer: new findings on the physiology and pathophysiology of skin pH. Am J Clin Dermatol 2002;3:261-72. 7. Brattsand M, Stefansson K, Lundh C, Haasum Y, Egelrud T. A proteolytic cascade of kallikreins in the stratum corneum. J Invest Dermatol 2005;124:198-203. 8. Hachem JP, Crumrine D, Fluhr J, Brown BE, Feingold KR, Elias PM. pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion. J Invest Dermatol 2003;121:345-53.

We are now facing an epidemic of cutaneous malignant melanoma (CMM), with projections that one in 100 whites will develop CMM by the year 2000. Physicians must employ their accrued knowledge of the epidemiologic and genetic aspects of CMM to maximize control. Excessive, intermittent exposure to sunlight during outdoor recreational activities has been implicated in the origin of CMM in whites. In addition, the recently demonstrated depletion of the ozone layer in the stratosphere of the northern hemisphere can significantly affect the incidence of skin cancer. It has been shown in Australia that exposure to sunlight in the first two decades of life significantly increases the risks of developing CMM.1To be cost-effective in the face of rising health care costs, we must be able to efficiently identify high-risk patients and families so that highly targeted surveillance, early diagnosis, and treatment can be accomplished. It will also be necessary

We evaluated the photoprotectioe efficacy of a broad-spectrum sunscreen containing a UVA screen (butyl methoxydibenzoyhnethane) and a UVB screen (octyl dimethyl p -aminobenzoic acid) in patients with hereditary polymorphic light eruption. At least 18 of the 30 patients who enrolled in the study were sensitive to sunlight through window glass, an indication of UVA sensitivity. Of the 21 patients who completed the clinical trial, the physician's evaluation was that 18 (86%) obtained good to excellent results. Self-evaluation by the patients revealed that 16 (76%) noted more photoprotection than from previous treatments.

The role of host factors in the etiology of pancreatic cancer has received a paucity of systematic investigation. Anecdotal reports and one population-based study have supported the concept that familial clustering of this disease exists. We have studied a kindred with a cancer-associated genodermatosis known as familial atypical multiple mole melanoma (FAMMM) syndrome (hereditary dysplastic nervus syndrome). Three key relatives have manifested pancreatic carcinoma. Since FAMMM may account for as much as 10% of the total malignant melanoma burden, its association with pancreatic cancer harbors important public health implications. Given the fact that the etiology of pancreatic cancer remains enigmatic, it is important to investigate all possible clues to its causality, including the potential role of host factors.