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Original Investigation |

Risk of Next Melanoma in Patients With Familial and Sporadic Melanoma by Number of Previous Melanomas FREE

Tianhui Chen, MD, PhD1; Mahdi Fallah, MD, PhD1; Asta Försti, PhD1; Elham Kharazmi, MD, PhD1; Kristina Sundquist, MD, PhD2,3; Kari Hemminki, MD, PhD1,2
[+] Author Affiliations
1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
2Center for Primary Health Care Research, Lund University, Malmö, Sweden
3Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California
JAMA Dermatol. 2015;151(6):607-615. doi:10.1001/jamadermatol.2014.4777.
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Published online

Importance  The risk of next melanoma in patients with 2 or more previous melanomas stratified by familial and sporadic cases separately has not yet been reported, although a few population-based studies have assessed the risk of second melanoma.

Objective  To assess the risk of next melanoma in patients with multiple primary melanomas by number of previous melanomas, stratified by demographic and melanoma characteristics.

Design, Setting, and Participants  Prospective population-based cohort study with follow-up from 1958 to 2010 using the Swedish Family-Cancer Database with information on cancer cases retrieved from the Swedish Cancer Registry. A total of 65 429 patients with invasive or in situ melanoma who received a diagnosis during 1958 through 2010 were observed for next melanoma incidence.

Main Outcomes and Measures  Standardized incidence ratios (SIRs) expressing risk of next melanoma by calculating the incidence of next (second, third, fourth, and fifth) melanoma in melanoma patients who had received a diagnosis of 1, 2, 3, and 4, respectively, previous melanomas, compared with the risk of first melanoma in the Swedish population.

Results  For patients with either familial or sporadic melanoma, we observed a stable 2- to 3-times elevated risk by increasing number of previous melanomas; for example, for 2 previous melanomas, the SIR was 2.8 (95% CI, 2.3-3.4) for patients with familial melanoma and 2.5 (95% CI, 2.3-2.7) for patients with sporadic melanoma. Overall risk of second melanoma was higher in patients with familial melanoma who received a diagnosis at younger than 40 years (SIR, 4.7 [95% CI, 3.9-5.6]), and we found a notable risk in young patients with familial melanoma during the first 5-year follow-up after first melanoma: SIR of 6.1 (95% CI, 4.0-9.0) for interval up to 1 year, 6.2 (95% CI, 3.2-11) for 2 to 3 years, and 19 (95% CI, 10-31) for 4 to 5 years. Risk was notable in young (<40 years) patients with sporadic melanoma within the first year of follow-up (SIR, 5.3 [95% CI, 4.3-6.4]) and afterward remained steadily elevated by 2 to 3 times.

Conclusions and Relevance  We found a stable 2- to 3-times elevated risk by number of previous melanomas for patients with either familial or sporadic melanoma. Notable risk in young patients with familial melanoma during first 5-year follow-up after first melanoma may suggest that it is important to refer these patients for clinical genetic testing.

The number of multiple primary cancers in general is increasing, and second malignant neoplasms make up approximately one-sixth of the total number of cancers reported to the Surveillance, Epidemiology, and End Results (SEER) program.1 In Sweden, multiple primary cancers made up approximately one-fifth of all reported cancers in 2012.2 According to the SEER program for the period 1973 through 2006, 3.5% of patients with an initial melanoma developed multiple primary melanomas (MPM).3 Family history of melanoma (even in situ) and personal history of melanoma are known risk factors for MPM.4,5 Among MPM cases, 20.8% are familial cases and 21.0% of those familial cases have mutations in the cyclin-dependent kinase inhibitor 2A (CDKN2A [OMIM 600160]) gene on chromosome 9p21. The probability of detection of CDKN2A mutations is elevated for patients with 3 or more melanomas.6 Family history and number of MPMs should be considered in genetic counseling, in which management options include increased cutaneous surveillance or genetic testing for CDKN2A.7

Although a few previous studies have assessed the risk of second melanoma, including 1 study from our group using an earlier version of the Swedish Family-Cancer Database (FCD), to our knowledge, the risk of next melanoma in patients with 2 or more previous melanomas has not been reported.3,8,9 Using the latest version of the FCD (FCD2010, updated in 2013), we aimed to assess the risk of next melanoma in patients with melanoma by number of previous melanomas, stratified by family history of melanoma (familial cases and sporadic cases separately), sex, age at diagnosis, subsite and histologic subtype of first melanoma, and by the combination of age at diagnosis of first melanoma and follow-up time between first and second melanomas. Our investigation may define high-risk subgroups of patients with MPM for individually targeted prevention and clinical intervention.

The Lund University Regional Ethics Committee in Sweden approved the study protocol. Informed consent was waived because anonymized cancer registry data were used. Details on the FCD2010 have been described elsewhere.10 Briefly, information on cancer cases was retrieved from the Swedish Cancer Registry, relying on separate compulsory notifications from clinicians, pathologists, and cytologists. Close to 100% of the registered neoplasms were histologically verified.11 The Swedish Cancer Registry records only primary tumors because metastasized tumors to other sites were registered only at the primary sites.12 Tumors were recorded according to the International Classification of Diseases, 7th Revision (ICD-7), since 1958. Information on up to 5 primary invasive cancers and 5 primary in situ carcinomas is available in the FCD2010. For multiple primary tumors occurring in the same organ or same organ system, only clearly separated tumors were accepted as multiple primaries and registered in the Swedish Cancer Registry.13 Data on family relationships, comprising all first-degree relatives (FDRs), including parents, siblings, and children, were obtained from the Multigeneration Register with high-quality and practically complete coverage.11 Four-digit ICD-7 codes were used for defining anatomical subsite (trunk, limbs, head or neck, multiple sites, and unspecified subsites). International Classification of Diseases for Oncology, 2nd or 3rd Edition, morphology codes, available from 1993 onward, were used for classification of histological subtypes, ie, superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and others.

Standardized incidence ratios (SIRs) were used to assess the risk of next melanoma by calculating the incidence of next (second, third, fourth, and fifth) melanoma in patients with melanoma who had received diagnoses of a number (1, 2, 3, and 4, respectively) of previous melanomas, comparing with the risk of first melanoma in the Swedish population. The expected numbers of next (second, third, fourth, and fifth) melanoma were calculated from the strata-specific incidence rate of the first melanoma in the Swedish population, multiplied by the corresponding person-years in patients with melanoma who had a number (1, 2, 3, and 4, respectively) of previous melanomas. Person-years at risk for the second, third, fourth, and fifth melanoma were accumulated for each patient, starting at the date of diagnosis of the first, second, third, and fourth melanoma, respectively, and terminating on the date of diagnosis of the next (second, third, fourth, and fifth, respectively) melanoma, emigration, or the closing date of the study (December 31, 2010), whichever came earliest.

All SIRs were adjusted for sex, age (5-year bands), calendar year (5-year bands), a 4-category residential area (large cities, South Sweden, North Sweden, or unspecified), and a 6-category socioeconomic level (farmer, manual worker, low- to middle-income office worker, high-income office worker or professional, company owner [except farmer], or other or unspecified). The 95% CIs for SIRs were calculated assuming that the cases followed a Poisson distribution. Further analyses were stratified by sex, age at diagnosis, subsite and histologic subtype of first melanoma, and by the combination of age at diagnosis of first melanoma and follow-up time between first and second melanomas. In addition, SIRs were calculated by formal testing of the differences in subgroup analyses after adjustment for all available confounding factors (eTables 1-3 in the Supplement). For instance, for the comparison between incidence of second melanoma in men and women, we used the golden standard method of indirect standardization (SIRs) so that age-, period-, residential-, and socioeconomic-specific (strata-specific) incidence rates of men were used as reference rates to calculate strata-specific expected numbers in women. Then the sum of the strata-specific observed values in women was divided by the sum of the strata-specific expected ones; the 95% CI for this comparison was also provided. Finally, separate analyses for patients with and without a family history of melanoma were also conducted to investigate potential differences between patients with familial and sporadic melanoma.

In the present study, patients with both invasive and in situ melanoma were included for proband and for a family history of melanoma because essentially equivalent results for invasive and in situ melanoma separately were found by sensitivity analyses. There were 65 429 total patients who received a diagnosis of a first primary melanoma during the years 1958 through 2010. In addition, we also conducted a sensitivity analysis restricted to patients with invasive melanoma who had a family history of invasive or in situ MPM, and using a detailed family history of melanoma (separate analysis for patients with 1 FDR with a single melanoma and for all patients who had ≥1 FDR with ≥1 melanoma) for overall risk in patients with familial melanoma (see last paragraph of Results). SAS software, version 9.3 (SAS Institute), was used for the data analysis.

Basic characteristics of first melanoma in patients with familial and sporadic melanoma are presented in Table 1. Among 65 429 total patients with a diagnosis of first melanoma, there were 4250 patients with familial and 61 179 patients with sporadic melanoma. First melanoma in patients with familial melanoma occurred more frequently at younger age at diagnosis (<50 years; 37.6%), in the trunk (42.1%), and with superficial spreading melanoma (67.4%) than in patients with sporadic melanoma (30.7%, 37.6%, and 60.1%, respectively). In total, MPM made up 5.5% of total patients, including 3578 patients with 2 melanomas, 572 patients with 3 melanomas, 143 patients with 4 melanomas, and 43 patients with 5 melanomas (eTable 3 in the Supplement). The mean (SD; range) difference in diagnosis age between neighboring melanomas was essentially similar (less than 2 years), except for first to second melanoma, that is, for patients with familial melanoma, 7.2 (8.5; 0-41) years between first and second melanomas, 3.6 (4.9; 0-22) years between second and third melanomas, 2.6 (2.3; 0-8) years between third and fourth melanomas, and 4.2 (4.5; 0-13) years between fourth and fifth melanomas, whereas for patients with sporadic melanoma, it was 6.2 (7.7; 0-46), 3.0 (4.2; 0-23), 2.7 (3.2; 0-15), and 2.0 (2.5; 0-11) years, respectively.

Table Graphic Jump LocationTable 1.  Basic Characteristics of First Melanoma in Patients With Familial or Sporadic Melanoma

Relative risks (SIRs) of next melanoma in patients by number of previous melanomas (compared with the risk of first melanoma in the Swedish population) are separately presented for patients with familial melanoma (Table 2), sporadic melanoma (Table 3), and all patients (eTable 3 in the Supplement; those with 3 or more melanomas were already included in patients with 2 melanomas). For both patients with familial melanoma (Table 2) and those with sporadic melanoma (Table 3), we found a stable 2-fold to 3-fold elevated risk by increasing number of previous melanomas (all 95% CIs overlapped). For instance, for patients with a single previous melanoma, the SIR was 2.5 (95% CI, 2.3-2.8) for patients with familial melanoma and 2.3 (95% CI, 2.3-2.4) for patients with sporadic melanoma; for patients with 4 previous melanomas, the SIR was 2.3 (95% CI, 1.3-3.9) for familial melanoma and 2.7 (95% CI, 1.8-3.9) for patients with sporadic melanoma. There was also no statistically significant sex difference in risks for both familial and sporadic cases because 95% CIs overlapped, consistent with the comparative SIRs in eTables 1 and 2 in the Supplement.

Table Graphic Jump LocationTable 2.  Standardized Incidence Ratios (SIRs) of Next Melanoma by Number of Previous Melanomas for Patients With Familial Melanomaa
Table Graphic Jump LocationTable 3.  Standardized Incidence Ratios (SIRs) of Next Melanoma by Number of Previous Melanomas for Patients With Sporadic Melanomasa

When stratified by age at diagnosis of the first melanoma, for patients with familial melanoma (Table 2), the SIR was significantly higher for age at diagnosis younger than 40 years than for other age groups (for patients with single previous melanoma, 4.7 [95% CI, 3.9-5.6]; 2 melanomas, 5.3 [95% CI, 3.9-7.2]; 3 melanomas, 5.8 [95% CI, 3.6-8.8]; and 4 previous melanomas, 3.6 [95% CI, 1.5-7.5]). The risk was also slightly higher in young patients (<40 years) with sporadic melanoma than in older ones, eg, SIR of 2.8 (95% CI, 2.6-3.2) in patients with sporadic melanoma with single previous melanoma (Table 3). In addition, the risk was statistically significantly elevated in patients who received a diagnosis at older than 80 years both in those with familial melanoma and those with sporadic melanoma, reaching an SIR of 2.8 (95% CI, 1.6-4.5) in patients with familial melanoma and 2.3 (95% CI, 2.0-2.5) in patients with sporadic melanoma with a single previous melanoma and 2.3 (95% CI, 1.7-3.1) in patients with sporadic melanoma with 2 previous melanomas. Nevertheless, we did not find a significant difference in risk of next melanoma by the stratification of age at diagnosis (eTables 1 and 2 in the Supplement).

The data stratified by socioeconomic status are presented in Tables 2 and 3 and in eTables 1 and 2 in the Supplement. When compared with manual workers (as the reference group), for patients with familial melanoma with 4 previous melanomas, we found significantly elevated risks for low- to middle-income office workers and for other or unspecified workers, whereas for sporadic cases, farmers were found to have significantly elevated risk of next melanoma for patients with 2 or 3 previous melanomas (only 1 case for patients with 3 previous melanomas). Nevertheless, for both familial and sporadic cases, we did not observe a significant difference in socioeconomic status for the risk of second melanoma.

When stratified by anatomical subsite of the first melanoma, the risk was notable at multiple sites for both familial and sporadic cases, for example, SIR of 4.1 (95% CI, 1.7-8.5) in patients with familial melanoma with 1 record of previous melanoma and 15 (3.0-43) in patients with familial melanoma with 2 records (3 cases); SIR was 3.8 (95% CI, 2.3-5.7) in patients with sporadic melanoma with a single previous record (Table 3). We did not find a significant difference among other anatomical subsites, although the risk was substantially elevated for patients with familial melanoma who had 4 previous melanomas and whose first melanoma occurred at the trunk (SIR, 5.0 [95% CI, 1.6-12]). In addition, when the analysis was stratified by subsite and sex, we observed a sex difference for some subgroups at the trunk and multiple sites (Table 2 and eTable 1 in the Supplement). For instance, for first melanoma at the trunk, men had a significantly elevated risk of next melanoma for patients with 4 previous melanomas compared with women, although there were only 2 cases for men and 3 cases for women. When the analysis was stratified by histologic subtype of the first melanoma, we did not observe a substantial difference in patients with familial or sporadic melanoma (Tables 2 and 3 and eTables 1 and 2 in the Supplement), although the SIR was extremely high for patients with familial nodular melanoma with 4 previous melanomas (but with only 1 case).

The risks of second melanoma in patients with familial and sporadic melanoma stratified by age at diagnosis of first melanoma and follow-up time between first and second melanomas (compared with the risk of first melanoma in their counterparts in the population) are presented in Table 4 (total cases are presented in eTable 4 in the Supplement). For patients with familial melanoma, the overall risk was highest in age at diagnosis younger than 40 years (SIR, 4.7 [95% CI, 3.9-5.6]) and a notable risk in young patients during first 5-year follow-up after first melanoma was observed, SIR of 6.1 (95% CI, 4.0-9.0) for follow-up of up to 1 year, 6.2 (95% CI, 3.2-11) for the interval 2 to 3 years, and 19 (95% CI, 10-31) for the interval 4 to 5 years; the risk was also higher afterward, reaching 5.3 (95% CI, 3.3-7.9) for the interval 6 to 9 years and 3.3 (95% CI, 2.5-4.3) after 10 years. For patients with sporadic melanoma, the overall risk was elevated 2 to 3 times for diagnosis age groups, for example, SIR of 2.8 (95% CI, 2.6-3.2) in young (<40 years) patients; the risk was notable in young (<40 years) patients within first-year follow-up (SIR, 5.3 [95% CI, 4.3-6.4]) and remained stable (2-3 times elevated) afterward, reaching 2.1 (95% CI, 1.8-2.5) after 10 years.

Table Graphic Jump LocationTable 4.  Standardized Incidence Ratios (SIRs) of Second Melanoma, Stratified by Age at Diagnosis of the First Melanoma and Follow-up Between First and Second Melanomas, for Patients With Familial and Sporadic Melanomaa,b

A sensitivity analysis restricted to patients with invasive melanoma who had a family history of invasive or in situ MPM essentially did not change overall results. For patients with familial melanoma, the SIR was 2.6 (95% CI, 2.3-2.9) for patients with 1 previous melanoma (251 cases), 2.3 (95% CI, 1.6-3.2) for patients with 2 previous melanomas (34 cases), 5.3 (95% CI, 2.1-11) for patients with 3 previous melanomas (7 cases), and 3.4 (95% CI, 0.7-10) for patients with 4 previous melanomas (3 cases); for patients with sporadic melanoma, the SIR was 2.5 (95% CI, 2.4-2.6) with 1484 cases, 2.5 (95% CI, 2.1-2.9) with 158 cases, 2.1 (95% CI, 1.3-3.1) with 24 cases, and 2.8 (95% CI, 0.6-8.3) with 3 cases, respectively. In addition, a sensitivity analysis restricted to a detailed family history of melanoma (separate analysis for patients with 1 FDR with a single melanoma and for patients with ≥1 FDR with ≥1 melanoma) for overall risk in patients with familial melanoma did not substantially change overall risk in patients with familial melanoma. For example, for family history of 1 FDR with a single melanoma, the SIR of next melanoma was 2.4 (95% CI, 2.1-2.7) for patients with familial melanoma with 1 previous melanoma (340 cases), 2.7 (95% CI, 2.1-3.4) for patients with 2 previous melanomas (79 cases), 2.3 (95% CI, 1.5-3.3) for patients with 3 previous melanomas (28 cases), and 2.4 (95% CI, 1.1-4.6) for patients with 4 previous melanomas (9 cases), whereas for the analysis including all patients with a family history of melanoma, the SIR was 2.3 (95% CI, 1.9-7.2) with 110 cases, 2.8 (95% CI, 1.8-4.0) with 28 cases, 4.7 (95% CI, 2.5-8.1) with 13 cases, and 3.3 (95% CI, 1.1-7.7) with 5 cases, respectively. Finally, a sensitivity analysis restricted to patients with in situ melanoma who had a family history of in situ MPM also did not essentially change the overall results (data not shown) and restriction of family history to invasive melanoma only also did not change the results (data not shown).

Given that the overall result for sensitivity analysis was essentially identical, in this study we included both invasive and/or in situ melanoma for proband and for a family history of melanoma in order to use large sample size to detect subtle differences in stratified analyses. Among the few population-based studies assessing the risk of second melanoma,3,8,9 this study additionally assessed the risk of next melanoma by the number of previous melanomas, stratified by familial and sporadic cases separately, and by sex, age at diagnosis, anatomical subsite, and histologic subtype of the first melanoma. To our knowledge, the risk of next melanoma in patients with 2 or more previous melanomas stratified by familial and sporadic cases separately has not yet been reported. Although the varied incidence of second primary melanoma by age at diagnosis of first melanoma and follow-up time after first melanoma has been previously reported,9 we further assessed the risk stratified by familial and sporadic cases separately, which has been not reported.

The present study has a number of strengths and limitations. First, our study covered a nationwide prospective cohort over a period of more than 50 years. Second, to our knowledge, our study is the largest study for MPM (3578 patients with 2-5 MPMs) and a large study for familial MPM (450 patients with familial melanoma with 2-5 MPMs). Third, we had complete and unbiased information on family history of melanoma and detailed information on number of previous melanomas stratified by familial and sporadic cases separately. A major limitation concerns the small number of cases for some stratifications in patients with 3 or more previous melanomas; for example, the SIR was extremely high for patients with familial nodular melanoma with 4 previous melanomas, but there was only 1 case. Hence, we did not consider the observations with very few cases to be major findings unless we found persistent patterns after stratification analyses. Another concern is in situ melanoma. In recent years, the number of in situ melanomas has been close to the number of invasive tumors and the premalignant tumors are probably preferentially diagnosed in patients with preexisting melanomas; nevertheless, in this study we included both invasive and in situ melanoma for proband and for family history of melanoma. We have already shown that family history of in situ melanoma is equally important4; in this study as well, sensitivity analyses performed including or omitting in situ melanoma and sensitivity analysis on in situ melanoma alone showed no substantial change in the results. Finally, SIRs (eTables 1-3 in the Supplement) calculated by formal testing of the differences in subgroup analyses provide adjusted differences and are also more tangible for clinical audiences. Other modeling methods such as negative binomial regression analysis with log of expected values as offset should provide essentially the same results.14

We found a notable higher risk of second melanoma in young patients with familial melanoma during first 5-year follow-up after first melanoma. Although increased awareness in patients and physicians or intensified surveillance may contribute to our findings, especially for elevated risk within first-year follow-up (Table 4), genetic predisposition and population-based exposure to globally increased UV radiation levels may contribute.15 Compared with middle-aged individuals, younger patients tend to spend more time in the sun, which may offer environmental stimulus for DNA damage and malignant transformation on the CDKN2A-mutated gene, resulting in progression and transformation of malignant neoplasia.3 Because the probability of detection of CDKN2A mutations is elevated for patients with MPM or who are young at onset of first melanoma,6 the probability of detection of CDKN2A mutations will be more elevated for young patients with familial melanoma with MPM. Therefore, a high probability of CDKN2A mutations, interplaying with UV radiation exposure, may also have contributed to the notable elevated risk in young patients with familial melanoma during first 5-year follow-up after first melanoma.16 For older patients with sporadic melanoma (≥80 years), diminished immune surveillance may contribute to elevated risk of second melanoma after DNA damage and malignant transformations were initiated by elevated chance of exposure to UV radiation due to retirement and more leisure time,9 although the effects of treatment of other diseases for elderly patients may also contribute because elderly individuals commonly have comorbidity. In addition, another unidentified high-penetrance gene or other susceptibility genes could also contribute to our finding, especially for young patients with familial melanoma, for example, mutations of the telomerase reverse transcriptase (TERT) gene identified in 2013 by our group17 and the microphthalmia-associated transcription factor (MITF) gene.1820

We found that patients with MPM made up 5.5% of all patients with melanoma, slightly higher than previous reports of 3.5% to 4.7% because we included both invasive and in situ melanomas.3,21 Our finding of a stable 2 to 3 times elevated risk by number of previous melanomas for both patients with familial melanoma and those with sporadic melanoma may suggest the major contribution of sun exposure rather than genetic predisposition to the risk of next melanoma. Although sun exposure data were not directly available in the present study, the analysis stratified by subsite of first melanoma may indirectly suggest the effect of sun exposure because the trunk commonly has less chance of having long-term sun exposure than the head or neck and limbs. We found that the risk was significantly elevated for patients with familial melanoma who had 4 previous melanomas and whose first melanoma occurred at the trunk (5.0-fold elevated), consistent with studies showing that intermittent exposure, rather than total exposure, is more important for development of melanoma.22,23 Nevertheless, we did not find a significant difference among other anatomical subsites except for multiple sites, at which we found notable risks for both familial and sporadic cases (4-fold in patients with familial melanoma with a single previous record and 15-fold in patients with familial melanoma with 2 previous records; 3.8-fold in patients with sporadic melanoma with a single previous record). In addition, we did not observe a substantial difference in the risks stratified by histologic subtype of first melanoma for patients with familial and sporadic melanoma, although our samples and follow-up time for histologic data were only restricted to patients who received a diagnosis after 1993.

It has been reported that the highest incidence rate has been observed on the trunk among men and on the legs among women.24 We found that for the subgroup of patients with familial melanoma with 4 previous melanomas and first melanoma at the trunk, men had a significantly elevated risk of fifth melanoma compared with women (Table 2 and eTable 1 in the Supplement), which has not been reported elsewhere, although the sample size was small (2 cases for men and 3 cases for women). In addition, although it has been reported that higher socioeconomic status increases the risk of melanoma diagnosis,25 we did not observe a significant difference in socioeconomic status for the risk of second melanoma for patients with either familial or sporadic melanoma; our findings of significantly elevated risks for low- to middle-income office workers and others or unspecified workers among patients with familial melanoma with 4 previous melanomas, and for farmers among patients with sporadic melanoma with 2 or 3 previous melanomas and for company owners among patients with sporadic melanoma with 2 or 3 previous melanomas, have not been reported elsewhere.

Although a consensus on genetic counseling in melanoma was established in 2012 that genetic counseling may be offered to families with a family history of melanoma or to individuals with MPM,7 our study additionally provides clinically relevant data that have not been reported, for example, the risk of next melanoma in patients with 2 or more previous melanomas stratified by familial and sporadic cases separately, and the risk of second melanoma by age at diagnosis of first melanoma and follow-up time after first melanoma stratified by familial and sporadic cases separately.

Our data provide new evidence to guide clinical genetic counseling for MPM and provide novel data on the risk stratifications, especially for young patients with familial melanoma. Our findings indicate that it is necessary to consider family history of melanoma and follow-up time after first melanoma for younger patients. Our findings may suggest that young patients with familial melanoma have a distinct etiology and that it is important to refer them for clinical genetic testing. Our findings may promote better understanding of the etiology of MPM.

Accepted for Publication: October 28, 2014.

Corresponding Author: Tianhui Chen, MD, PhD, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany (t.chen@dkfz.de).

Published Online: February 11, 2015. doi:10.1001/jamadermatol.2014.4777.

Author Contributions: Drs Chen and Fallah had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Chen, Fallah, Försti, Hemminki.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Chen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Chen, Fallah, Kharazmi.

Obtained funding: Sundquist, Hemminki.

Administrative, technical, or material support: Försti, Sundquist, Hemminki.

Study supervision: Fallah, Försti, Sundquist, Hemminki.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by German Cancer Aid (Deutsche Krebshilfe), the Swedish Research Council, the Swedish ALF project grants, and the Swedish Council for Working Life.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Bishop  JN, Harland  M, Randerson-Moor  J, Bishop  DT.  Management of familial melanoma. Lancet Oncol. 2007;8(1):46-54.
PubMed   |  Link to Article
Horn  S, Figl  A, Rachakonda  PS,  et al.  TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959-961.
PubMed   |  Link to Article
Yokoyama  S, Woods  SL, Boyle  GM,  et al.  A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99-103.
PubMed   |  Link to Article
Bertolotto  C, Lesueur  F, Giuliano  S,  et al; French Familial Melanoma Study Group.  A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480(7375):94-98.
PubMed   |  Link to Article
Ghiorzo  P, Pastorino  L, Queirolo  P,  et al; Genoa Pancreatic Cancer Study Group.  Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res. 2013;26(2):259-262.
PubMed   |  Link to Article
McCaul  KA, Fritschi  L, Baade  P, Coory  M.  The incidence of second primary invasive melanoma in Queensland, 1982-2003. Cancer Causes Control. 2008;19(5):451-458.
PubMed   |  Link to Article
Mason  RS, Reichrath  J.  Sunlight vitamin D and skin cancer. Anticancer Agents Med Chem. 2013;13(1):83-97.
PubMed   |  Link to Article
Narayanan  DL, Saladi  RN, Fox  JL.  Ultraviolet radiation and skin cancer. Int J Dermatol. 2010;49(9):978-986.
PubMed   |  Link to Article
Stang  A, Pukkala  E, Sankila  R, Söderman  B, Hakulinen  T.  Time trend analysis of the skin melanoma incidence of Finland from 1953 through 2003 including 16,414 cases. Int J Cancer. 2006;119(2):380-384.
PubMed   |  Link to Article
Pearce  J, Barnett  R, Kingham  S.  Slip! Slap! Slop! Cutaneous malignant melanoma incidence and social status in New Zealand, 1995-2000. Health Place. 2006;12(3):239-252.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Basic Characteristics of First Melanoma in Patients With Familial or Sporadic Melanoma
Table Graphic Jump LocationTable 2.  Standardized Incidence Ratios (SIRs) of Next Melanoma by Number of Previous Melanomas for Patients With Familial Melanomaa
Table Graphic Jump LocationTable 3.  Standardized Incidence Ratios (SIRs) of Next Melanoma by Number of Previous Melanomas for Patients With Sporadic Melanomasa
Table Graphic Jump LocationTable 4.  Standardized Incidence Ratios (SIRs) of Second Melanoma, Stratified by Age at Diagnosis of the First Melanoma and Follow-up Between First and Second Melanomas, for Patients With Familial and Sporadic Melanomaa,b

References

Wood  ME, Vogel  V, Ng  A, Foxhall  L, Goodwin  P, Travis  LB.  Second malignant neoplasms: assessment and strategies for risk reduction. J Clin Oncol. 2012;30(30):3734-3745.
PubMed   |  Link to Article
Åberg  A. Cancer Incidence in Sweden 2012. Stockholm, Sweden: National Board of Health and Welfare; 2014.
Bradford  PT, Freedman  DM, Goldstein  AM, Tucker  MA.  Increased risk of second primary cancers after a diagnosis of melanoma. Arch Dermatol. 2010;146(3):265-272.
PubMed   |  Link to Article
Chen  T, Hemminki  K, Kharazmi  E, Ji  J, Sundquist  K, Fallah  M.  Multiple primary (even in situ) melanomas in a patient pose significant risk to family members. Eur J Cancer. 2014;50(15):2659-2667.
PubMed   |  Link to Article
Ferrone  CR, Ben Porat  L, Panageas  KS,  et al.  Clinicopathological features of and risk factors for multiple primary melanomas. JAMA. 2005;294(13):1647-1654.
PubMed   |  Link to Article
Helsing  P, Nymoen  DA, Ariansen  S,  et al.  Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas. Genes Chromosomes Cancer. 2008;47(2):175-184.
PubMed   |  Link to Article
Badenas  C, Aguilera  P, Puig-Butillé  JA, Carrera  C, Malvehy  J, Puig  S.  Genetic counseling in melanoma. Dermatol Ther. 2012;25(5):397-402.
PubMed   |  Link to Article
Zhang  H, Bermejo  JL, Sundquist  J, Hemminki  K.  Modification of second cancer risk after malignant melanoma by parental history of cancer. Br J Cancer. 2008;99(3):536-538.
PubMed   |  Link to Article
DiFronzo  LA, Wanek  LA, Elashoff  R, Morton  DL.  Increased incidence of second primary melanoma in patients with a previous cutaneous melanoma. Ann Surg Oncol. 1999;6(7):705-711.
PubMed   |  Link to Article
Chen  T, Fallah  M, Kharazmi  E, Ji  J, Sundquist  K, Hemminki  K.  Effect of a detailed family history of melanoma on risk for other tumors: a cohort study based on the nationwide Swedish Family-Cancer Database. J Invest Dermatol. 2014;134(4):930-936.
PubMed   |  Link to Article
Hemminki  K, Li  X, Plna  K, Granström  C, Vaittinen  P.  The nation-wide Swedish family-cancer database—updated structure and familial rates. Acta Oncol. 2001;40(6):772-777.
PubMed   |  Link to Article
Liu  H, Hemminki  K, Sundquist  J.  Renal cell carcinoma as first and second primary cancer: etiological clues from the Swedish Family-Cancer Database. J Urol. 2011;185(6):2045-2049.
PubMed   |  Link to Article
Frödin  JE, Ericsson  J, Barlow  L.  Multiple primary malignant tumors in a national cancer registry—reliability of reporting. Acta Oncol. 1997;36(5):465-469.
PubMed   |  Link to Article
Youlden  DR, Youl  PH, Soyer  HP, Aitke n  JF, Baade  PD.  Distribution of subsequent primary invasive melanomas following a first primary invasive or in situ melanoma in Queensland, Australia, 1982-2010. JAMA Dermatol. 2014;150(5):526-534.
PubMed   |  Link to Article
Hemminki  K, Boffetta  P.  Multiple primary cancers as clues to environmental and heritable causes of cancer and mechanisms of carcinogenesis. IARC Sci Publ. 2004;(157):289-297.
PubMed
Bishop  JN, Harland  M, Randerson-Moor  J, Bishop  DT.  Management of familial melanoma. Lancet Oncol. 2007;8(1):46-54.
PubMed   |  Link to Article
Horn  S, Figl  A, Rachakonda  PS,  et al.  TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959-961.
PubMed   |  Link to Article
Yokoyama  S, Woods  SL, Boyle  GM,  et al.  A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99-103.
PubMed   |  Link to Article
Bertolotto  C, Lesueur  F, Giuliano  S,  et al; French Familial Melanoma Study Group.  A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480(7375):94-98.
PubMed   |  Link to Article
Ghiorzo  P, Pastorino  L, Queirolo  P,  et al; Genoa Pancreatic Cancer Study Group.  Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history. Pigment Cell Melanoma Res. 2013;26(2):259-262.
PubMed   |  Link to Article
McCaul  KA, Fritschi  L, Baade  P, Coory  M.  The incidence of second primary invasive melanoma in Queensland, 1982-2003. Cancer Causes Control. 2008;19(5):451-458.
PubMed   |  Link to Article
Mason  RS, Reichrath  J.  Sunlight vitamin D and skin cancer. Anticancer Agents Med Chem. 2013;13(1):83-97.
PubMed   |  Link to Article
Narayanan  DL, Saladi  RN, Fox  JL.  Ultraviolet radiation and skin cancer. Int J Dermatol. 2010;49(9):978-986.
PubMed   |  Link to Article
Stang  A, Pukkala  E, Sankila  R, Söderman  B, Hakulinen  T.  Time trend analysis of the skin melanoma incidence of Finland from 1953 through 2003 including 16,414 cases. Int J Cancer. 2006;119(2):380-384.
PubMed   |  Link to Article
Pearce  J, Barnett  R, Kingham  S.  Slip! Slap! Slop! Cutaneous malignant melanoma incidence and social status in New Zealand, 1995-2000. Health Place. 2006;12(3):239-252.
PubMed   |  Link to Article

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Supplement.

eTable 1. Standardized Incidence Ratios (SIRs) for Patients With Familial Melanoma of Next Melanoma by Number of Previous Melanomas Using Formal Testing of the Difference in Subgroup Analyses

eTable 2. Standardized Incidence Ratios (SIRs) for Patients With Sporadic Melanoma of Next Melanoma by Number of Previous Melanomas Using Formal Testing of the Difference in Subgroup Analyses

eTable 3. Standardized Incidence Ratios (SIRs) for Patients With All Melanoma of Next Melanoma by Number of Previous Melanomas Using Formal Testing of the Difference in Subgroup Analyses

eTable 4. Standardized Incidence Ratios (SIRs) of Second Melanoma for Patients With All Melanoma, Stratified by Age at Diagnosis of the First Melanoma and Follow-up Between First and Second Melanomas

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