Multiple synchronous primary melanomas; A case report

Background:Although multiple primary melanomas (MPMs) have been reported in the literature, the subgroup of synchronous melanomas (SMs) remains understudied.Methods:We conducted a comprehensive systematic review of the English literature from 1972 to 2023 to characterize SM. Our objective was to clarify the definition, determine incidence and prognosis, and present recommendations.Results:We found 18 case series articles and six case reports that met our criteria. Twelve of eighteen studies defined SM as a second primary melanoma identified within 1 month. The total number of SM patients reported was 1083. The cumulative percentage of MPM in total melanoma patients was 2.9 %, and the cumulative percentage of SM patients in MPM patients was 31.3%. SM patients trended toward higher body anatomical concordance, older age, and male sex. Despite limited data, SMs do not show a worse prognosis for patients compared with single melanomas.Conclusions:Despite a lack of consensus in the past, we recommend that SM be defined as a second primary melanoma detected within 1 month of the initial diagnosis. SMs comprise almost one-third of MPM cases and do not seem to carry any worse prognosis than the patients presenting with single melanoma. We believe older age and male sex may be more prone to SM. We recommend patient education, self-skin evaluations and TSE at initial and follow-up visits. Neither randomized controlled trials nor meta-analyses on SM exist. Ideally, further studies with a large cohort of patients are needed to accurately define SM.

The National Comprehensive Cancer Network (NCCN) developed clinical practice guidelines for germline pathogenic variants in highly penetrant genes, such asTP53andPTEN, and in moderately penetrant genes, such asCHEK2, ATM andPALB2. Whether the practice of radiographic surveillance of patients with pathogenic variants in genes other than BRCA1/2 complies with current NCCN guidelines remains unclear. Retrospective review of patients identified with pathogenic variants in genes other than BRCA1/2 from 2007 through 2017 to determine if radiographic surveillance was in accordance with NCCN guidelines for mammography and consideration of magnetic resonance imaging (MRI). Exclusions included variants of unknown significance, pathogenic variants not associated with an increased risk of breast cancer, and previous breast cancer diagnosis. After exclusions, 35 patients with pathogenic variants in ATM, CDH1, CHEK2, NBN, PALB2, PTEN, and STK11 genes were reviewed to assess whether radiographic surveillance was in accordance with NCCN guidelines. Guidelines for those with variants in ATM, CHEK2 and NBN includes annual mammography with tomosynthesis and consideration of breast MRI at age 40, variants in CDH1 and PALB2 at age 30, variants in PTEN at age 30-35 or 5-10 years before the earliest family breast cancer, and variants in STK11 at age 25. Of these 35 patients, 11 (31%) received mammography only; 11 (31%) received mammography and MRI, and 13 (37%) received no radiographic surveillance. Two of the 35 (6%) patients who received radiographic surveillance were diagnosed with ductal carcinoma in situ or invasive breast cancer. Thirty-one percent of patients with pathogenic variants in genes other than BRCA1/2 received both mammography and MRI. Thirty-seven percent of patients with these highly penetrant and moderately penetrant genes received no radiographic follow-up, clearly demonstrating an opportunity for improvement.

Survival rates for melanoma have increased in recent years, a higher number of patients survive after diagnosis, and, therefore, are at an increased risk of developing second primary melanoma. The aim of this literature review is to identify and integrate the incidence rates and other characteristics of multiple primary melanomas. A total of 36 independent studies were included in this review. The incidence of multiple primary melanomas reported ranged from 1.1% to 20.4%. Synchronous melanomas account for 5% to 66% of the reported lesions. The most common site for both first and subsequent melanomas is the trunk. Superficial spreading melanoma is the most common histological type in both first and subsequent primary melanoma. Regarding the mean Breslow index, subsequent melanomas appeared to be thinner than first melanomas. Our review suggests that melanoma patients are at a higher risk of developing a second primary melanoma and long-term surveillance is needed.

To the Editor: People with a history of melanoma have a higher risk of developing subsequent primary melanomas than the general population; however, a difference in outcome between those with multiple primary melanomas (MPMs) and a single primary melanoma (SPM) is not established.1Peek G. Olsen C.M. Baade P. et al.Survival in patients with multiple primary melanomas: systematic review and meta-analysis.J Am Acad Dermatol. 2020; 83: 1406-1414Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Using a comprehensive, population-based dataset with long-term follow-up, we compared 10-year melanoma-specific mortality and overall mortality between people with MPMs and SPM. The Melanoma Patterns of Care study is a population-based observational study of residents in the state of New South Wales, Australia, who had a melanoma reported to the state cancer registry over 12 months in 2006-07, with follow-up until 2018 (median 11.9 years).2Watts C.G. McLoughlin K. Goumas C. et al.Association between melanoma detected during routine skin checks and mortality.JAMA Dermatol. 2021; 157: 1425-1436Crossref PubMed Scopus (26) Google Scholar People with a melanoma before study entry were excluded. Logistic regression analyses were performed to assess 10-year melanoma-specific mortality difference between groups. The analyzed data were from 3404 people (2830 had SPM, 574 developed a MPM during the follow-up period). Supplementary Table I, available via Mendeley at https://doi.org/10.17632/yknjyk9tfz.1 shows the patient and lesion characteristics for the first and thickest melanomas stratified by SPM and MPMs. The multivariable regression adjusted for pathological characteristics of the thickest lesion in the MPM group showed no significant differences in 10-year melanoma-specific mortality between the two groups (odds ratio 0.85, 95% confidence interval: 0.58-1.24, P = .40, Table I). These findings were consistent with the sensitivity analyses using parameters of the first primary melanoma among patients with MPMs (odds ratio 1.34, 95% confidence interval: 0.92-1.96, P = .12), although using first lesion characteristics may introduce survival bias.1Peek G. Olsen C.M. Baade P. et al.Survival in patients with multiple primary melanomas: systematic review and meta-analysis.J Am Acad Dermatol. 2020; 83: 1406-1414Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Other factors independently associated with higher melanoma-specific mortality in the multivariable analysis using data from the thickest lesion were male sex, disadvantaged socioeconomic status (based on location of residence), and Breslow thickness; and there were borderline-significant associations with body site, ulceration, and mitotic rate (Table I). The 10-year overall mortality results are presented in Supplementary Table II, available via Mendeley at https://doi.org/10.17632/yknjyk9tfz.1.Table ILogistic regression model for 10-year melanoma-specific mortality, using pathological factors from the first and thickest primary melanoma (selected factors)CharacteristicsNThickest lesionFirst lesionUnivariableMultivariable∗Variables with a P value of <0.2 in the univariable analysis were included in multivariable models as adjustment factors.UnivariableMultivariabsle∗Variables with a P value of <0.2 in the univariable analysis were included in multivariable models as adjustment factors.Odds ratio (95% CI)P valueOdds ratio (95% CI)P valueOdds ratio (95% CI)P valueOdds ratio (95%)P valueStatus SPM28301.00.661.00.401.00.661.00.12 MPM5741.08 (0.77-1.51)0.85 (0.58-1.24)1.08 (0.77-1.51)1.34 (0.92-1.96)Gender Males20491.00<.011.00.031.00<.011.00.03 Females13550.58 (0.44-0.77)0.70 (0.51-0.97)0.58 (0.44-0.77)0.70 (0.51-0.96)Age categories Quintile 19091.00<.011.00.121.000.011.000.22 Quintile 28581.37 (0.93-2.03)1.29 (0.84-1.98)1.37 (0.93-2.03)1.27 (0.83-1.95) Quintile 38001.59 (1.08-2.33)1.33 (0.86-2.05)1.59 (1.08-2.33)1.33 (0.86-2.06) Quintile 48371.84 (1.27-2.68)0.88 (0.57-1.35)1.84 (1.27-2.68)0.93 (0.61-1.44)Socioeconomic status†Socioeconomic status is based on postcode of residence. Quintile 1 represents the most disadvantaged status and quintile 5 represents the least disadvantaged status. Quintile 12901.00<.011.00<.011.00<.011.00<.01 Quintile 25231.58 (0.95-2.63)1.72 (0.97-3.04)1.58 (0.95-2.63)1.62 (0.92-2.86) Quintile 310660.75 (0.45-1.25)0.78 (0.45-1.36)0.75 (0.45-1.25)0.75 (0.43-1.30) Quintile 46371.02 (0.60-1.71)1.13 (0.63-2.04)1.02 (0.60-1.71)1.06 (0.59-1.89) Quintile 58880.87 (0.52-1.44)1.02 (0.58-1.80)0.87 (0.52-1.44)0.91 (0.51-1.59)Family history‡These characteristics were collected by clinician questionnaire and were not available for every patient. Absent15951.00.191.00.691.00.191.00.64 Present1920.84 (0.44-1.59)0.88 (0.44-1.78)0.84 (0.44-1.59)0.90 (0.45-1.81) Unknown16171.23 (0.95-1.61)1.15 (0.79-1.66)1.23 (0.95-1.61)1.17 (0.81-1.70)Breslow thickness In situ (0)3991.00<.011.00<.011.00<.011.00<.01 0-0.815901.63 (0.48-5.51)1.26 (0.34-4.64)1.37 (0.52-3.58)1.18 (0.41-3.40) 0.9-1.02316.64 (1.85-23.77)3.89 (0.98-15.38)5.47 (1.96-15.26)3.54 (1.14-11.03) 1.1-2.057412.54 (3.89-40.38)5.88 (1.63-21.21)8.18 (3.24-20.65)4.10 (1.42-11.82) 2.1-4.037029.27 (9.14-93.72)11.80 (3.24-42.98)19.50 (7.78-48.86)8.15 (2.79-23.77) >4.023160.94 (18.99-195.53)22.40 (6.04-83.12)38.13 (15.13-96.07)14.56 (4.87-43.58)Body site Head and neck7081.00.031.00.071.00.031.00.02 Trunk11950.95 (0.68-1.33)1.23 (0.83-1.83)1.10 (0.78-1.55)1.56 (1.04-2.35) Upper limbs8540.58 (0.39-0.88)0.72 (0.46-1.14)0.65 (0.43-0.98)0.86 (0.54-1.36) Lower limbs6471.02 (0.70-1.50)1.17 (0.75-1.83)1.11 (0.75-1.64)1.34 (0.85-2.11)Melanoma subtype Superficial spreading16101.00<.011.00.551.00<.011.00.82 Nodular4645.69 (4.14-7.82)1.17 (0.79-1.73)5.32 (3.86-7.34)1.18 (0.80-1.75) Lentigo4410.52 (0.27-0.98)0.88 (0.43-1.81)0.62 (0.35-1.11)1.16 (0.60-2.25) Other2153.79 (2.46-5.84)1.19 (0.72-1.97)3.52 (2.27-5.45)1.35 (0.81-2.24) Not specified6740.91 (0.59-1.41)0.78 (0.47-1.29)1.06 (0.70-1.60)1.13 (0.71-1.80)Ulceration Absent23651.00<.011.00.061.00<.011.00.07 Present4294.84 (3.65-6.42)1.35 (0.96-1.91)4.70 (3.52-6.27)1.42 (1.00-2.02) Missing6100.41 (0.24-0.70)0.62 (0.31-1.24)0.49 (0.30-0.79)0.78 (0.41-1.46)Regression Absent12021.00<.011.00.121.00<.011.00.56 Present11890.32 (0.23-0.45)0.79 (0.53-1.15)0.37 (0.27-0.52)0.86 (0.59-1.25) Missing10130.55 (0.40-0.74)1.26 (0.85-1.85)0.53 (0.39-0.72)1.09 (0.73-1.62)Mitotic rate (n/mm2) <110101.00<.011.00.061.00<.011.00<.01 1-26805.04 (2.90-8.77)1.88 (1.02-3.48)5.44 (3.14-9.46)2.46 (1.34-4.50) 3-1054713.71 (8.11-23.17)2.31 (1.23-4.34)14.57 (8.61-24.64)3.24 (1.73-6.07) >1015520.31 (11.16-36.99)1.88 (0.91-3.90)20.86 (11.32- 38.46)2.67 (1.27-5.62) Missing10122.22 (1.24-3.96)1.31 (0.66-2.59)2.32 (1.31-4.12)1.48 (0.77-2.87)Pathological factors are from the thickest and first primary melanoma diagnosed during the study period. The survival time starts from their first melanoma diagnosed in the period between October 2006 and October 2007. A missing category was set for Breslow thickness to keep the samples consistent between models.CI, Confidence interval; MPM, multiple primary melanomas; SPM, single primary melanoma.∗ Variables with a P value of <0.2 in the univariable analysis were included in multivariable models as adjustment factors.† Socioeconomic status is based on postcode of residence. Quintile 1 represents the most disadvantaged status and quintile 5 represents the least disadvantaged status.‡ These characteristics were collected by clinician questionnaire and were not available for every patient. Open table in a new tab Pathological factors are from the thickest and first primary melanoma diagnosed during the study period. The survival time starts from their first melanoma diagnosed in the period between October 2006 and October 2007. A missing category was set for Breslow thickness to keep the samples consistent between models. CI, Confidence interval; MPM, multiple primary melanomas; SPM, single primary melanoma. Sex, Breslow thickness, ulceration status, and socioeconomic disadvantage have been identified in other studies as factors independently associated with melanoma-specific survival.3Kricker A. Armstrong B.K. Goumas C. et al.Survival for patients with single and multiple primary melanomas: the genes, environment, and melanoma study.JAMA Dermatol. 2013; 149: 921-927Crossref PubMed Scopus (30) Google Scholar,4Coory M. Smithers M. Aitken J. Baade P. Ring I. Urban-rural differences in survival from cutaneous melanoma in Queensland.Aust N Z J Public Health. 2006; 30: 71-74Crossref PubMed Scopus (38) Google Scholar The worse prognosis for patients living in socioeconomically disadvantaged areas may be related to poorer access to medical care or education. The main limitation is the lack of adjustment for treatment modality (eg systemic therapy) in the multivariable analysis. At the time of the baseline survey, effective systemic therapies were unavailable and survival rates for patients with advanced melanoma were very poor. Given that death from melanoma can occur many years after diagnosis,5Baade P.D. Whiteman D.C. Janda M. et al.Long-term deaths from melanoma according to tumor thickness at diagnosis.Int J Cancer. 2020; 147: 1391-1396Crossref PubMed Scopus (17) Google Scholar treatment during later years of follow-up may have improved survival outcomes. It is possible that this had more impact in the MPM group as people who developed a SPM in the earlier years may have died before developing a MPM and before systemic treatments became available. The results of our study suggest that the number of primary melanomas is not an independent risk factor for mortality. In addition, the detection of melanoma at an early stage (with a thin Breslow thickness) rather than an intrinsic biologic factor remains the biggest influence on melanoma mortality after diagnosis of 1 or more melanomas. Richard A Scolyer has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. Scott W Menzies has received fees for advisory board participation from MoleMap Australia and Scibase AB. John F Thompson has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus Inc, and travel and conference support from GSK, Provectus Inc and Novartis. Yuan Ni, Caroline G Watts, Christine Madronio, Bruce K Armstrong, Rachael L Morton, Graham J Mann, Anne E Cust, and Serigne N Lo have no conflicts of interest to declare.

BackgroundPopulation-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.MethodsIn a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.ResultsPathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.ConclusionsThis study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

eP064: Consumer-initiated genetic testing identifies individuals predisposed to multiple hereditary cancer syndromes

P3-09-05: Clinical outcome of patients with advanced triple negative breast cancer with germline and somatic variants in homologous recombination gene

&lt;div&gt;AbstractBackground:&lt;p&gt;Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear.&lt;/p&gt;Methods:&lt;p&gt;We investigated the associations of 69 SNPs in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma in the international, population-based Genes, Environment, and Melanoma study. Per-minor-allele ORs and 95% confidence intervals (CI) for individuals with MPM “cases” (&lt;i&gt;n&lt;/i&gt; = 1,205) relative to single primary melanoma “controls” (&lt;i&gt;n&lt;/i&gt; = 2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis (57 of the 68 independent GWAS SNPs available).&lt;/p&gt;Results:&lt;p&gt;Thirteen SNPs in 11 gene regions (&lt;i&gt;PARP1&lt;/i&gt;, &lt;i&gt;CYP1B1/RMDN3&lt;/i&gt;, &lt;i&gt;TERT&lt;/i&gt;, &lt;i&gt;RAPGEF5&lt;/i&gt;, &lt;i&gt;TYRP1&lt;/i&gt;, &lt;i&gt;MTAP&lt;/i&gt;, &lt;i&gt;CDKN2A/CDKN2B&lt;/i&gt;, &lt;i&gt;KLF4&lt;/i&gt;, &lt;i&gt;TYR&lt;/i&gt;, &lt;i&gt;SOX6&lt;/i&gt;, and &lt;i&gt;ASIP&lt;/i&gt;) were statistically significantly associated (&lt;i&gt;P&lt;/i&gt; &lt; 0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest versus lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI, 2.10–3.78; &lt;i&gt;P&lt;/i&gt; = 7.5 × 10&lt;sup&gt;−13&lt;/sup&gt;); this association was attenuated but remained statistically significant after excluding SNPs individually associated with MPM (OR = 1.75, 95% CI, 1.32–2.31).&lt;/p&gt;Conclusions:&lt;p&gt;Inherited genetic variants spanning 11 gene regions were independently associated with MPM. Nonsignificant SNPs were associated with MPM when aggregated into a PRS, indicating that their cumulative effect may influence MPM risk despite lacking individual statistical significance in our study population.&lt;/p&gt;Impact:&lt;p&gt;Our findings provide additional evidence that these loci are associated with melanoma risk and estimate the magnitude of their genetic effect on subsequent (multiple) primary melanoma risk.&lt;/p&gt;&lt;/div&gt;

Genetic Testing in Cardiovascular Medicine.

The CEP104 gene (OMIM: 616,690) encodes the centrosome protein 104 (CEP104) that is involved in cilia function. Pathogenic variants in this gene have been described in four patients diagnosed with Joubert syndrome (JBTS) 25. Here, we challenged the concept that pathogenic variants in CEP104 gene are only involved in the development of JBTS 25. In a clinical setting, whole-exome sequencing (WES) was applied to investigate pathogenic variants in patients with unexplained developmental delay or intellectual disability (DD/ID).WES revealed a novel homozygous nonsense variant (c.643C > T) in CEP104 (NM _014704.3) in a girl with mild intellectual disability, hypotonia, and imbalanced gait. Her brain MRI data did not show molar tooth sign (MTS) or any other brain anomalies. Our study introduced a novel variant in the CEP104 gene that results in an ID phenotype other than JBTS25. Comparison of her phenotype with that of eight previously published DD/ID patients harboring pathogenic variants in CEP104 gene revealed that more than half of them did not show JBTS related symptoms. Therefore, we suggest that the CEP104 gene might also be involved in a disorder other than JBTS 25, a point that deserves to be emerged in the OMIM database.

BackgroundOver the past decades, many regions have experienced a steady increase in the incidence of cutaneous melanoma. Here, we report on incidence trends for subsequent primary melanoma.MethodsIn this nationwide population-based study, patients diagnosed with a first primary cutaneous melanoma reported to the Swedish Cancer Registry were followed for up to 10 years for a diagnosis of subsequent primary melanoma. Patients were grouped with patients diagnosed with first melanoma in the same decade (1960s, 1970s, 1980s, 1990s, and 2000s, respectively). Frequencies, incidence rates (IRs), standardized incidence ratios (SIRs), and 95% confidence intervals (CIs) for second melanomas were calculated. All tests of statistical significance were 2-sided.ResultsOf patients with melanoma, 54 884 were included and 2469 were diagnosed, within 10 years, with subsequent melanomas. Over the 5 decades, there was a statistically significant steady increase in the frequency, IR, and SIR for second primary melanoma. For example, in the 1960s cohort, less than 1% (IR = 1.0, 95% CI = 0.5 to 1.7, and IR = 1.1, 95% CI = 0.5 to 1.9 per 1000 person-years in women and men, respectively) had second primary melanoma, and this rose to 6.4% (IR = 7.5, 95% CI = 6.8 to 8.3, per 1000 person-years) in the women and 7.9% (IR = 10.3, 95% CI = 9.3 to 11.2, per 1000 person-years) in the men in the 2000s cohort. This rise was seen independent of age, sex, invasiveness, or site of the melanoma. Further, in patients diagnosed with a second melanoma, the frequency of those having more than 2 melanomas increased statistically significantly and was 0.0% in the 1960s and rose to 18.0% in the 2000s (P < .001).ConclusionsThis is the first study to evaluate and report on a rising trend for subsequent primary melanoma. Additional primary melanomas worsen the patients’ survival, and precautions are needed to turn this steep upgoing trend.

Lack of association between CDKN2A germline mutations and survival in patients with melanoma: A retrospective cohort study

eP061: Genetic risk for breast and ovarian cancer in a diverse and unselected population

Disorders of brain formation can occur from pathogenic variants in various alpha and beta tubulin genes. Heterozygous pathogenic variants in the beta tubulin isotype A gene, TUBB2A, have been recently implicated in brain malformations, seizures, and developmental delay. Limited information is known regarding the phenotypic spectrum associated with pathogenic variants in this gene given the rarity of the condition. We report the sixth individual with a de novo heterozygous TUBB2A pathogenic variant, who presented with a severe neurological phenotype along with unique features of arthrogryposis multiplex congenita, optic nerve hypoplasia, dysmorphic facial features, and vocal cord paralysis, thereby expanding the gene-related phenotype.