PURPOSE:To evaluate cancer risk, age-specific penetrance, and mortality associated with heterozygous pathogenic or likely pathogenic (P/LP) germline PALB2 variants identified through genomic ascertainment and to assess modification by family history of cancer. PATIENTS AND METHODS:We conducted a case-control study in two large population-based adult cohorts: the UK Biobank (n=469,580) and Geisinger MyCode (n=167,050). Individuals with heterozygous PALB2 P/LP variants were identified via exome sequencing and compared with non-carriers. Cancer diagnoses and vital status were obtained from linked registry and electronic health record data. We used multivariable logistic regression to estimate odds ratios (ORs) for cancer outcomes and Cox proportional hazards models to estimate hazard ratios (HRs) for all-cause mortality. Age-specific cumulative incidence (penetrance) was estimated using Kaplan-Meier methods. Models were adjusted for birth year, sex (when applicable), smoking status, and body mass index; stratified analyses assessed modification by family history of cancer. RESULTS:PALB2 P/LP variant prevalence was 1:571 in UK Biobank and 1:940 in MyCode, with the higher prevalence in the UK cohort driven by the PALB2 p.Trp1038Ter founder variant. Compared with non-carriers, heterozygotes had significantly increased odds of any cancer, female breast cancer, pancreatic cancer, and cancers of ill-defined or secondary sites in both cohorts (P < 0.01). Adjusted hazard ratios for any cancer and female breast cancer ranged from 1.7 to 3.6. All-cause mortality was increased among PALB2-heterozygotes (HR 1.61-1.67), and survival after cancer diagnosis was reduced. Family history further modified cancer risk. CONCLUSION:Genomic ascertainment of PALB2-heterozygotes identifies elevated risk for multiple cancers and increased mortality, although risks were lower than estimates from familial ascertainment. These findings inform risk management for individuals identified through genomic screening.

Some melanoma-prone families linked to the 9p21 locus, harboring the established susceptibility gene CDKN2A, lack pathogenic protein-coding variants. Using whole-exome and targeted sequencing, we identified three rare single-nucleotide variants in two melanoma-prone families and one sporadic melanoma case. Variants map to a conserved CTCF-bound region within the first intron of CDKN2B that physically interacts with CDKN2A. Analysis of UK Biobank showed significant enrichment of variants in this region in melanoma cases. Variants result in diminished CTCF binding in vitro. CTCF ChIP-seq in fibroblasts from the carriers of the largest family demonstrated loss of CTCF binding, accompanied by weakened promoter interactions and allele-specific reduction of CDKN2A p16 transcript expression from the variant haplotype. CRISPR-based perturbation of this region and editing of the large family variant into melanocytes resulted in reduced expression of p14 and p16 CDKN2A transcripts. These findings suggest that non-coding regulatory variants function as high-penetrance susceptibility alleles in melanoma families by altering CDKN2A function.

Abstract PURPOSE To evaluate cancer risk, age-specific penetrance, and mortality associated with heterozygous pathogenic or likely pathogenic (P/LP) germline PALB2 variants identified through genomic ascertainment and to assess modification by family history of cancer. PATIENTS AND METHODS We conducted a case-control study in two large population-based adult cohorts: the UK Biobank (n=469,580) and Geisinger MyCode (n=167,050). Individuals with heterozygous PALB2 P/LP variants were identified via exome sequencing and compared with non-carriers. Cancer diagnoses and vital status were obtained from linked registry and electronic health record data. We used multivariable logistic regression to estimate odds ratios (ORs) for cancer outcomes and Cox proportional hazards models to estimate hazard ratios (HRs) for all-cause mortality. Age-specific cumulative incidence (penetrance) was estimated using Kaplan–Meier methods. Models were adjusted for birth year, sex (when applicable), smoking status, and body mass index; stratified analyses assessed modification by family history of cancer. RESULTS PALB2 P/LP variant prevalence was 1:571 in UK Biobank and 1:940 in MyCode, with the higher prevalence in the UK cohort driven by the PALB2 p.Trp1038Ter founder variant. Compared with non-carriers, heterozygotes had significantly increased odds of any cancer, female breast cancer, pancreatic cancer, and cancers of ill-defined or secondary sites in both cohorts (P < 0.01). Adjusted hazard ratios for any cancer and female breast cancer ranged from 1.7 to 3.6. All-cause mortality was increased among PALB2 -heterozygotes (HR 1.61–1.67), and survival after cancer diagnosis was reduced. Family history further modified cancer risk. CONCLUSION Genomic ascertainment of PALB2 -heterozygotes identifies elevated risk for multiple cancers and increased mortality, although risks were lower than estimates from familial ascertainment. These findings inform risk management for individuals identified through genomic screening.

Importance:The prevalence of germline pathogenic variants in familial melanoma genes has primarily been studied in individuals with a personal or family history of cancer, an approach that may introduce ascertainment bias. Objective:To estimate the prevalence of pathogenic variants in clinically actionable familial melanoma genes and their associated cancer risks. Design, Settings, and Participants:This was a genome-first analysis of 2 population-scale genomically ascertained cohorts of individuals registered in the UK Biobank (UKBB) and the US Geisinger MyCode (GMC) databases, each linked with institutional (GMC) or national (UKBB) cancer registry data from 1970 through 2024. Data analyses were conducted from January 2025 through January 2026. Exposures:Germline pathogenic variant status in familial melanoma genes. Main Outcomes and Measures:Prevalence of pathogenic variants in 8 major familial melanoma genes: ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, and TERT promoter; and associated cancer risks among individuals in the UK and US who had been genomically ascertained. Cancer odds ratios and time to cancer analyses were adjusted for sex, birth year, body mass index, and smoking status. Results:The analysis included a total of 696 665 individuals who were genomically ascertained, 227 286 (mean [SD] age, 57.7 [19.6] years) from GMC and 469 379 (mean [SD] age, 70.0 [8.0] years) from UKBB. The cohorts were predominantly female (GMC, 60.6%; UKBB, 54.2%), and of European genetic ancestry (GMC, 93.6%; UKBB, 94.2%). The combined prevalence of the pathogenic variants across all genes evaluated-ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, and TERT promoter-ranged from 0.5% (GMC) to 0.9% (UKBB) in both cohorts. Among individuals with multiple cutaneous melanomas or a first cutaneous melanoma diagnosed before age 40 years, pathogenic variant prevalence exceeded the 2.5% threshold commonly used to recommend germline testing for high- and moderate-penetrance cancer susceptibility genes. Case-control analyses replicated established associations for CDKN2A (brain, cutaneous melanoma, head and neck, pancreas), MITF E318K (cutaneous melanoma, kidney), and POT1 (cutaneous melanoma, hematologic, thyroid). Additional associations, either novel or inconsistently reported, were observed for BAP1 (prostate), CDKN2A (biliary tract, breast, nonmelanoma skin, small intestine), MITF E318K (cervix, nasal cavity and middle ear, nonmelanoma skin), and POT1 (myeloma). In both cohorts, individuals with CDKN2A PVs or MITF E318K developed cutaneous melanoma at younger ages than did noncarriers, although age-of-onset patterns for internal cancers were less consistent. Conclusions and Relevance:In this cohort study, the prevalence of pathogenic variants in familial melanoma genes and their associated cancer risks were estimated, findings that may inform and revise germline testing recommendations and cancer risk counseling. These data also suggest that the spectrum of cancer risk for several genes may be broader than previously recognized.

BACKGROUND:The large and growing burden of keratinocyte carcinoma (KC), including basal cell (BCC) and squamous cell carcinoma (SCC) suggests a need to identify high-risk individuals. We examined the association between KC risk and history of blistering sunburns in childhood and adulthood and investigated whether sun sensitivity modifies these associations. METHODS:Data were obtained from the large, nationwide U.S. Radiologic Technologists cohort, with baseline sunburn history and sun sensitivity traits collected via self-administered questionnaires. Participants were followed until diagnosis of first primary cancer or completion of a follow-up questionnaire (2003-2014). Hazard ratios (HR) and 95% confidence intervals (95%CIs) were estimated using Cox proportional hazards models. RESULTS:Among 40,204 participants, those reporting ever blistering sunburn had higher risk of BCC (HR=1.37;95%CI:1.26,1.49) and SCC (HR=1.41;95%CI:1.19,1.66). The HR of BCC per blistering sunburn in childhood and adulthood were 1.06 (95%CI:1.05,1.07) and 1.05 (95%CI:1.04,1.06) respectively. The HRs for SCC were 1.08 (95%CI:1.06,1.11) and 1.07(95%CI:1.05,1.09) per blistering sunburn in childhood and adulthood, respectively. Most sun sensitivity factors and other measures of UVR exposure did not significantly modify these associations. CONCLUSIONS:Number of blistering sunburns was associated with increased KC risk independently of an individual's pigmentary features and ambient UVR. The associations were similar for childhood and adulthood sunburns. IMPACT:History of blistering sunburn is an important risk factor for KC, even among groups that might otherwise be overlooked due to their overall lower risk of KC, such as individuals who have darker pigmentary features or those residing in locations with less ambient UVR.

BACKGROUND:Few epidemiological studies have distinguished the effects of solar ultraviolet (UV) radiation (UVR) wavelength, including UVB and UVA, on the risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. OBJECTIVES:We aimed to evaluate the association between ambient UVB and UVA exposure and the incidence of BCC and SCC. METHODS:Using data from the nationwide US Radiologic Technologists cohort, satellite-based noontime ambient UVR was obtained based on residential history (< 13, 13-19, 20-39, 40-64, and ≥ 65 years). Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated for associations between UVB, UVA quintile (Q), and first primary BCC and SCC in mutually adjusted and stratified models, additionally adjusted for sun sensitivity characteristics. RESULTS:There were 62 595 non-Hispanic White participants aged 22-90 years at baseline (1983-1998). During a median 25.5 years of follow-up, 6339 incident BCCs and 1253 incident SCCs were reported. Annual and summer UVB and UVA were each positively associated with both BCC and SCC risk before mutual adjustment. After adjusting for UVA, summer (but not annual) UVB Q5 vs. Q1 was associated with BCC (IRR 1.41, 95% CI 1.13-1.77) and SCC (IRR 1.69, 95% CI 1.01-2.84). After adjusting for UVB, annual (but not summer) UVA Q5 vs. Q1 was associated with BCC (IRR 1.42, 95% CI 1.13-1.77) and SCC (IRR 1.84, 95% CI 1.10-3.06). CONCLUSIONS:Both summer UVB and annual UVA were independently associated with higher risks of both BCC and SCC. Our results suggest that cumulative lifetime UVA exposure may be an underappreciated contributor to BCC and SCC risk. If confirmed, these findings may indicate that public health interventions are required to promote avoidance of excessive UVB and UVA exposure among susceptible populations.

Background and purpose: Approximately 5–10% of cutaneous melanoma occurs in individuals with a family history of the disease. While known high-penetrance genes, such as CDKN2A, explain some cases, a substantial proportion of hereditary melanoma remains genetically undefined. Recently, germline variants in genes involved in telomere regulation, including POT1, TERT, ACD, and TERF2IP, have been identified in melanoma-prone families. This study investigated the prevalence and pathogenicity of POT1 variants in a Swedish familial melanoma cohort. Patient/material and methods: A total of 168 familial melanoma cases were screened for CDKN2A, CDK4, BAP1, and POT1. The population frequency of pathogenic variants (PVs) was assessed using the SweGen and the gnomAD databases. Functional evaluation was performed using a saturation genome editing (SGE) assay. Telomere length analysis was performed using quantitative polymerase chain reaction (qPCR) on blood-derived DNA from melanoma patients and healthy controls. The melanomas of the carriers were reviewed by expert dermatopathologists. Results: Among the 161 CDKN2A/CDK4/BAP1-negative melanoma families included in this cohort, only one likely PV in POT1 (c.676C > A, p.His226Asn) was identified (0.6%). Population data confirmed its rarity. The carrier family exhibited multiple early-onset melanomas, with two out of three invasive cases displaying spitzoid morphology, and several other tumors. No significant telomere length differences were observed between carriers and controls. Two additional POT1 variants of uncertain significance were detected; both were predicted to be benign. Interpretation: POT1 PVs were rare in the studied Swedish familial melanoma cases, implying limited contribution to hereditary melanoma in this population. Nonetheless, the identification of a previously unknown likely PV further supports the need for continued genetic screening in selected cases. POT1 testing should be considered in families with multiple melanomas, early onset and spitzoid histopathology, and co-occurring with other syndromic tumors.

Given the large and growing burden of keratinocyte carcinomas (KCs) in the United States, there is a pressing need to identify individuals at high risk. To quantify the association between KC risk and history of blistering sunburns in childhood and adulthood and to investigate whether individual sun sensitivity and other measures of ultraviolet radiation modify these associations. We examined blistering sunburns and KC risk in the nationwide U.S. Radiologic Technologists cohort study. Baseline data (1983-2005) on lifetime sunburn history and sun sensitivity traits were collected via self-administered questionnaires. Participants were followed until the diagnosis of a first primary cancer or completion of a follow-up questionnaire (2012-2014). Radiologic technologists without a prior cancer who reported White race or Hispanic ethnicity and completed both the baseline and follow-up questionnaires. History of blistering sunburns before (childhood) and after (adulthood) age 15 years. Risk increase for basal and squamous cell carcinoma (BCC/SCC) per blistering sunburn. Among 40,204 radiologic technologists (2% Hispanic; mean age at baseline:56 years), those reporting at least one blistering sunburn had a 37% higher risk of BCC and a 41% higher risk of SCC. The risk of BCC increased by 6% (95% confidence interval [95% CI], 5-7) and 5% (95% CI, 4-6) for each childhood and adulthood blistering sunburns, respectively. Similar findings were observed for SCC, with risk increasing by 8% (95% CI, 6-11) and 7% (95% CI, 5-9) for childhood and adulthood blistering sunburns, respectively. These associations were not significantly modified by most individual sun sensitivity traits and other measures of ultraviolet radiation. Individuals with ≥5 blistering sunburns occurring across varying ages of exposure appear to be at particularly high risk for KCs and may benefit from heightened skin cancer surveillance. Belinda L. Gorsuch, Jim Z. Mai, Martha S. Linet, Michael R. Sargen, Mark P. Little, Bruce H. Alexander, Cari M. Kitahara, Elizabeth K. Cahoon. Impact of sun sensitivity and ultraviolet radiation on the association between blistering sunburns and keratinocyte carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr B015.

Large congenital melanocytic nevi/nevus (LCMN) are caused by genetic events that activate the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathway. Individuals with LCMN are prone to developing aggressive melanomas during childhood. Targeted therapies are needed to treat this form of melanoma and manage LCMN symptoms such as pruritus and pain, which significantly impact quality of life. Here, we present the first case of an LCMN with an NTRK fusion driver event. The patient presented with an atypical proliferative nodule arising in the background nevus. RNA sequencing of the proliferative nodule with background nevus identified a pathogenic LMNA::NTRK1 fusion. The fusion resulted in constitutive expression of TrkA, demonstrated by strong cytoplasmic pan-TRK staining, along with activation of the MAPK/ERK pathway, as indicated by positive nuclear and cytoplasmic staining for phosphorylated ERK. The background nevus beneath the proliferative nodule also expressed pan-TRK and phosphorylated ERK, suggesting that the NTRK1 fusion occurred prior to the formation of the proliferative nodule. This case broadens the spectrum of driver events for LCMN and suggests that screening for TRK fusions in LCMN should be considered when systemic therapy is being considered for melanoma or symptom management.

Limited information is available on the clinicopathologic features and management of pediatric CRTC1::TRIM11 (CTRTs) and MED15::ATF1 -rearranged tumors (MARTs). In this series of pediatric CTRTs ( n  = 5) and MARTs ( n  = 2), all tumors exhibited spitzoid morphology and expressed melanocytic markers. Metastatic progression occurred in one CTRT and two MARTs: all three received immunotherapy, resulting in disease control in two patients and one death due to progressive disease. A fourth individual had lymph node micrometastasis that remained stable without progression. This case series highlights the potentially aggressive behavior of these tumors and suggests that immunotherapy may be an effective treatment option for advanced disease.

Merkel cell carcinoma (MCC) and melanoma are important contributors to skin cancer mortality in the United States. We evaluated their epidemiology using the United States cancer registry data. In 2000-2021, 19,444 MCCs and 646,619 melanomas of the skin were diagnosed. Ninety percent of MCCs and 95% of melanomas were in non-Hispanic White individuals. More than 70% of MCCs versus 37% of melanomas occurred in people aged ≥70 years. Excess MCCs and melanomas were observed on the head and neck (observed:expected: MCC, 5.15; melanoma, 2.47). Among non-Hispanic White individuals, ambient UVR exposure was associated with melanoma arising on the head and neck (incidence rate ratios of 1.15-1.20 for MCC and 1.24-1.49 for melanoma, comparing quintiles 3-5 with quintile 1). Cancer-specific mortality was higher among patients with MCC than among those with melanoma (hazard ratio = 2.33, 95% confidence interval = 2.26-2.42) but improved in both groups after 2011 when BRAF and checkpoint inhibitors were introduced. In conclusion, melanoma exhibited stronger associations with race and ambient UVR exposure, while MCC was more likely to arise on the head and neck (perhaps reflecting the distribution of precursor cells). To ensure prompt treatment, clinicians should be on alert when diagnosing these cancers.

BACKGROUND:Next-generation sequencing (NGS) is becoming more commonly used for diagnosis in dermatopathology. It's critical to appraise its efficacy and limitations. Distinguishing benign deep penetrating nevi (DPN) from deep penetrating like-melanoma (DPN-M) is a challenging diagnostic scenario even for experienced dermatopathologists. METHODS:We sent a two-phase survey (pre-and postgenomics) to 32 experienced dermatopathologists to evaluate 39 diagnostically challenging cases from the DPN/WNT-activated family of melanocytic neoplasms. RESULTS:With NGS data, interobserver agreement improved from 0.41 to 0.51 (p < 0.0001) in distinguishing DPN-M from nonmelanoma cases. Overall diagnostic accuracy improved, mostly driven by a 16% increase in accurate diagnosis of DPN-M. However, in two cases, the inclusion of genomics shifted the majority vote from a correct to an incorrect diagnosis. A total of 218 diagnostic changes occurred between Survey 1 and 2. Among the changes, 132 votes moved toward the correct diagnosis while 86 moved toward an incorrect diagnosis. The shift in voting which resulted in improved diagnostic accuracy was statistically significant (p = 0.0001). CONCLUSIONS:NGS has the potential to improve interobserver agreement and diagnostic accuracy. We provide guidance on the utilization of bioinformatic data to maximize its benefits and improve diagnostic accuracy and interobserver agreement.

BACKGROUND:Over 90% of US children with cancer are treated at Children's Oncology Group (COG) centers, which seek to maximize enrollment in therapeutic and biobanking studies. Rare cancers have demonstrated lower than expected COG enrollment. We evaluated trends in COG rare cancer enrollment compared to US incidence from Surveillance, Epidemiology, and End Results (SEER) registries, examining the impact of COG therapeutic trials and Project:EveryChild, a cancer biobank/registry. PROCEDURE:COG and SEER data from 2002 to 2020 were queried for US patients younger than 18 years old with adrenocortical carcinoma (ACC), nasopharyngeal carcinoma (NPC), retinoblastoma (RB), thyroid carcinoma, and melanoma. We compared demographic data between COG and SEER, extrapolating incidence for each cancer to analyze trends in COG enrollment. RESULTS:Patient characteristics, including age, sex, and race, were similar between COG (n = 2184) and SEER (n = 5514). COG enrollment for rare cancers remained low (11%). Initiating Project:EveryChild did not increase enrollment (12% pre- vs. 8% post-Project:EveryChild; p < 0.01). For cancers with available therapeutic trials (ACC, NPC, and RB), COG enrollment was higher during trial accrual (40%) than when no trial was open (12%; p < 0.01). Patient geography and income did not appear as barriers to COG enrollment. CONCLUSIONS:Although children with rare cancers enrolled in COG studies reflect the US population, enrollment in the COG registry/biospecimen repository continues to be limited in the absence of therapeutic trials, impacting data and biospecimens available to inform therapeutic trial development. Expansion of therapeutic trials or free molecular testing through the Molecular Characterization Initiative may increase data and biospecimens for these rare cancers.

Fraction of mutation signatures of mutants with a variant allele frequency less than 20% versus those with an allele frequency between 30% and 45%.

Pediatric melanoma is the most common skin cancer in children and treatment relies on accurate staging. The American Academy of Dermatology recommends excisional biopsy for suspicious skin lesions, however, partial shave biopsies are often performed, the impact of which is unknown in pediatric and adolescent/young adult (AYA) patients. The aim of this retrospective case series study was to evaluate the impact of the diagnostic biopsy method on staging, treatment, and treatment-related outcomes in pediatric/AYA patients with melanoma. Among 103 pediatric/AYA patients with atypical cutaneous melanocytic lesions, the most common biopsy method was partial shave (68/103, 66.0%) followed by punch (20/103, 19.4%), excisional (14/103, 13.6%), and incisional nonshave (1/103, 1%). Over half of all biopsies yielded a positive deep margin, reflecting compromised microstaging (56/103, 55.4%), the majority occurred following partial shave (52/56, 92.9%) compared with other techniques (P < 0.001). All 11 patients with wider surgical target margins of wide local excision and 8/9 patients with sentinel lymph node biopsy performed due to positive deep margin, underwent a partial shave biopsy (P = 0.05 and 0.32, respectively). Almost half of all patients who underwent partial shave biopsy had a clinically suspected abnormal melanocytic tumor prior to biopsy (31/68, 45.6%; P = 0.03). Of 56 patients who had compromised microstaging, 17 (30.4%) had a diagnosis of melanoma (P = 0.17). Pediatric/AYA patients frequently undergo partial shave biopsy, which is associated with more invasive definitive surgical treatment due to compromised microstaging. These results may help optimize care of patients with cutaneous melanocytic tumors.

Heatmaps of selected significantly altered pathways. A. Sirtuin signaling. B. Rho signaling C. TP53 signaling.

TERT expression in each histological category.

Correlation between tumor purity as determined by pathology versus as calculated by PURPLE.