Germline CDKN2A Mutations Research Articles

BIOM-08. CDKN2A --AN INDEPENDENT CYCLIN-DEPENDENT KINASE INHIBITOR VARIANT ASSOCIATED WITH MALIGNANCY AND WITH SMALL VESSEL STROKE, AS A POTENTIAL MARKER FOR RISK OF LARGE-VESSEL STROKE COMPLICATING BENIGN TERATOMA

Abstract BACKGROUND Cyclin-dependent kinase inhibitor variants, particularly those of CDKN2A are known to be associated with autosomal dominant Familial Atypical Multiple Mole/Melanoma Syndrome and pancreatic cancer predisposition. These variants are associated with risk of small vessel stroke in African/ African-American populations, and are risk factors for stroke in Nordic populations with hypertension, independent of cardiovascular risk factors. METHODS We performed a case review of a female presenting in late infancy with a central nervous system teratoma, that later was complicated by a right hemispheric middle cerebral artery (MCA)stroke, associated with a CDKN2A germline mutation. RESULTS This 14month old female presented with transient alterations of consciousness and apparent abdominal migraine events with pernicious vomiting. Neuroimaging revealed a right heterogeneous para- suprasellar mass and bilateral complex arachnoid adjacent cysts. She was observed closely for any progression, as the lesion was immediately adjacent to the optic chiasm. One year after presentation, she developed an acute ischemic right middle cerebral artery (MCA) stroke and had radiographic evidence of severe stenosis and decreased flow primarily within the right supra-clinoid internal carotid artery, the M1 segment and portion of the right A1 segment of cerebral vessels, with decreased enhancement and number of vessels in the distal right MCA territory. The vessels did not appear to be compressed by any mass effect. The radiologic appearance was consistent with vasospasm. The patient upon stoke recovery, underwent near- complete resection of the mass with no evidence of disruption of the capsule surrounding it and no vascular infiltration. Pathology revealed the expected teratoma with prominence of pancreatic acinar structures, and molecular evidence of a variant of CDKN2A, which was present in the patient and mother in the germline. CONCLUSION We propose that the imaging evidence of a vasculopathy was related to the genotype at the cyclin- dependent kinase site.

A-265 - Phenocopies in melanoma families with germline mutations in CDKN2A are associated to MC1R polymorphisms and high total body nevus count

A-265 - Phenocopies in melanoma families with germline mutations in CDKN2A are associated to MC1R polymorphisms and high total body nevus count

Germline mutations in pediatric cancer cohort with mixed-ancestry Mexicans.

Childhood cancer is one of the primary causes of disease-related death in 5- to 14-year-old children and currently no prevention strategies exist to reduce the incidence of this disease. Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed-ancestry Mexican pediatric patients with solid and hematological cancers. We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole-exome sequencing. All variants were identified following GATK best practices. We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed-ancestry Mexicans. This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.

Prognosis of CDKN2A germline mutation in patients with familial melanoma: a systematic review and meta-analysis.

Familial melanoma is defined as melanoma occurring in two or more first-degree relatives by the WHO. Germline mutations are isolated in a subset of them. It is well known that CDKN2A is the most frequently mutated high-risk gene in familial melanoma, however, the prognosis it confers to patients who carry its mutations is still controversial. This review aims to assess whether germline mutations imply a worse prognosis in patients with familial melanoma. A systematic review and meta-analysis were conducted by searching the electronic databases PubMed/MEDLINE, EMBASE, and Cochrane Library. Data from 3 independent populations were eventually included in the meta-analysis, involving 291 cases and 57 416 controls. The results of this systematic review and meta-analysis suggest that there is a tendency for patients with germline mutations in the CDKN2A gene to have a worse overall survival (HR = 1.30, 95% CI = 0.99-1.69, P = 0.05) and melanoma-specific survival (HR = 1.5, 95% CI = 0.97-2.31, P = 0.07). Carrier patients would not only have more incidence of melanoma and a higher risk of a second melanoma, but they also seem to have a worse prognosis. The inclusion of gene panel testing in clinical practice and the collaboration within consortia are needed to provide further evidence on the prognosis of these patients.

Oral Squamous Cell Carcinoma (OSCC) in a Patient with CDKN2A Germline Mutation

Oral Squamous Cell Carcinoma (OSCC) in a Patient with CDKN2A Germline Mutation

Single-cell and bulk RNA sequencing identifies T cell marker genes score to predict the prognosis of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal malignancies, with limited biomarkers identified to predict its prognosis and treatment response of immune checkpoint blockade (ICB). This study aimed to explore the predictive ability of T cell marker genes score (TMGS) to predict their overall survival (OS) and treatment response to ICB by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data. Multi-omics data of PDAC were applied in this study. The uniform manifold approximation and projection (UMAP) was utilized for dimensionality reduction and cluster identification. The non-negative matrix factorization (NMF) algorithm was applied to molecular subtypes clustering. The Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was adopted for TMGS construction. The prognosis, biological characteristics, mutation profile, and immune function status between different groups were compared. Two molecular subtypes were identified via NMF: proliferative PDAC (C1) and immune PDAC (C2). Distinct prognoses and biological characteristics were observed between them. TMGS was developed based on 10 T cell marker genes (TMGs) through LASSO-Cox regression. TMGS is an independent prognostic factor of OS in PDAC. Enrichment analysis indicated that cell cycle and cell proliferation-related pathways are significantly enriched in the high-TMGS group. Besides, high-TMGS is related to more frequent KRAS, TP53, and CDKN2A germline mutations than the low-TMGS group. Furthermore, high-TMGS is significantly associated with attenuated antitumor immunity and reduced immune cell infiltration compared to the low-TMGS group. However, high TMGS is correlated to higher tumor mutation burden (TMB), a low expression level of inhibitory immune checkpoint molecules, and a low immune dysfunction score, thus having a higher ICB response rate. On the contrary, low TMGS is related to a favorable response rate to chemotherapeutic agents and targeted therapy. By combining scRNA-seq and bulk RNA-seq data, we identified a novel biomarker, TMGS, which has remarkable performance in predicting the prognosis and guiding the treatment pattern for patients with PDAC.

Abstract 5219: Frequency of germline mutations in Mexican children with cancer

Abstract Childhood cancer is a leading cause of death by disease in children from 5 -14 ages, for whom there are no prevention strategies. Due to early-age of diagnosis and short-time environmental factors exposition, increasing evidence suggests childhood cancer could have stronger association with germline alterations in predisposition cancer genes. It has been estimated that up to 30% all childhood cancer diagnosis may be caused by germline variants, but their frequency and distribution remain unclear. Elucidating the prevalence and role of germline mutations in the development of childhood cancer is crucial for understanding its bases, causes, cancer-risk reduction plan, surveillance, and treatment. Here, we present a pilot study on cancer children’s patients and their relatives. A total of 40 Mexican-mestizo children with any cancer diagnosis were recruited from several Institutions of Health in Mexico and a sample of saliva or blood was obtained. Whole Exome Sequencing was performed and bioinformatic analysis was carried out following GATK best practices for germline genetic variants. Additionally, we evaluated a risk selection tool for recognition of genetic predisposition in pediatric cancer patients. Pathogenic or likely-pathogenic genetic variants (mutations) were identified from the application of a filtering chain based on ACMG guidelines, and they were subsequently validated by Sanger sequencing. Germline mutations in MSH6, NF1, MUTYH, CDKN2A, CHEK2, DICER1, FANCA and SBDS genes were identified in 5/40 (12.5%) patients with cancer, only 3 of 5 index cases (60%) reported family history of cancer and all patients meet at least one criterion of the risk selection tool. Two patients were carriers of one mutation, while in three patients were identified 2 pathogenic variants. Additionally, we identified four nonsense candidate genetic variants on EWSR1, FANCL, EPCAM and HRAS genes and two pathogenic variants in non-cancer predisposition gene, ABCA4. Our results show for the first time a higher frequency (12.5%) of germline mutations in cancer predisposition genes in Mexican-mestizo children with cancer. The lack of family history in two carriers showed the need to establish standardized suspicion criteria for identification of children with higher risk of cancer who can benefitfrom genetic testing. Further characterization of additional genetic variants identified without clinical classification will be important to evaluate their real contribution, as well as the influence of environmental factors on de novo mutation promotion. Citation Format: Oscar Alonso Luna, Jorge Meléndez Zajgla, Marta Zapata Tarres, Luis Enrique Juárez Villegas, Elvia Cristina Mendoza Caamal, Elianeth Rey Helo, Socorro Aida Borges Yanez, Gabriela Elisa Mercado Celis, Rodrigo Barquera Lozano. Frequency of germline mutations in Mexican children with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5219.

The use of digital dermoscopy in the surveillance of melanocytic skin lesions: A real-life retrospective study comparing university hospital and private practices

BackgroundFew studies have evaluated the role of digital dermoscopy (DD) in the surveillance of pigmented lesions in real-life practice. Patients and methodsPatients followed with DD by 4 hospital dermatologists (group 1) and 4 private dermatologists (group 2) were retrospectively included if they had had at least 2 DD examinations for a minimum of 4 pigmented lesions. Their characteristics, risk factors, history of excision of benign nevi and melanomas prior to and during the DD follow-up, and characteristics of detected melanomas, were recorded. ResultsOne hundred and ninety-six patients were included in group 1 and 205 in groups 2. A family history of melanoma (25% vs. 12%, p<0.01), a personal history of melanoma before DD follow-up (47% vs. 15%, p<0.01), and a family (3% vs. 0%, p=0.01) and personal (8% vs. 1%, p<0.01) germline CDKN2a mutation were more frequent in group 1 than in group 2. In both groups, the number of excisions of benign lesions was higher before DD follow-up (380 and 347, respectively) than during DD follow-up (194 and 132). During follow-up, 29 melanomas were detected in group 1, with a median Breslow thickness of 0.4mm, versus 1.3mm for melanomas diagnosed before DD follow-up (p<0.02). In group 2, 4 melanoma and 5 superficial atypical melanocytic proliferations of unknown significance were detected. The median Breslow thickness of newly diagnosed melanomas was 0.35mm vs. 0.6mm before DD follow-up (p=0.1). ConclusionIn both populations in real-life practice, DD seemed to allow the detection of thin melanomas and to decrease the rate of “futile” resections.

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals

BackgroundSurveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. MethodsIndividuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. Results165 individuals (“FPC-cohort” N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected.Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. ConclusionSerum N-glycan monitoring may support early detection in a pancreas surveillance program.

Molecular Features and Clinical Management of Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer.

Hereditary pancreatic cancers are caused by several inherited genes. Familial pancreatic cancer is defined as pancreatic cancer arising in a patient with at least two first-degree relatives with pancreatic cancer in the absence of an identified genetic cause. Hereditary pancreatic cancer syndromes and familial pancreatic cancers account for about 10% of pancreatic cancer cases. Germline mutations in BRCA1, BRCA2, ATM, PALB2, CDKN2A, STK11, and TP53 and mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are among the well-known inherited susceptibility genes. Currently available targeted medications include poly (ADP-ribose) polymerase inhibitors (PARP) for cases with mutant BRCA and immune checkpoint inhibitors for cases with mismatch repair deficiency. Loss of heterozygosity of hereditary pancreatic cancer susceptibility genes such as BRCA1/2 plays a key role in carcinogenesis and sensitivity to PARP inhibitors. Signature 3 identified by whole genome sequencing is also associated with homologous recombination deficiency and sensitivity to targeted therapies. In this review, we summarize molecular features and treatments of hereditary pancreatic cancer syndromes and surveillance procedures for unaffected high-risk cases. We also review transgenic murine models to gain a better understanding of carcinogenesis in hereditary pancreatic cancer.

Abstract IA-40: CDKN2A germline rare coding variants and risk of pancreatic cancer in minority populations

Abstract Performing genetic epidemiology studies in underrepresented populations is challenging, but is extremely important in order to understand how cancer impacts differing populations, This can then allow more tailored and nuanced management of persons at risk. Our group at Mayo Clinic encountered some interesting preliminary findings regarding CDKN2A, but given small numbers of subjects in our registry, we needed to partner with other collaborators to have enough statistical power to make sense of the findings and generate a publishable result. This talk will focus on the means of doing this, the importance of team-based science across centers, and future opportunities. Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites. WeTo date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects. Methods: We performed a case-control study of germline mutations in CDKN2A among patients with incident pancreatic cancer and controls, focused on underrepresented minority populations. We sequenced CDKN2A in 220 African American pancreatic cancer cases, 900 noncancer African American controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 Non-Hispanic White patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in African Americans versus Non-Hispanic Whites, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced. Race/ethnicity categorization was from self-report. Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G&amp;gt;A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P ¼ 0.004) compared with African American and Nigerian controls (17/1,083). Further, African American cases had higher frequency of RCVs: 5.0% (OR, 13.4;95%CI, 4.9–36.7; P &amp;lt; 0.001) compared with Non-Hispanic White cases (0.4%). Conclusions: CDKN2A RCVs are more common in African Americans than in Non-Hispanic White patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among African Americans. Citation Format: Robert McWilliams. CDKN2A germline rare coding variants and risk of pancreatic cancer in minority populations [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA-40.

Hereditary oral squamous cell carcinoma associated with CDKN2A germline mutation: a case report

BackgroundGermline CDKN2A mutations are a well-known cause of familial atypical multiple mole melanoma (OMIM #155601) and melanoma-pancreatic cancer syndrome (OMIM #606719). Increased risk of head and neck squamous cell carcinoma (HNSCC), particularly oral squamous cell carcinoma (OSCC) in those with germline CDKN2A mutations, has been described. However, screening for HNSCC is not a routine practice in patients with CDKN2A germline mutations and these mutations are not a conventional test for HNSCC patients without obvious risk factors.Case presentationWe describe a female with no smoking history who developed oral squamous cell carcinoma at age 39 and had a complex clinical course of recurrent multifocal squamous cell carcinoma (SCC) and carcinoma in situ of the oral cavity and oropharynx. Detailed family history demonstrated that her mother was diagnosed with OSCC and melanoma in her 40 s, and her maternal grandfather was diagnosed with metastatic melanoma in his 40 s. Genetic testing of the patient and her mother revealed CDKN2A c.301G>T mutation. She was referred to genetic counseling as well as to dermatology, gastroenterology, and neurology for cancer surveillance. She was treated with resections and has no evidence of disease 3 years after diagnosis.ConclusionsWe report a family with a CDKN2A c.301 G>T mutation who also have significant history of OSCC, adding to the growing body of literature suggesting increased risk of HNSCC, particularly OSCC, in CDKN2A germline mutation carriers. It is important to consider CDKN2A mutation testing in familial HNSCC and young patients without obvious risk factors. Moreover, surveillance for HNSCC should be routine practice in those with a CDKN2A germline mutation.Graphical abstract

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

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

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Cutaneous Melanomas Arising during Childhood: An Overview of the Main Entities.

Cutaneous melanomas are exceptional in children and represent a variety of clinical situations, each with a different prognosis. In congenital nevi, the risk of transformation is correlated with the size of the nevus. The most frequent type is lateral transformation, extremely rare before puberty, reminiscent of a superficial spreading melanoma (SSM) ex-nevus. Deep nodular transformation is much rarer, can occur before puberty, and must be distinguished from benign proliferative nodules. Superficial spreading melanoma can also arise within small nevi, which were not visible at birth, usually after puberty, and can reveal a cancer predisposition syndrome (CDKN2A or CDK4 germline mutations). Prognosis is correlated with classical histoprognostic features (mainly Breslow thickness). Spitz tumors are frequent in adolescents and encompass benign (Spitz nevus), intermediate (atypical Spitz tumor), and malignant forms (malignant Spitz tumor). The whole spectrum is characterized by specific morphology with spindled and epithelioid cells, genetic features, and an overall favorable outcome even if a regional lymph node is involved. Nevoid melanomas are rare and difficult to diagnose clinically and histologically. They can arise in late adolescence. Their prognosis is currently not very well ascertained. A small group of melanomas remains unclassified after histological and molecular assessment.

The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of CDKN2A and CDK4

Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking. We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries]. Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings (P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families. Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families. The study findings support the clinical benefit of screening (physician and self) for this high-risk population.

A rare germline CDKN2A variant (47T>G; p16-L16R) predisposes carriers to pancreatic cancer by reducing cell cycle inhibition

Germline mutations in CDKN2A, encoding the tumor suppressor p16, are responsible for a large proportion of familial melanoma cases and also increase risk of pancreatic cancer. We identified four families through pancreatic cancer probands that were affected by both cancers. These families bore a germline missense variant of CDKN2A (47T>G), encoding a p16-L16R mutant protein associated with high cancer occurrence. Here, we investigated the biological significance of this variant. When transfected into p16-null pancreatic cancer cells, p16-L16R was expressed at lower levels than wild-type (WT) p16. In addition, p16-L16R was unable to bind CDK4 or CDK6 compared with WT p16, as shown by coimmunoprecipitation assays and also was impaired in its ability to inhibit the cell cycle, as demonstrated by flow cytometry analyses. In silico molecular modeling predicted that the L16R mutation prevents normal protein folding, consistent with the observed reduction in expression/stability and diminished function of this mutant protein. We isolated normal dermal fibroblasts from members of the families expressing WT or L16R proteins to investigate the impact of endogenous p16-L16R mutant protein on cell growth. In culture, p16-L16R fibroblasts grew at a faster rate, and most survived until later passages than p16-WT fibroblasts. Further, western blotting demonstrated that p16 protein was detected at lower levels in p16-L16R than in p16-WT fibroblasts. Together, these results suggest that the presence of a CDKN2A (47T>G) mutant allele contributes to an increased risk of pancreatic cancer as a result of reduced p16 protein levels and diminished p16 tumor suppressor function.

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).

FRAMe: Familial Risk Assessment of Melanoma—a risk prediction tool to guide CDKN2A germline mutation testing in Australian familial melanoma

Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of individuals diagnosed with melanoma under 40years of age, number of individuals diagnosed with more than one primary melanoma, and number of individuals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of individuals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .

The tumor genetics of acral melanoma: What should a dermatologist know?

Dermatologists stand at the gateway of individualization of classification, treatment, and outcomes of acral melanoma patients. The acral melanoma genetic landscape differs in vital ways from that of other cutaneous melanomas. These differences have important implications in understanding pathogenesis, treatment, and prognosis. The selection of molecularly targeted therapy must be adapted for acral melanoma. It is also critical to recognize that tumor development is far more complex than an isolated event, reliably treated by a medication acting on a single target. Tumors exhibit intratumor genetic heterogeneity, metastasis may have different genetic or epigenetic features than primary tumors, and tumor resistance may develop because of the activation of alternative genetic pathways. Microenvironmental, immune, and epigenetic events contribute and sustain tumors in complex ways. Treatment strategies with multiple targets are required to effectively disrupt the tumor ecosystem. This review attempts to translate the current molecular understanding of acral melanoma into digestible concepts relevant to the practice of dermatology. The focus is tumor genetics defining potentially treatable cancer pathways, contextualized within the relevant pathologic and molecular features.