Melanoma Syndrome Research Articles

Multiple outcomes of the germline p16INK4a mutation affecting senescence and immunity in human skin.

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts invitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types invivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance invivo.

Abstract C123: Exploring the cancer phenotype of a potential CDKN2A founder variant, c.146T>C (p.Ile49Thr), in Hispanic/Latinos of predominately Mexican ancestry

Abstract BACKGROUND: CDKN2A germline pathogenic/likely pathogenic variants (PVs) cause familial atypical multiple mole melanoma syndrome, which increases melanoma (MEL) and pancreatic cancer (PC) risk. The interpretation of genetic test results can be complicated by discordant variant classifications. CDKN2A c.146T>C (ClinVar ID:127523) is such a variant and is classified as likely pathogenic at some laboratories and as uncertain at others. Furthermore, the variant frequency in Hispanic/Latinos (H/Ls) is higher than typically expected for a PV in CDKN2A and some functional studies support that it is a PV. METHODS: Genetic counseling databases at various institutions were queried for demographic, personal and family cancer history data for individuals with known PVs in CDKN2A, with c.146T>C, and c.–2G>A (ClinVar ID:141245), a benign CDKN2A variant (BV) seen in H/Ls to serve as a comparator. The association between personal and/or family history of PC and/or MEL and demographic/clinical characteristics was tested using Fischer exact test, Chi-square test, and post-hoc test with ANOVA. Odds ratios were calculated with multinomial logistic regression. RESULTS: Overall, 219 individuals were identified; 109 with c.146T>C, 60 with other CDKN2A PVs, and 50 with the BV; 82% were female, 76% H/L, and 70% had a personal cancer history – 18% (n=27) had MEL and 10% (n=16) had PC. By variant group, 99% (c.146T>C) and 96% (BV) were H/L; 85% and 84% of Mexican ancestry, respectively. MEL was reported in 38% (n=22) of other PVs, 5% (n=5) of c.146T>C, and not at all in the BV group. Those with c.146T>C were 92% less likely to have MEL than other CDKN2A PVs (p<0.001), with no difference in mean age at diagnosis, 32y vs. 40y, respectively (p=0.71). Seven (12%) of other PVs had PC compared to 6% (n=7) of c.146T>C and 4% (n=2) of the BV. While this difference was not significant (p=0.27), the mean age at diagnosis in c.146T>C was significantly younger than other PVs (32y vs. 71y; p=0.02). When including family history, those with c.146T>C were 80% less likely to have a personal AND family history of MEL than other PVs (p<0.001), but the odds of having both a personal AND family history of PC was not significantly different (p=0.52). CONCLUSION: In the largest CDKN2A c.146T>C study (n=109) to date, MEL was significantly less frequent in individuals with this variant compared to other PVs CDKN2A. A similar, non-significant, trend was seen for PC. Notably, individuals with c.146T>C who developed PC presented at a significantly younger age than individuals with other CDKN2A PVs. The presence of c.146T>C in H/Ls of mostly Mexican ancestry suggests it may be a founder variant. While more research is needed to further refine cancer penetrance and associations, the conservative approach is to manage c.146T>C as per CDKN2A PV guidelines. Given the frequency of this variant in genomic databases, clarifying clinical impact is vital for risk- appropriate management and to reduce existing cancer disparities faced by many H/Ls. Citation Format: Daisy Hernandez, Ashlie Browning, Amber Gemmell, Karlena Lara-Otero, Mariana Niell-Swiller, Kathyrn A. Mraz, Amie Blanco, Yvonne Cardona, Emmeline Chang, Jacob Comeaux, Julie O. Culver, James M. Ford, Natalia Gutierrez, Daniella Kamara, Beth Y. Karlan, Ming Li, Jacqueline Mersch, Qi Nie, Maria L. Wei, Charité N. Ricker. Exploring the cancer phenotype of a potential CDKN2A founder variant, c.146T>C (p.Ile49Thr), in Hispanic/Latinos of predominately Mexican ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C123.

Two Japanese families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A: a case report

BackgroundGermline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) (OMIM #155,601), which is associated with an increased risk of pancreatic ductal adenocarcinoma and melanoma. FAMMM has been reported globally, but it is quite rare in Japan. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling.Case presentationThe first case is a 74-year-old woman with a diagnosis of pancreatic carcinoma with multiple liver metastases. She had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. Whole exon sequencing detected a germline CDKN2A variant evaluated as likely pathogenic. The results were disclosed to her daughters after she died, and the same CDKN2A variant was detected in one of the daughter. The daughter was referred to a nearby hospital for her clinical management. The second case is a 65-year-old man with pancreatic ductal adenocarcinoma. He had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. He underwent a comprehensive genomic profiling test using pancreatic cancer tissue, and detected a presumed germline pathogenic variant of CDKN2A. Germline testing confirmed the same CDKN2A variant. Genetic analysis of his relatives produced negative results. Other blood relatives are scheduled for genetic analysis in the future. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling.ConclusionsIn current Japanese precision medicine, comprehensive genetic analysis can reveal rare genetic syndromes and offer us the opportunity to provide health management for patients and their relatives. However, gene-specific issues are raised in terms of the evaluation of a variant’s pathogenicity and the extent of surveillance of the at-risk organs due to a lack of genetic and clinical data concerning CDKN2A variant carriers in Japan.

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients

Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, such as ACD, TERF2IP, and TERT. We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel (ACD, BAP1, CDK4, CDKN2A, POT1, TERT, TERF2IP, MC1R, and MITF). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families.

Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance.

687 Background: The international, multi-center Pancreatic Cancer Early Detection (PRECEDE) Consortium enrolls high-risk individuals (HRIs) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Enrollment began in 2020, and despite challenges related to the COVID-19 pandemic, the PRECEDE Consortium rapidly accrued a large cohort of HRIs. The purpose of this study is to describe the characteristics of this cohort and assess racial, ethnic, and sex-based disparities. Methods: The PRECEDE Consortium (NCT04970056) is a prospective, multicenter study focused on improving survival from PDAC through early detection. Data from all HRIs who met criteria for PDAC surveillance and enrolled between May 2020 - March 2022 were collected and included in the analysis. Results: During the study period, 1299 HRIs enrolled in PRECEDE at 32 centers. HRIs were excluded if enrollment data was incomplete or criteria for PDAC surveillance were not met. Of 1113 who were included, 47.2% met criteria for familial pancreatic cancer (FPC) and 45.4% had a family history of PDAC along with a PV in a PDAC-risk gene (BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). The remainder had familial atypical mole melanoma syndrome (5.7%), Peutz-Jeghers syndrome (1.6%), or hereditary pancreatitis (0.2%). More females than males enrolled (65.9% vs. 33.5%). The distribution of HRIs by race and ethnicity is depicted; the majority identified as white (87.7%). Study participants were primarily from the US (82.7%), the median age was 61 (27-85) and 18.5% had Ashkenazi Jewish ancestry. Nearly all HRIs consented to allow access to imaging data (99.6%), collection of germline DNA (97.7%), and biosample collection (99.5%). There were no race, ethnicity, or sex-based differences in rates of consent for collection of imaging, DNA, or biosamples. Conclusions: Enrollment of HRIs in prospective studies of PDAC surveillance is essential for advancing early detection research in PDAC. A distinct advantage of the PRECEDE Consortium for examining enrollment disparities is that recruitment began in 2020, providing a unique and current snapshot of the international PDAC surveillance landscape. Despite the recent attention on addressing disparities in healthcare delivery, significant racial, ethnic, and sex-based disparities persisted in the cohort of HRIs enrolled in the PRECEDE Consortium. Ensuring that the diversity of participants in the PRECEDE Consortium mirrors the communities served by participating centers is crucial. Further examining and addressing the reasons for these disparities is a major focus of the PRECEDE Consortium moving forward. [Table: see text]

Tebentafusp (Kimmtrak)


 CADTH recommends that Kimmtrak be reimbursed by public drug plans for the treatment of unresectable or metastatic uveal melanoma (mUM) if certain conditions are met.
 Kimmtrak should only be covered to treat adults with uveal melanoma whose cancer cannot be removed by surgery or has spread and who have tested positive for the HLA-A*02:01 gene. Patients receiving Kimmtrak should be in relatively good health (i.e., have a good performance status, as determined by a specialist). Cancer in central nervous system should either be controlled or that there be no spread of cancer to the brain at all.
 Kimmtrak should only be reimbursed if prescribed by a specialist with expertise in managing uveal melanoma and cytokine release syndrome, and the cost of Kimmtrak is reduced.

The management of hereditary melanoma, FAMMM syndrome and germline CDKN2A mutations: a narrative review

Familial atypical multiple mole melanoma (FAMMM) syndrome is a rare autosomal dominant disorder, in which patients present with a large number of melanocytic naevi and a strong history of malignant melanoma, usually at a young age. The most common genetic alteration, implicated in 40 per cent of FAMMM syndrome families, is a mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A).1 CDKN2A encodes the tumour suppressor gene p16INK4a, a critical cell cycle inhibitor.2 The diagnosis and management of patients with FAMMM syndrome is relevant to the plastic surgeon who manages melanoma. However, clear guidelines on its diagnostic criteria and its relationship to associated but distinct syndromes, such as hereditary melanoma and B-K mole syndrome, are lacking in the extant literature. The aim of this review is to clarify the diagnostic criteria and management principles for FAMMM syndrome. We propose a new system of classifying FAMMM syndrome patients as a subset of all patients with hereditary melanoma. We also present a management algorithm for these distinct patient groups (FAMMM syndrome, hereditary melanoma and germline CDKN2A mutations).

Awareness, knowledge, and attitudes towards sun protection among patients with melanoma and atypical mole syndrome.

BACKGROUNDPatients with atypical mole syndrome (AMS) have a 3- to 20-fold higher risk of developing malignant melanoma (MM) than individuals without. The most modifiable risk factor for developing MM is the ongoing ultraviolet exposure.AIMTo assess awareness, knowledge, and attitudes towards sun protection among patients with MM and AMS.METHODSFrom January 2020 till December 2021, a written survey was administered to patients with MM and AMS and a control group who attended a specialist mole clinic at the Dermatology Department of the University Hospital of Heraklion in Heraklion, Crete, Greece. Demographic data and photoprotective practices, knowledge, and perceived barriers were collected. Relevant statistical analyses were performed using SPSS IBM 25.RESULTSIn total, 121 subjects consented and participated in the survey. Their mean age was 43.92 ± 12.55 years. There were 66 (54.4%) females and 55 (45.4%) males. Forty-seven (38.8%) patients had AMS, 26 (21.5%) had a past medical history of MM, and 48 (39.7%) attended the clinic for a full skin checkup for their naevi without having AMS or MM. Although 104 (86%) participants reported using sunscreen with the majority of them (59/121 = 48.8%) wearing sunscreen with a sun protection factor of > 50, only 22 (18.2%) patients did so every day and only 20 (16.5%) all year round. Approximately 74.4% of patients recalled having received advice on how to protect their skin from sunlight, and 73% were interested in receiving education about sun protection. The most mentioned barriers in photoprotection were concerns over adequate vitamin D and lack of time. CONCLUSIONDespite mentioning having received adequate education in photoprotection, adherence to photoprotection practices is suboptimal in patients with MM and AMS.

Germline predisposition in oncologic and dermatologic melanoma cohorts.

10523 Background: Melanoma has recently been suggested to be a highly heritable cancer with high twin-twin concordance. In contrast, prior studies on patients with familial atypical multiple mole melanoma (FAMMM) syndrome, multiple primary melanomas and early age of onset, all known to be associated with germline CDKN2A/CDK4 pathogenic variants, suggest that individuals with melanoma who carry germline alterations are rare. We studied the overall prevalence of germline cancer predisposition in a large prospective oncologic cohort with comparison to other defined cohorts of individuals with melanoma with available germline data. Methods: Individuals who presented to medical oncology clinic with a diagnosis of melanoma and personal or family history of multiple cancers were offered germline testing with a commercially available next generation sequencing panel (Invitae, San Francisco, CA). Eligibility criteria required ≥ 2 melanomas in an individual or family; melanoma and other cancer(s) in an individual; melanoma and at least 2 other cancers in 1st- or 2nd-degree relatives; age ≤35 at diagnosis; or limited family structure. Comparative analysis of germline NGS data from 3 additional selected and non-selected melanoma datasets was performed. Results: In a cohort of 400 oncology patients with melanoma who consented to commercial germline testing of 85 cancer-associated genes, a germline pathogenic/likely pathogenic (gP/LP) positive rate of 15.3% (n = 61) was observed. Genes previously associated with inherited melanoma ( BAP1, BRCA1/2, CDKN2A, MITF, TP53) comprised less than one-third of gP/LP variants (20, 32.7%); the majority of germline variants were in cancer predisposition genes not traditionally associated with melanoma (e.g. BRIP1, CHEK2, MSH2, PMS2, MLH1, RAD51C, BLM). Family history of non-cutaneous cancer (42, 69%) and personal history of melanoma with ≥ 1 non-cutaneous cancer (22, 36%) were the most common eligibility criteria met in gP/LP variant carriers. Analysis of germline data from other large oncologic and dermatologic melanoma datasets yielded gP/LP variant positive rates of 10.6% in an unselected oncologic melanoma cohort (TCGA, n = 470), 15.8% in a selected commercial testing cohort (Invitae, n = 12,571), and 14.5% in a highly selected, primarily dermatologic subset (Boston-Athens, n = 289). Conclusions: In oncologic and dermatologic cohorts, germline testing of selected individuals with melanoma yields rates of clinically impactful P/LP variant detection which exceed consensus standards for pretest probability. Most P/LP variants were found in genes associated with non-cutaneous cancers. Obtaining a family and personal history of cancer, particularly non-cutaneous cancers, and referring for broad panel-based germline testing in all individuals with melanoma are recommended.

Poly Adenosine Diphosphate-Ribose Polymerase (PARP) Inhibitors in Pancreatic Cancer.

Pancreatic cancer is the third most common cause of cancer death in the United States and eleventh worldwide. The majority of patients present with advanced disease with five-year overall survival of less than 10%. Traditional chemotherapy has been the mainstay treatment for years, with limited improvement in survival. Relative success has been achieved with agents targeting the DNA damage repair (DDR) mechanisms with poly adenosine diphosphate-ribose polymerase (PARP) inhibitors. The initial benefit was observed in patients with germline breast cancer-associated (BRCA) mutations. Multiple trials are now underway exploring PARP inhibitors in other DDR mutations such as the ataxia-telangiectasia mutated (ATM) gene and the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene (familial atypical multiple mole and melanoma syndrome), mismatch repair genes (Lynch syndrome), and others. PARP inhibitors are being evaluated as a single agent or combination chemotherapy, immunotherapy, and maintenance after chemotherapy. Here, we review current clinical trials targeting various DDR mutations and treatment strategies.

CDKN2A-positive melanoma patient treated with combination immunotherapy – A case report

Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.

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

Epidemiology and Risk Factors of Melanoma: A Review.

We are currently witnessing a worldwide increase in the incidence of melanoma. Incidence in Europe is about 25 cases per 100,000 population, while in Australia it reaches a rate of 60 new cases per 100,000. While the epidemiological curves of the 1980's and 1990's suggested an increase in the incidence of melanoma across all age groups, the last 10 years' data indicates a 5% reduction in the incidence of thin melanoma in young individuals aged between 15 and 24. This suggests a positive impact of primary prevention campaigns [1-2]. The risk factors associated with melanoma are different and multifactorial: on one hand there is a genetic predisposition, as evidenced by the increased risk in patients with dysplastic nevus syndrome, with familial melanoma or familial melanoma syndromes; on the other hand, the unprotected interaction between UV rays and phototypes I-II increases the risk of developing melanoma, especially in case of sunburns in pediatric age. This review aims to summarize melanoma epidemiology and risk factors.

Pancreas in Hereditary Syndromes: Cross-sectional Imaging Spectrum.

A wide spectrum of hereditary syndromes predispose patients to distinct pancreatic abnormalities, including cystic lesions, recurrent pancreatitis, ductal adenocarcinoma, nonductal neoplasms, and parenchymal iron deposition. While pancreatic exocrine insufficiency and recurrent pancreatitis are common manifestations in cystic fibrosis and hereditary pancreatitis, pancreatic cysts are seen in von Hippel-Lindau disease, cystic fibrosis, autosomal dominant polycystic kidney disease, and McCune-Albright syndrome. Ductal adenocarcinoma can be seen in many syndromes, including Peutz-Jeghers syndrome, familial atypical multiple mole melanoma syndrome, Lynch syndrome, hereditary breast and ovarian cancer syndrome, Li-Fraumeni syndrome, and familial pancreatic cancer syndrome. Neuroendocrine tumors are commonly seen in multiple endocrine neoplasia type 1 syndrome and von Hippel-Lindau disease. Pancreatoblastoma is an essential component of Beckwith-Wiedemann syndrome. Primary hemochromatosis is characterized by pancreatic iron deposition. Pancreatic pathologic conditions associated with genetic syndromes exhibit characteristic imaging findings. Imaging plays a pivotal role in early detection of these conditions and can positively affect the clinical outcomes of those at risk for pancreatic malignancies. Awareness of the characteristic imaging features, imaging-based screening protocols, and surveillance guidelines is crucial for radiologists to guide appropriate patient management. ©RSNA, 2021.

Germline POT1 Variants Can Predispose to a Variety of Hematologic Neoplasms

Germline mutations in the shelterin component protection of telomeres 1 (POT1) were recently found to be associated with familial chronic lymphocytic leukemia (CLL), melanoma, glioma, and several other familial cancer syndromes. The role of POT1 mutations in myeloid neoplasms and other hematologic malignancies, however, remains unknown. To explore the role of POT1 variants in hematologic neoplasms, we analyzed POT1 variants in 3323 consecutive patients who underwent next-generation sequencing (NGS) of a panel of hematologic malignancy-associated genes at our institution and characterized the clinical and pathological characteristics of patients with germline and somatic POT1 mutations. Of 3323 consecutive patients who underwent NGS, 2770 patients had a hematologic malignancy (lymphoid n = 1299, myeloid n = 934, and both lymphoid and myeloid n = 537), while 553 patients were evaluated for non-malignant cytopenias. All 57 patients (2.06%) carrying either a POT1 disease-associated variant or variant of uncertain significance had a hematologic malignancy compared to no identified POT1 variants in 553 patients with benign cytopenias (OR = 23.5, p < 0.001), suggesting that the presence of POT1 variants was predictive of a hematologic malignancy. Of 57 patients, 33 had lymphoid malignancies, 23 had myeloid neoplasms, and 2 had a lymphoid and myeloid neoplasm (Fig 1). Patient variants were classified as germline or somatic using constitutional DNA sequencing, POT1 emergence/disappearance over time, or POT1 maintenance in remission. In the absence of these data, likely germline or likely somatic designations were made by assessing variant allele frequencies against clinical/pathologic characteristics. 18 patients (33%) were found to have germline or likely germline POT1 variants (29% and 42% in the lymphoid and myeloid malignancy groups, respectively). Another 6 patients (11%) had variants whose germline status could not be determined. Of the 17 unique germline POT1 variants, 10 were missense and located within mapped functional protein domains, while 7 were classified as predicted loss-of-function (pLOF) due to a disruption of start, premature stop, frameshift, or spice site alteration. Patients with hematological malignancies had a ~5-8x increased odds of having a germline pLOF POT1 variant compared to cancer-free individuals in the Genome Aggregation Database (gnomAD, n = 113,108 exomes, OR = 7.5, p < 0.001) or in the Penn Medicine BioBank (PMBB, n = 7877, OR = 5.0, p = 0.010), with a prevalence of 0.25% compared to 0.03% and 0.05%, respectively. Germline pLOF POT1 variants were significantly more enriched in patients with myeloid (gnomAD: OR = 6.1, p = 0.02) and lymphoid (gnomAD: OR = 9.8, p < 0.001; PMBB: OR = 6.5, p = 0.004) malignancies. In 33 patients with lymphoid malignancies and POT1 variants, the most common diagnoses were CLL/SLL (n = 21, germline n = 6, somatic n = 12), CD5- CD10- indolent B cell neoplasms (n = 4, germline n = 1, somatic n = 3), and multiple myeloma (n = 3, all somatic) (Table 1). Lymphoid malignancies with a germline POT1 variant had a relative paucity of additional mutations; in contrast, somatic POT1 variants frequently co-occurred with other mutations, most commonly with TP53 (Fig 2, n = 5, 23%). Among 23 patients with myeloid malignancies, patients with germline POT1 variants developed malignancies at a significantly younger age compared to those whose POT1 variants were somatic (median age 59.5 vs 70.5 years, p = 0.04). The most common diagnosis in patients with myeloid neoplasms carrying germline POT1 variants was MPN (germline n = 5, somatic n = 1). AML, MDS/MPN, and MDS occurred in 4, 3, and 1 patients respectively. All patients with myeloid neoplasms had additional disease-associated mutations, with the most common co-occurring variants in TET2 (n = 7), JAK2 (n = 6, co-occurring with 50% of germline POT1 myeloid variants), and NRAS (n = 6). In conclusion, this is the first comprehensive analysis of POT1 variants in an unselected hospital-based population undergoing molecular testing for variants associated with hematologic malignancies. Our results show that the presence of POT1 variants is predictive of having a hematologic neoplasm and that over 30% of POT1 variants in hematologic malignancy patients are germline. Our study expands the spectrum of POT1-associated familial neoplasms and highlights the needs for better recognition of familial hematologic cancer syndromes. Disclosures No relevant conflicts of interest to declare.

Outcomes of endoscopic ultrasound as a one-off pancreatic cancer screening tool for 122 high- and moderate-risk patients.

Background and AimPancreatic cancer (PC) carries a poor prognosis and is often detected at later stages. Screening programs for moderate‐ and high‐risk people are still under debate. We present the results from a prospective study on endoscopic ultrasound (EUS) as a one‐off screening tool for pancreatic cancer screening.MethodsAsymptomatic patients with moderate‐ or high‐risk of PC were invited to participate. Moderate risk consisted of one first‐degree and at least one second‐degree relative with PC and no PC‐associated genetic mutations. High risk consisted of >1 first‐degree relatives with PC or PC‐associated mutations (i.e. BRCA2, Lynch Syndrome, Familial Atypical Multiple Mole Melanoma Syndrome, STK11, or PALB2). All included patients had genetic counseling and a screening EUS done. Primary outcome was the detection of PC on EUS. Secondary outcomes assessed the evolution of psychological symptoms based on the Impact of Events Scale (IES) and Personal Consequences Questionnaire (PCQ) before and after the screening took place.ResultsA total of 122 patients had a screening EUS performed between 2013 and 2019; 60 were male, 55.8 years was the mean age, 78 were at high risk for PC, and 25 had PC‐associated mutations. No pancreatic cancers were identified at the one‐off EUS screening. Overall, patients' IES/PCQ scores did not change after screening and feedback of no malignancy, with the exception of females (less concerned about PC after screening EUS).ConclusionsEUS did not detect any PCs in either a moderate‐ or high‐risk population as a one‐off screening method. The EUS procedure and genetic counseling improved psychological symptoms for the female subset of this population.

Reduction of T Lymphoma Cells and Immunological Invigoration in a Patient Concurrently Affected by Melanoma and Sezary Syndrome Treated With Nivolumab

Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients’ response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients’ response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).

Genetic predisposition to childhood cancer: A retrospective cohort analysis in a multidisciplinary genetic cancer counseling Unit.

e13643 Background: The incidence of childhood cancer in Spain is 18, 2 cases per 100.000 inhabitants per year. The presence of predisposing genetic factors has been revealed in approximately 10% of patients, in them the detection of genetic mutations associated is essential in order to establish the correct clinical management of patients and their relatives. However, genetic counseling in this population is currently underestimated since, not all patients with pediatric malignancies have a family history of cancer or other clinical signs to suspect and inheritance syndrome. Methods: The Unit for Predisposition to Child and Adolescent Cancer of the University Hospital La Paz in Madrid, Spain, is composed by the Units of Clinical Oncology, Pediatric Hemathology-Oncology, and Genetics. Inclusion criteria are based on the characteristics of the individual's neoplasia, family characteristics and other phenotypic characteristics.The molecular study is carried out through Next Generation Sequencing, Direct Sequencing and / or MLPA. In the present study, a retrospective and descriptive analysis of the cases studied from September 2018 to December 2019 was carried out. Results: The Pediatric Cancer Predisposition Functional Unit of the La Paz University Hospital attended during the years 2018 and 2019 a 58 patients with suspected predisposition syndromes to childhood cancer belonging to 41 families. The following inheritance syndromes have been identified: hereditary retinoblastoma in 14 families with mutation in the RB1 gene, Li Fraumeni syndrome in 1 family with mutation in the TP53 gene, multiple endocrine neoplasia type 2A by RET gene mutation in 1 family, 1 hereditary melanoma syndrome with a CDKN2A mutation, and inheritance family leukemia in 1 family with a PAX5 gene mutation. Other cases studied have been negative-non informative, with the following neoplasms of the index cases: unilateral retinoblastoma, hepatoblastoma, hamartomatous colon polyposis, lymphoma, leukemia and soft tissue sarcoma. In addition to the molecular diagnosis of the index case, both cases and family members received genetic counseling and adequate clinical management, adapted to each syndrome. Conclusions: The multidisciplinary and specialized approach improves the diagnosis and monitoring of patients with suspected syndromes of predisposition to childhood cancer and allows the establishment of prevention strategies and early diagnosis individualized to each family.

Characteristics of early-onset pancreatic cancer and its association with familial pancreatic cancer and hereditary pancreatic cancer syndromes.

The incidence of pancreatic cancer is high among those in their sixties to seventies but low in those in their fifties or younger. Although there is no unified definition regarding the age of early‐onset pancreatic cancer, previously published reports suggest that, compared to later‐onset pancreatic cancer patients, early‐onset pancreatic cancer patients tend to be detected at advanced stages and thus have poor prognoses, but they do not show significantly higher rates of patients with genetic factors. On the other hand, it has been reported that patients with familial pancreatic cancer and hereditary pancreatic cancer syndromes often develop pancreatic cancer at a young age. The broad definition of familial pancreatic cancer is pancreatic cancer in patients who have two or more first‐degree relatives with pancreatic cancer; whereas the narrow definition of familial pancreatic cancer is the broad definition of familial pancreatic cancer, while excluding those with inherited tumor syndromes. Hereditary tumors developing pancreatic cancer include hereditary pancreatitis, hereditary breast and ovarian cancer, Peutz‐Jeghers syndrome, familial atypical multiple mole melanoma syndrome, familial adenomatous polyposis, and hereditary non‐polyposis colorectal cancer, all of which are autosomal dominant hereditary diseases. This study reviews the clinical characteristics of early‐onset pancreatic cancer and its association with familial pancreatic cancer and hereditary pancreatic cancer syndromes.

Development of esophageal squamous cell cancer in patients with FAMMM syndrome: Two clinical reports

Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary syndrome characterized by multiple dysplastic nevi and melanoma. Patients with FAMMM may have a heterozygous, inactivating, pathogenic germline variant in the CDKN2A gene, especially the NM_000077.4: c.225_243del19 (p.p75fs) variant, also known as p16-Leiden variant. Patients with this variant are at high risk for developing melanomas and pancreatic cancer due to somatic inactivation of the wild-type CDKN2A allele. The combination of an inactivating germline CDKN2A mutation and somatic inactivation of the wild-type CDKN2A allele in the same cell results in tumor formation. It has been suggested that carriers of a germline CDKN2A mutation are also at increased risk for several other cancer types, including esophageal cancer. Here, we describe two unrelated patients with the p16-Leiden variant who developed esophageal squamous cell cancer. Evidence of loss of the wild-type CDKN2A allele was obtained in the tumor tissue of both patients indicating biallelic inactivation of p16 in the tumor cells. These results suggest that these patients developed esophageal squamous cell cancer in the context of FAMMM syndrome.