Familial Atypical Multiple Mole Melanoma Research Articles

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.

CDKN2A Gene Mutations: Implications for Hereditary Cancer Syndromes.

Malignant neoplasms, including pancreatic cancer and melanoma, are major global health challenges. This study investigates melanoma pancreatic syndrome, a rare hereditary tumor syndrome associated with CDKN2A gene mutations. CDKN2A mutations contribute to a lifetime risk of melanoma ranging from 28% to 67%. This study reports the clinical features of six individuals with CDKN2A mutations and identifies recurrent alterations such as c.307_308del, c.159G>C and c.71G>C. It highlights the need for CDKN2A mutation testing in suspected cases of familial atypical multiple mole melanoma. Clinically significant variants show associations with melanoma and pancreatic cancer. The challenges of treating individuals with CDKN2A mutations are discussed, and the lack of specific targeted therapies is highlighted. Preclinical studies suggest a potential benefit of CDK4/6 inhibitors, although clinical trials show mixed results. This study underscores the importance of continued research into improved diagnostic and therapeutic strategies to address the complexities of hereditary cancer syndromes.

Germline Pathogenic Variants in Squamous Cell Carcinoma of the Head and Neck.

Head and neck squamous cell carcinoma (HNSCC) presents a significant global health problem with variable geographic distribution and risk factors, including tobacco and alcohol abuse, human papillomavirus infections, and genetic predisposition. While the majority of cases are sporadic, several well-defined hereditary syndromes have been associated with a higher risk of developing HNSCC including Li-Fraumeni syndrome, Fanconi anaemia, Bloom syndrome, familial atypical multiple mole melanoma, and dyskeratosis congenita. There is also evidence of familial clusters of HNSCC, suggesting a genetic component in the development of the disease. Germ-line genetic testing in HNSCC using next-generation sequencing has revealed a wide range of germline variants, some of which were not anticipated based on standard guidelines. These variants may influence treatment decisions and have the potential to be targeted with precision medicine in the future. Despite these advances, routine germline genetic testing for HNSCC is not currently recommended and remains reserved for HNSCC cases with early onset or strong family cancer history. However, the increasing availability of germline genetic testing warrants development of more comprehensive and standardized testing protocols. Germline genetic testing also has the potential to influence precision-guided treatment in HNSCC patients carrying germline pathogenic variants.

Overview of familial syndromes with increased skin malignancies.

The vast majority of skin cancers can be classified into two main types: melanoma and keratinocyte carcinomas. The most common keratinocyte carcinomas include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Multiple familial syndromes have been identified that can increase the risk of developing SCC, BCC, and/or melanoma. The major syndromes include oculocutaneous albinism for SCC, basal cell nevus syndrome for BCC, familial atypical multiple mole-melanoma syndrome, and hereditary breast and ovarian cancer syndrome for melanoma. In addition, familial syndromes that can predispose individuals to all three major skin cancers include xeroderma pigmentosum and Li-Fraumeni syndrome. This review highlights the epidemiology, risk factors, pathogenesis, and etiology of the major and minor syndromes to better identify and manage these conditions. Current investigational trials in genomic medicine are making their way in revolutionizing the clinical diagnosis of these familial syndromes for earlier preventative measures and improvement of long-term prognosis in these patients.

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).

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.

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li–Fraumeni syndrome (LFS), Peutz–Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband’s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

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

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.

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.

Familial pancreatic cancer: who should be considered for genetic testing?

Determining how many female patients who underwent breast imaging meet the eligibility criteria for genetic testing for familial pancreatic cancer (FPC). A total of 42,904 patients seen at the Newton-Wellesley Hospital between 2007 and 2009 were retrospectively reviewed. The first four categories were based on pancreatic cancer-associated syndromes: (1) hereditary breast and ovarian cancer (HBOC), (2) Lynch syndrome (LS), (3) familial atypical multiple mole melanoma (FAMMM), and (4) family history of FPC (FH-FPC). PancPRO (5) and MelaPRO (6) categories were based on risk scores from Mendelian risk prediction tool. Exactly 4445 of 42,904 patients were found to be in at least one of the six risk categories. About 5.7% of patients were classified as being at high risk for HBOC, 2.3% as being at high risk for LS, 0.1% as being at high risk for FAMMM, 0.1% as being at high risk for FH-FPC, 2.7% as being at high risk based on PancPRO, and 0.2% as being at high risk based on MelaPRO. About 10.4% of the female patients were classified as being at high risk for FPC. This finding emphasizes the importance of applying criteria to the general population, in order to ensure that individuals with high risk are identified early.

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.

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.

Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer.

Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.

Skin Cancer Associated Genodermatoses: A Literature Review.

Skin cancer has become the most common type of cancer worldwide as a result of environmental exposure and medical treatments. A small group of patients are genetically predisposed to skin cancer and this article is intended as a diagnostic tool when encountering patients with multiple skin cancer lesions. The disorders are described with clinical characteristics, genetics and management. The most common syndromes associated with basal cell carcinoma are: Gorlin-Goltz syndrome, Rombo syndrome, and Bazex-Dupré-Christol syndrome. Multiple squamous cell carcinomas can be related to: xeroderma pigmentosum, Ferguson-Smith, Muir-Torre syndrome, Mibelli-type porokeratosis, keratitis-ichthyosis-deafness syndrome, Rothmund-Thomson syndrome, Bloom syndrome, and epidermodysplasia verruciformis. Malignant melanoma can be inherited, as in familial atypical multiple mole melanoma syndrome.

Concordant and discordant cancers in familial atypical multiple mole melanoma syndrome (FAMMM) with the CDKN2A mutation

Concordant and discordant cancers in familial atypical multiple mole melanoma syndrome (FAMMM) with the CDKN2A mutation

CDKN2A founder mutation in pancreatic ductal adenocarcinoma patients without cutaneous features of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome

BackgroundApproximately 5% to 10% of pancreatic ductal adenocarcinoma (PDAC) has a hereditary basis. In most of these defined hereditary cancer syndromes, PDAC is not the predominant cancer type. Traditional criteria for publicly funded genetic testing typically require the presence of a set combination of the predominant syndrome-associated cancer types in the family history.We report the identification of a CDKN2A pathogenic variant in a PDAC-prone family without the cutaneous features of multiple moles or melanoma that are characteristic of the Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome identified in a universal testing algorithm for inherited mutations in pancreatic cancer patients.Case presentationWe present the case of two brothers of English ancestry diagnosed with PDAC within the same 12 month period, at the respective ages of 63 and 64 years of age. Neither brother reported a personal history of multiple moles or melanoma. Family history was positive for two second-degree relatives diagnosed with PDAC but was negative for other cancers or multiple moles in first- and second-degree relatives. Due to the absence of melanoma, this family did not meet provincial criteria for publicly funded genetic testing. Clinical genetic testing offered through a research grant identified a pathogenic variant in the CDKN2A gene c.377 T > A (p.Val126Asp). This variant is a North American founder mutation believed to pre-date colonization.ConclusionsThis case reminds clinicians to consider the possibility of a germline CDKN2A mutation in families with a high prevalence of PDAC, even in the absence of moles or melanoma. This case supports recent guidelines published by the American College of Medical Genetics and Genomics (ACMG) that genetics referrals are indicated in families with three or more cases of PDAC regardless of other cancer types in the family. A multi-gene panel approach is of particular benefit in diagnosing inherited cancer susceptibility in PDAC-only families.

Abstract 4286: What have we learned from pancreatic cancer patients undergoing multigene panel testing

Abstract Purpose: The relevance of inherited pathogenic variants in cancer predisposition genes to pancreatic cancer (PC) is not well understood. Several small studies have identified pathogenic variants in 4% to 14% of unselected PC patients using multigene panels of predisposition genes, but only BRCA2, ATM, and PALB2 have been clearly implicated in this disease. We aimed to assess the clinical and molecular characteristics of PC patients referred for hereditary cancer genetic testing, and to estimate the risk of PC associated with pathogenic variants in panel-based cancer predisposition genes. Methods: PC patients (n=1,819) were ascertained from a large cohort of over 140,000 patients undergoing multigene panel testing (MGPT) of predisposition genes between March 2012 and June 2016 at a single diagnostic laboratory. Clinical histories and molecular results were reviewed and summarized. Gene-level variant frequencies among PC cases were compared to those from the Exome Aggregation Consortium (ExAC) to calculate gene-specific pancreatic cancer risk ratios. Results: PC patients were predominantly Caucasian (76.5%) and female (58.9%), with a median age at diagnosis of 61 years (51.7). Of these, 33.5% reported additional cancer primaries, and 44.8% reported a family history of PC. Overall, 15.4% of PC patients were found to have at least one pathogenic/likely pathogenic variant in panel-based predisposition genes. Genes with the highest frequencies of pathogenic/likely pathogenic variants included BRCA2 (3.9%), ATM (3.6%), CHEK2 (excluding p.Ile157Thr) (2.0%), PALB2 (1.5%), VHL (1.4%), CDKN2A (1.2%), BRCA1 (0.8%), and MSH6 (0.8%). 21.8% of BRCA1 and BRCA2 carriers did not meet BRCA1/2 testing criteria and 61.5% of MSH6 carriers did not meet Lynch syndrome testing criteria. No CDKN2A families met diagnostic criteria for familial atypical multiple mole melanoma syndrome, and 44% did not report any personal or family history of melanoma. To estimate associations between pathogenic variants and pancreatic cancer, Caucasian PC cases were compared to non-Finnish European, non-TCGA ExAC reference controls. Pathogenic variants in ATM, BRCA2, CDKN2A, MSH6, and PALB2 were significantly associated with high PC risks. Pathogenic variants in BRCA1 were associated with a moderate risk of PC (RR=2.7). Conclusions: These findings shed light on the spectrum of mutations that can be expected for PC patients referred for cancer predisposition testing. The results confirm the associations of CDKN2A and BRCA2 variants with PC, and expand on the phenotypic spectrum associated with these variants. Furthermore, these results suggest that ATM, PALB2, and MSH6 may be high-risk PC genes, warranting further investigation in case-control and family-based studies. Citation Format: Holly LaDuca, Chunling Hu, Hermela Shimelis, Eric Polley, Jenna Lilyquist, Mary Helen Black, Brigette Tippin Davis, David E. Goldgar, Jill Dolinsky, Fergus J. Couch. What have we learned from pancreatic cancer patients undergoing multigene panel testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2017-4286