Considerations for Germline Testing in Melanoma: Updates in Behavioral Change and Pancreatic Surveillance for Carriers of CDKN2A Pathogenic Variants

Abstract

The largest proportion of hereditary melanoma cases are due to pathogenic variants (PVs) in the CDKN2A/p16 gene, which account for 20%-40% of familial melanomas and confer up to a 30%-70% lifetime risk for melanoma in individuals with these variants. In addition, PVs in the CDKN2A gene also increase risk for pancreatic cancer (~5–24% lifetime risk). Individuals with PVs in the CDKN2A gene also tend to have an earlier onset of cancer. Despite these known risks, uptake of germline testing has been limited in the past, largely due to perceptions of limited benefit for patients. Prevention recommendations have been developed for individuals with CDKN2A PVs as well the providers who care for them. On the patient level, behavioral modifications regarding melanoma prevention such as wearing sunscreen, limiting prolonged sun exposure and practicing general sun safety can help reduce risks. Germline testing can provide motivation for some individuals to adhere to these lifestyle changes. On the provider level, pancreatic cancer surveillance for individuals with CDKN2A PVs has been increasingly endorsed by expert consensus, although the efficacy of these surveillance methods remains under study. This review summarizes the updated surveillance guidelines for individuals with CDKN2A PVs and explores the impact of genetic counseling and testing in influencing behavioral changes in these individuals.

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

“…Through both univariable and multivariable analyses, we also revealed that high CDKN2A and SMAD4 mutation abundances in ctDNA but not in tumor and high ARID1A mutation abundances in both ctDNA and tumor at baseline and/or the second measurement were linked to inferior OS and/or PFS. Pathogenic variants in CDKN2A increase the risk for pancreatic cancer (~ 5% to 24% lifetime risk), and individuals with pathogenic variants in CDKN2A tend to have an earlier onset of cancer [ 65 , 66 ]. SMAD4, a transforming growth factor (TGF)-β/BMP signaling effector and a tumor suppressor, is frequently mutated in PDAC and actively participates in the interaction between cancer and stromal myeloid cells and mediates the response of cancer cells to stromal chemokine [ 67 ].…”

Multilocus inherited neoplasia allele syndrome: report of uncommon combinations between CHEK2/ATM and BRCA1/CDKN2A genes

“…It encodes two proteins, p16 INK4A , an inhibitor of cyclindependent kinase, and p14 ARF , which binds to the p53-stabilising protein MDM2. p16 INK4A produces G1 cell cycle arrest by inhibiting retinoblastoma protein phosphorylation, and p14 ARF performs its p53-dependent function by binding and inhibiting MDM2 protein in both G1/S and G2/M phases [16][17][18]. CDKN2A PVs give a lifetime risk of 28%-76% for melanoma and an absolute risk of 15% for pancreas cancer [6].…”

Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice

“…The CDKN2A/ MLH1-positive patient with CRC should also undergo preventive screening tests for pancreatic cancer and melanoma, while the BRCA1/MSH2-positive patient with endometrial cancer should also be screened for tumors associated with the hereditary breast and ovarian cancer syndrome. [34][35][36] Tumor analysis of double heterozygotes revealed a biallelic inactivation of the MMR gene with germline alteration in both samples (as defined by a variant allele frequency of >85%), whereas the other alteration was monoallelic. This finding suggests that the presence of MSI in these patients was driven by double somatic hits in the MMR genes.…”