Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts

Does autoimmune vitiligo protect against COVID-19 disease?

The SARS-CoV-2 pandemic has evolved to a global health problem with a dramatic morbidity and mortality rate impacting our daily life and those of many patients. While there is evidence that some diseases are associated with an increased risk for development of a more severe course of COVID-19, little is known on protective conditions. Importantly, clearance of viral infection and protection against disease manifestation crucially depends on functional innate and adaptive immunity and the interferon signalling axis. Here, we hypothesize that patients with non-segmental vitiligo (NSV), an autoimmune skin (and mucosal) disorder, may clear SARS-CoV-2 infection more efficiently and have a lower risk of COVID-19 development. Conversely, in case of COVID-19 development, vitiligo autoimmunity may influence the cytokine storm-related disease burden. In addition, immune activation during SARS-CoV-2 infection or COVID-19 disease might increase vitiligo disease activity. Our hypothesis is based on the shift of the immune system in NSV towards adaptive type 1 (IFNγ and CD8 T cells) and innate immune responses. Identified susceptibility genes of NSV patients may further confer increased antiviral activity. To validate our hypothesis, we suggest an international consortium to perform a retrospective data registry and patient-reported study on a large number of NSV patients worldwide during the COVID-19 pandemic

Immunophenotypic Analysis Reveals Differences in Circulating Immune Cells in the Peripheral Blood of Patients with Segmental and Nonsegmental Vitiligo

Accumulating studies have indicated immune-based destruction of melanocytes in both segmental vitiligo (SV) and non-SV (NSV). Whereas SV often occurs unilaterally during childhood and stabilizes after an initial period of activity, the disease course of NSV is usually slowly progressive, with new lesions occurring bilaterally during life. This suggests an involvement of distinct pathophysiology pathways, specifically increased systemic immune activation in patients with NSV but not in patients with SV. This research aimed to identify the differences in immune cells in the blood of patients with SV and NSV through immunophenotyping of circulating cells. Regulatory T cells were unaffected in patients with SV compared with that in healthy controls but decreased in patients with NSV. In patients with NSV, the reduction in regulatory T cells was associated with the presence of other systemic autoimmune comorbidities, which were less present in SV. Similarly, the absence of a melanocyte-specific antibody response in patients with SV suggests less involvement of B-cell immunity in SV. These data show that in contrast to patients with NSV, no increased systemic immunity is found in patients with SV, indicating that SV pathogenesis is associated with a localized cytotoxic reaction targeting epidermal melanocytes

IFN-γ-induced PD-L1 expression on human melanocytes is impaired in vitiligo

Mounting evidence shows that the PD-1/PD-L1 axis is involved in tumor immune evasion. This is demonstrated by anti-PD-1 antibodies that can reverse tumor-associated PD-L1 to functionally suppress anti-tumor T-cell responses. Since type I and II interferons are key regulators of PD-L1 expression in melanoma cells and IFN-γ-producing CD8+ T cells and IFN-α-producing dendritic cells are abundant in vitiligo skin, we aimed to study the role of PD-1/PD-L1 signalling in melanocyte destruction in vitiligo. Moreover, impaired PD-1/PD-L1 function is observed in a variety of autoimmune diseases. It is, therefore, hypothesized that manipulating PD-1/PD-L1 signalling might have therapeutic potential in vitiligo. The PD-1+ T cells were abundantly present in situ in perilesional vitiligo skin, but expression of PD-L1 was limited and confined exclusively to dermal T cells. More specifically, neither melanocytes nor other epidermal skin cells expressed PD-L1. Exposure to IFN-γ, but also type I interferons, increased PD-L1 expression in primary melanocytes and fibroblasts, derived from healthy donors. Primary human keratinocytes only showed increased PD-L1 expression upon stimulation with IFN-γ. More interestingly, melanocytes derived from non-lesional vitiligo skin showed no PD-L1 upregulation upon IFN-γ exposure, while other skin cells displayed significant PD-L1 expression after exposure. In a vitiligo skin explant model, incubation of non-lesional vitiligo skin with activated (IFN-γ-producing) T cells from vitiligo lesions was previously described to induce melanocyte apoptosis. Although PD-L1 expression was induced in epidermal cells in these explants, this induction was completely absent in melanocytes. The lack of PD-L1 upregulation by melanocytes in the presence of IFN-γ-producing T cells shows that melanocytes lack protection against T-cell attack during vitiligo pathogenesis. Manipulating PD-1/PD-L1 signalling may, therefore, be a therapeutic option for vitiligo patients

Expert opinion about laser and intense pulsed light (IPL)-induced leukoderma or vitiligo: a cross-sectional survey study

Vitiligo patients may desire laser hair removal, skin rejuvenation, vascular treatments, and other laser or intense pulsed light (IPL) assisted treatments. However, there is a risk of inducing new depigmented patches (Koebner phenomenon). In absence of guidelines on the safe use of laser or IPL in vitiligo patients, dermatologists tend to be reluctant to administer these treatments. The aim of this survey study was to provide an estimation of the occurrence and related risk factors of laser/IPL-induced leukoderma or vitiligo. A cross-sectional survey study was performed among 15 vitiligo experts from 11 countries, with 14 questions about affected patients, involved laser/IPL treatments and the physicians’ approach. In a total of 11,300 vitiligo patients, laser/IPL-induced leukoderma or vitiligo was reported in 30 patients (0.27%). Of these, 12 (40%) patients had a medical history of vitiligo and seven (58%) of these patients had stable (> 12 months) vitiligo before the treatment. Most frequently reported were hair removal procedures and localization of the face and legs. Side effects like blistering, crusting, and erosions occurred in 56.7% of the cases. These vitiligo experts based their advice on the risk of the laser treatment on stability of the vitiligo (43%) and activity signs (50%), and 50% discuss the risks before starting a laser treatment. Relevant activity signs are the Koebner phenomenon (57.1%), confetti-like lesions (57.1%) and hypochromic borders (50%). Laser-induced leukoderma or vitiligo is an uncommon phenomenon. Remarkably, a minority had a medical history of vitiligo of which 58% were stable. Consequently, most cases could not have been prevented by not treating vitiligo patients. However, a majority had laser/IPL-induced skin damage. Therefore, caution is advised with aggressive settings and test-spots prior to the treatment are recommended. This study showed significant variation in the current recommendations and approach of vitiligo experts regarding laser/IPL-induced leukoderma or vitiligo

Hereditary diffuse gastric cancer: updated clinical practice guidelines

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined