Familial Cancer最新文献

The clinical spectrum of paediatric NF2-SWN is broad and differs from that seen in the cohort of patients presenting over age 30, where symptoms typically relate to enlarging schwannoma, meningioma or ependymoma. Paediatric cases tend to have a multisystemic presentation with a high tumour burden and significant physical and psychological morbidity. Visual impairment as well as dermatological and non-tumour neurological features are common. Genetic testing characteristically identifies a germline pathogenic variant (often truncating) in the NF2 gene. This review explores the spectrum of clinical disease that arises in NF2-SWN when presenting in childhood.

Pancreatic cancer (PDAC) surveillance programs are recommended for individuals with a PDAC lifetime-risk ≥ 5% to improve outcomes. While familial adenomatous polyposis (FAP) is linked to increased PDAC risk, robust data to guide surveillance recommendations is lacking. This study evaluates PDAC risk in a large FAP-cohort.Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥ 18 years) with a confirmed (likely) pathogenic APC variant. Cumulative PDAC incidence, adjusted for death as competing risk, was compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥ 18 years) with a confirmed (likely) pathogenic APC variant. Cumulative PDAC incidence, adjusted for death as competing risk, was compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. The US-cohort (n = 357) and NL-cohort (n = 1000) had a median age at the end of follow-up of 46 years (IQR, 32.0-60.0) and 60 years (IQR, 47.5-72.5), respectively. The cumulative risk of PDAC by age 70 was 1.3% (95% CI, 0.2-8.4) in the US cohort and 0.6% (95% CI 0.2-1.7) in the NL cohort. When combining both FAP-cohorts, the cumulative risk of PDAC by age 70 was 0.7% (95% CI, 0.3-1.8). For comparison, the cumulative incidence of PDAC in the general population at age 70 was 0.3% (95% CI 0.3-0.3), corresponding to a relative risk of 2.2 (95% CI, 0.9-5.7). Our findings indicate that PDAC risk in FAP patients is not statistically significantly higher than in the general population. As the cumulative incidence remains below the 5% threshold, PDAC surveillance is not recommended.

Schwannomatosis refers to a group of rare genetic syndromes characterized by a predisposition to develop nerve sheath tumors, specifically schwannomas. Although germline and mosaic (described in the NF2 gene) pathogenic variants in NF2, SMARCB1, and LZTR1 account for the majority of cases, a subset of affected individuals remains without a definitive molecular diagnosis, including those associated with 22q loss of heterozygosity at the tumor level. The absence of a specific disease cause limits effective risk assessment, clinical surveillance, and genetic counselling. In recent years, advances in sequencing technologies have facilitated the identification of novel candidate driver genes. However, the rarity of these findings makes it challenging to establish their pathogenic relevance. This review aims to evaluate the current knowledge of genetic contributors to schwannomatosis in patients for whom routine genetic testing fails to detect a molecular cause in the known associated genes. On chromosome 22, DGCR8 and SOX10 have emerged as novel susceptibility genes, supported by accumulating molecular and clinical data. In addition, genes such as CDKN2A and SMARCA4 may also contribute to schwannomatosis in the context of broader tumor predisposition syndromes. These emerging genetic associations may help explain a proportion of schwannomatosis cases that currently lack a molecular diagnosis, while there is still room for the discovery of non-coding alleles or mosaic forms of known schwannomatosis-related conditions as well as novel genes that could explain unresolved cases.

The three major schwannomatosis genes, NF2, LZTR1 and SMARCB1, are all located within approximately 9 megabases on chromosome 22 and cause three genetically distinct conditions with significant clinical phenotypic overlap. All forms of schwannomatosis predispose to the development of multiple schwannomas, but display differences in tumour location and long-term prognosis. In addition, high levels of mosaic disease can complicate clinical diagnosis. Genetic diagnosis can be critical for distinguishing between the three conditions to optimise clinical management, especially in cases of mosaic disease. This review summarises the distinctions between the clinical and genetic characteristics of each form of schwannomatosis and discusses the genetic analytic tools that are typically used to detect the variants found in these conditions.

Hybrid neurofibroma/schwannoma tumors (HNS) represent a still underrecognized, yet clinically and diagnostically significant entity within the spectrum of schwannomatosis (SWN). While classical schwannomas have been well known for decades, HNS have only recently been described as a distinct histological pattern, composed of intermixed features typical of both schwannomas and neurofibromas. Differentiating HNS from pure neurofibroma (Nf) is critical, as misclassification may lead to an incorrect diagnosis of neurofibromatosis type 1 rather than SWN. The distinction of hybrid tumors (more precisely HNS) is especially important in SWN forms outside the neurofibromatosis type 2 (NF2) spectrum (NF2-SWN), where major diagnostic criteria are less well defined, making histological differentiation even more significant. At the molecular level, HNS frequently show alterations in the genes NF2, LZTR1, and SMARCB1, often accompanied by characteristic losses of chromosome 22q. In addition, recurrent somatic mutations have been identified in genes such as ERBB2, RET, KMT2A, and CTNNA3. Methylation profiling classifies HNS within the schwannoma spectrum, supporting the hypothesis that they may be a morphological variant rather than a distinct entity, although this has not yet been conclusively confirmed. Histologically, HNS are characterized by a combination of mostly schwannoma-associated Antoni A patterns, collagen-rich neurofibroma-like areas, lymphocytic infiltrates, and, in some cases, plexiform growth. Given the diagnostic challenges, artificial intelligence-based image analysis, such as whole-slide imaging and radiomics, may offer valuable tools for more accurate identification of these tumors in the future. Initial studies in related fields have shown that such approaches can even surpass human-level accuracy. Nevertheless, an accurate histological and, if necessary, molecular evaluation remains essential-particularly for the correct classification as SWN and for ensuring appropriate genetic counseling to affected individuals.

Germline pathogenic variants within the highly conserved exonuclease domain of the POLD1 gene predisposes to colorectal (CRC) and endometrial (EC) cancers. Tumours with POLD1-deficiency demonstrate unique genomic features including hypermutation and tumour mutational signatures (TMS) SBS10c, SBS10d and SBS20. The classification of variants within POLD1 remains challenging. The utility of incorporating tumour hypermutation status and TMS profiles into POLD1 gene-specific variant classification guidelines developed by ClinGen-InSiGHT remains to be established. We report a family with eight members heterozygous for the germline POLD1 c.1420C > A (p.Leu474Ile) variant. This variant resides within the exonuclease domain, is absent in gnomADv4.1 and is classified as a variant of uncertain clinical significance. Formalin-fixed paraffin embedded tissue and matched blood-derived DNA from person 001 (EC, 1 adenoma, 2 sessile serrated lesions), and two cousins, 009 (EC, 3 adenomas), and 010 (breast cancer, EC, CRC, 4 adenomas, 2 sessile serrated lesions and 1 traditional serrated adenoma) were tested using a custom multigene panel to determine tumour mutational burden (TMB) and TMS. All three ECs demonstrated characteristics of POLD1-deficiency namely hypermutated TMB and predominance of SBS10d. The CRC, 62.8% of the adenomas and 60% of the serrated polyps demonstrated SBS10c as the dominant TMS. EC, CRC, breast and multiple polyps from three family members heterozygous for the germline POLD1 c.1420C > A variant demonstrated hypermutation and SBS10c and SBS10d TMS, genomic features associated with defective POLD1. Somatic TMB and TMS profiling of multiple independent lesions demonstrated utility for identifying POLD1-deficiency suggesting this approach can support variant classification for POLD1.

Objectives of the study were to determine the success, complication and recurrence rate of endoscopic papillectomies in familial adenomatous polyposis (FAP) patients. Ampullary adenoma is frequent in familial adenomatous polyposis (FAP) patients. Endoscopic papillectomy is technically demanding for laterally spreading ampullary adenomas and bleeding, perforation and pancreatitis represent typical complications. 40 FAP patients undergoing endoscopic papillectomy were retrospectively analyzed. Data on periprocedural complications, histopathology, resection techniques and success were collected. Endoscopic papillectomy was performed in 21 male and 19 female patients. Mean adenoma size was 14 mm (8-40 mm). Additional mucosal resection was performed in 45%. Immediate and delayed bleeding occurred in 33% (n = 13) and 13% (n = 5), respectively. Bleeding was associated with male sex and pancreatic endoprosthesis. Endoscopically manageable perforation occurred in 2 patients. Acute pancreatitis occurred in 25% (n = 10) and was significantly associated with female sex. Histopathology revealed papillitis in 5% (n = 2), adenoma with low-grade dysplasia in 73% (n = 29), high-grade dysplasia in 13% (n = 5), and adenocarcinoma in 5% (n = 2). Cumulative recurrence-free resection was achieved in 94% (n = 33/35) after a mean of 1.4 procedures at a median follow-up of 591 days (range 15-2605). Endoscopic papillectomy shows a high clinical success in FAP patients even with laterally spreading adenoma. Adenoma recurrence can be successfully treated with a limited number of reinterventions.