Familial Cancer最新文献

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by a germline pathogenic variant in the MEN1 tumor suppressor gene. Patients with MEN1 have a high risk for primary hyperparathyroidism (PHPT) with a penetrance of nearly 100%, pituitary adenomas (PitAd) in 40% of patients, and neuroendocrine neoplasms (NEN) of the pancreas (40% of patients), duodenum, lung, and thymus. Increased MEN1-related mortality is mainly related to duodenal-pancreatic and thymic NEN. Management of PHPT differs from that of patients with sporadic disease, as the surgical approach in MEN1-related PHPT includes near-total or total parathyroidectomy because of multigland hyperplasia in most patients and the consequent high risk of recurrence. NEN management also differs from patients with sporadic disease due to multiple synchronous and metasynchronous neoplasms. In addition, the lifelong risk of developing NEN requires special considerations to avoid excessive surgeries and to minimize damage to the patient's function and well-being. This progress report will outline current insights into surveillance and management of the major clinical manifestation of MEN1 syndrome in children and adults with MEN1 diagnosis. In addition, we will discuss MEN1-like clinical presentation with negative MEN1-genetic workup and future clinical and research directions.

Several extra-colonic manifestations, including duodenal polyposis and desmoid tumors, are well-described manifestations in familial adenomatous polyposis (FAP). More recently, an increase in gastric cancer diagnoses has been observed in FAP. This case series presents nine patients with FAP who were diagnosed with gastric cancer at our FAP expertise center, of whom eight were diagnosed between 2017 and 2023, while before 2017 the only diagnosis of gastric cancer was in 2001. Among the nine cases of gastric cancer, seven were located in the proximal stomach amidst carpeting fundic gland polyposis and two were located in the distal stomach. Despite ongoing advances in endoscopic technology, all patients were diagnosed during regular endoscopic surveillance, and six of the nine patients died within two years. We aim to raise awareness on gastric cancer risk in FAP patients and stress the urgent need of improved gastric surveillance strategies with timely detection of gastric cancer precursors.

Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome whereby the lifetime risk of developing gastrointestinal and genitourinary cancers rises by to over 50%. It is caused by heterozygous variants in the DNA mismatch repair genes- MLH1, MSH2, MSH6 and PMS2, with the majority detected in MLH1 and MSH2. Recurrently observed LS-associated variants in apparently unrelated individuals have either arisen de novo in different families due to mutation hotspots or are inherited from a common ancestor (founder) that lived several generations back. Testing for founder variants can facilitate molecular diagnosis of LS more efficiently and cost effectively than screening for all possible variants in the MMR genes. Here, we report a study of the missense variant c.306G > T in the MLH1 gene, the first potential founder variant identified in LS patients of Indian ethnicity. Haplotype analysis consisting of 25 LS carriers with the MLH1 c.306G > T variant and 100 healthy controls confirmed a shared haplotype in cases spanning a 27.8 kb region encompassing the c.306G > T variant (𝝌² = 96.418; p = < 0.0001). Age of variant analysis suggests the variant to have arisen in the population approximately 800 years (95% CI: 670-934 years) ago. Furthermore, it is estimated that c.306G > T variant is likely to be observed in 6.4% of all LS patients of Indian ethnicity. These findings have important implications for genetic counselling and molecular diagnosis of Lynch syndrome.

Retinoblastoma (RB) is the most common intraocular malignancy in children, and patients with family history of retinoblastoma are at high risk of disease. While intensive screening programs have led to earlier diagnosis and higher rates of globe salvage, visual outcomes have not improved. Handheld optical coherence tomography (HH-OCT) is a non-invasive imaging modality that can be utilized for screening, diagnosis, and monitoring of Familial RB. We present a case of a patient who was found to have bilateral Familial RB with HH-OCT after having a normal fundoscopic exam. This case demonstrates the utility of HH-OCT imaging and suggests that further research is needed to see whether screening guidelines should require OCT imaging during screening.

Nephrotic syndrome is a common clinical presentation of glomerulopathy. A glomerulopathy as a paraneoplastic manifestation caused by underlying malignancy is rare. In patients with a solid tumor, membranous nephropathy is the most frequent paraneoplastic glomerulopathy. We present a case of recurrent paraneoplastic nephrotic syndrome caused by minimal change disease in a patient with Lynch syndrome. Over the years, a decrease in creatinine clearance and nephrotic-range proteinuria repeatedly functioned as a warning signal for underlying malignancies; consecutively, a colon adenocarcinoma, renal cell carcinoma and gastric adenocarcinoma were diagnosed. After treatment of the malignancies the nephrotic syndrome resolved without immunosuppressive therapy. Our patient also developed a primary lung carcinoma thrice, which did not cause an exacerbation of the minimal change disease. To further elucidate the mechanism behind the development of this phenomenon, we performed immunohistochemical analysis for vascular endothelial growth factor (VEGF) on the different tumor specimens. We found a high VEGF expression in the gastro-intestinal tumors, whereas the VEGF expression in the lung tumors was low, suggesting an association between VEGF expression and the development of paraneoplastic minimal change disease. This case report not only underlines the importance of considering a malignancy as a cause for (recurrent) nephrotic syndrome, especially in patients with an increased risk of developing malignancies like Lynch syndrome patients, but also suggests a role for VEGF in the pathogenesis of paraneoplastic minimal change disease.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by endocrine tumors, typically from parathyroid, pancreatic, or anterior pituitary origin. In addition, benign cutaneous soft tissue tumors are prevalent in MEN1 patients. Although sarcomas have been reported in MEN1 patients it is unclear if these tumors should be considered as part of the MEN1 syndrome. Here, five patients with a MEN1 syndrome and a sarcoma are described. In all five sarcomas loss of heterozygosity of the MEN1 gene and loss of expression of menin are shown, suggesting that sarcomas may be a phenotypic expression of MEN1 syndrome.

Hereditary cancer predisposition disorders account for up to 10% of all pediatric cancers. Genetic counseling for families of the proband includes risk assessment and recommendations for cascade genetic testing for parents and siblings, but there is no standardized method for cascade testing in place resulting in variability in how clinics approach cascade genetic testing. We explored the uptake and outcomes associated with a family-based approach to cascade testing, for non-syndromic cancer predisposition disorders, at a pediatric cancer genetics clinic serving an ethnically diverse patient population. A retrospective chart review was conducted to evaluate test uptake in the parents and siblings of 106 pediatric probands. The study included 99 mothers, 97 fathers, 116 full siblings, and 53 half siblings who were recommended testing due to genetic risk. Of these relatives, 156 (43%) had documentation of completed cascade testing within twenty-four months after the proband's result disclosure. Completion of cascade testing varied by the type of family member and degree of relatedness. 41% of mothers (41/99) were tested in comparison to 26% of fathers (26/97) and 70.6% of full siblings (82/116) were tested compared to 13.2% of half siblings (7/53). Statistical analysis using chi-squared tests revealed that siblings were more likely to have completed testing than parents (p < 0.001). Furthermore, amongst parents, mothers were more likely to complete testing than fathers (p = 0.03) and amongst siblings, full siblings were more likely to complete testing than half siblings (< 0.001). The proband's age (p = 0.008), parents' preferred language (p = 0.002), and interpreter use during visit (p = 0.004) were the factors associated with differences in test uptake amongst siblings, whereas the proband's race/ethnicity (p = 0.019) was the only factor associated with differences in test uptake amongst parents. The most common barriers noted in charts for lack of test completion included country of residence, lack of insurance, and loss to follow-up. In conclusion, we found that test uptake differed significantly among relatives of a proband with siblings being more likely to test than parents. We also found differences in the demographic and clinical factors associated with test uptake in parents and siblings. Future studies need to validate these differences and further explore the underlying cause of variation in test uptake among relatives.

Despite its clinical value, cascade genetic testing (CGT) in hereditary cancer syndromes remains underutilized for a number of reasons, including ineffective family communication of genetic risk information. Therefore, alternative strategies are being explored to improve CGT uptake rates; one such strategy is direct contact with at-risk relatives by healthcare professionals with proband consent. It is unclear how Italian laws and regulations pertaining to CGT-including the EU General Data Protection Regulation (GDPR)-should be understood and implemented in the context of such alternative strategies. The authors constructed a hypothetical case about CGT, reviewed laws and regulations on informed consent, privacy, and the right not to know, and analyzed how those laws and regulations might apply to different communicative strategies relevant to the case and aimed at supporting CGT. A constitutionally consistent reading of Italian law and of the GDPR, an integral part of the Italian privacy framework, suggests that multiple communicative approaches may be legally permissible in Italy to support the CGT process. This includes direct contact by healthcare professionals with proband consent, provided certain conditions are met. Understanding the effectiveness of such approaches in improving CGT uptake will require further research efforts.