Haploinsufficiency of the NF1 gene is associated with protection against diabetes

Abstract Background The hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of the NF1 gene. Here, we used a cohort of 1410 patients with NF1 to study the association of the NF1 gene with type 1 (T1D) and type 2 diabetes (T2D). Methods A total of 1410 patients were confirmed to fulfil the National Institutes of Health diagnostic criteria for NF1 by individually reviewing their medical records. The patients with NF1 were compared with 14 017 controls matched for age, sex and area of residence as well as 1881 non-­NF1 siblings of the patients with NF1. Register-based information on purchases of antidiabetic medication and hospital encounters related to diabetes were retrieved. The Cox proportional hazards model was used to calculate the relative risk for diabetes in NF1. Results Patients with NF1 showed a lower rate of T2D when compared with a 10-fold control cohort (HR 0.27, 95% CI 0.17 to 0.43) or with their siblings without NF1 (HR 0.28, 95% CI 0.16 to 0.47). The estimates remained practically unchanged after adjusting the analyses for history of obesity and dyslipidaemias. The rate of T1D in NF1 was decreased although statistically nonsignificantly (HR 0.58, 95% CI 0.27 to 1.25). Conclusion Haploinsufficiency of the NF1 gene may protect against T2D and probably T1D. Since NF1 negatively regulates the Ras signalling pathway, the results suggest that the Ras pathway may be involved in the pathogenesis of diabetes.</p

Pediatric malignancies in neurofibromatosis type 1: A population‐based cohort study

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome with an incidence of 1:2,000. Patients with NF1 have an increased cancer risk and mortality, but there are no population‐based cohort studies specifically investigating the risk of childhood malignancies. We used the Finnish NF1 cohort to analyze the incidence, risk and prognosis of malignancies in NF1 patients </p

Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors

AbstractBACKGROUND: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers.METHODS: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls.RESULTS: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P=0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population.CONCLUSIONS: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.</p

Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study

PurposeNeurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1.MethodsWe included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan–Meier analysis with delayed entry.ResultsOne hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0–84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8–76.8) and 49.8% (95%CI = 39.3–63.0). Breast cancer–specific 10-year survival was 64.2% (95% CI = 53.5–77.0%) compared with 91.2% (95% CI = 87.3–95.2%) in the non-NF1 age-matched population at increased risk of breast cancer.ConclusionWomen with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.</p

Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas

Neurofibromatosis 1 (NF1) occurs in 1:2000 births. The main diagnostic signs are visible on the skin, and this opens several interesting aspects for dermatological point of view. The NF1 syndrome is caused by mutations in the NF1 gene which encodes the tumor suppressor protein neurofibromin. Neurofibromin functions as a Ras-GTPase-activating protein (RasGAP), and NF1 mutations lead to overactivation of the Ras signalling pathway. The NF1 gene and neurofibromin have intriguing functions in keratinocytes and melanocytes. Neurofibromin regulates melanin synthesis and keratinocyte differentiation in a currently unknown manner. The NF1 gene has also an important but poorly understood role in tumorigenesis and cancer. Compared to the general population, NF1 patients have a fivefold risk for cancer and a more than 2000-fold risk for neurogenic malignancies. Mutations of the NF1 gene are common in numerous cancer types in patients without NF1, and this suggests a more general role for the NF1 gene in oncogenesis. In melanoma, NF1 mutations seem to drive tumorigenesis and contribute to drug resistance. In this article, we review the literature on neurofibromin with special attention to keratinocytes, melanocytes, NF1-related tumors and melanoma.</p