Genetic Variation in MicroRNA-423 Promotes Proliferation, Migration, Invasion, and Chemoresistance in Breast Cancer Cells

MicroRNA-423 (miR-423) is highly expressed in breast cancer (BC). Previously, our group showed that the SNP rs6505162:C>A located in the pre-miR-423 was significantly associated with increased familial BC risk in patients with a strong family history of BC. Therefore, in this study, we evaluated the functional role of rs6505162 in mammary tumorigenesis in vitro to corroborate the association of this SNP with BC risk. We found that rs6505162:C>A upregulated expression of both mature miR-423 sequences (3p and 5p). Moreover, pre-miR-423-A enhanced proliferation, and promoted cisplatin resistance in BC cell lines. We also showed that pre-miR-423-A expression decreased cisplatin-induced apoptosis, and increased BC cell migration and invasion. We propose that the rs6505162-A allele promotes miR-423 overexpression, and that the rs6505162-A allele induces BC cell proliferation, viability, chemoresistance, migration, and invasion, and decreases cell apoptosis as a consequence. We suggest that rs6505162:C>A is a functional SNP site with potential utility as a marker for early diagnosis, prognosis, and treatment efficacy monitoring in BRCA1/2-negative BC patients, as well as a possible therapeutic target.

A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family

Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer’s disease (EOAD). Recently, emerging studies have reported several novel PSEN1 mutations among Asians. In this study, a PSEN1 Val96Phe mutation was discovered in two siblings from Malaysia with a strong family history of disease. This is the second report of PSEN1 Val96Phe mutation among EOAD patients in Asia and in the world. Patients presented symptomatic changes in their behaviors and personality, such as apathy and withdrawal in their 40s. Previous cellular studies with COS1 cell lines revealed the mutation increased the amyloid-β42 (Aβ42) productions. In the present study, whole-exome sequencing was performed on the two siblings with EOAD, and they were analyzed against the virtual panel of 100 genes from various neurodegenerative diseases. In silico modeling was also performed on PSEN1 Val96Phe mutation. This mutation was located on the first transmembrane helix of PSEN1 protein, resulting significant intramolecular stresses in the helices. This helical domain would play a significant role in γ-secretase cleavage for the increased Aβ42 productions. Several other adjacent mutations were reported in this helical domain, including Ile83Thr or Val89Leu. Our study suggested that perturbations in TMI-HLI-TMII regions could also be associated with C-terminal fragment accumulation of APP and enhanced amyloid productions.

Episodic Unilateral Limb Pain and Migraine–A Case Report, Hitherto an Unnamed Entity!

Background: Migraine limb pain is a very under-recognized manifestation of migraine in which episodic pain happens in the peripheral limbs. Despite its description for many years, only limited clinical details are known. Only case reports and case series with limb pain as a symptom of migraine are reported in the literature. In this case report, important features of episodic unilateral limb pain and it’s association with migraine has been discussed. Case presentation: Here the author (a neurologist) describes episodic limb pain from his own experience, which started in childhood and used to be episodic, unilateral and with changing sides. In view of various features mimicking migraine, classical manifestation of migraine in later life and a strong family history , episodic unilateral limb pain in childhood is likely a form of peripheral migraine. Conclusion: Unilateral episodic limb pain with various features mimicking migraine is a very important clinical entity. This case should help in understanding the clinical details of peripheral limb pain -a relatively under-diagnosed symptom of migraine

POS1004 BOTH SPONDYLOARTHRITIS AND PSORIATIC ARTHRITIS PATIENTS HAVE STRONG FAMILY HISTORIES

Background:Family history is one of the hallmarks of spondyloarthritis (SpA) and psoriatic arthritis (PsA) [1, 2]. Some patients have a strong family history that more than 2 relatives have spondyloarthritis related diseases. The effects of strong family history on SpA features were not known very well.Objectives:The aim of this study is to evaluate the effects of family history in SpA and PsA patients.Methods:HUR-BIO (Hacettepe University Biologic Registry) is a prospective, single center database of biological treatments since 2005, and to date 3071 SpA and 526 PsA patients have been recorded. Demographic, clinical characteristics, disease activity parameters, a detailed family history of SpA and SpA features (presence of SpA including PsA, psoriasis, inflammatory bowel disease and uveitis) and laboratory data before anti-TNF treatments of the patients were noted.Results:2807 SpA (53.6% male) and 506 PsA (31.4% male) patients’ family history were available and analysed. A positive family history was noted in 27.6% of the SpA and 31.0% of the PsA patients (ns). 7.4% of the SpA patients and 8.9% of the PsA patients had family history in more than one relative (Table 1). In SpA patients with a family history, uveitis was more frequent than patients without (14.4% vs 10.6%, p=0.006). Except for a higher male predominance and uveitis (53% vs 32% p=0.006 and 9% vs 2% p=0.003 respectively) in patients with ≥2 relatives with SpA features, there were no differences in PsA patients regarding family history. The presence of family history and HLA-B27 (63.7% vs 37.6%, p<0.001) positivity were associated in SpA patients but not in PsA patients (31.2% vs 20.0, p=0.13).Conclusion:Family history was present in about one third of the patients of PsA and SpA. It is not uncommon for two or more family members to have a SpA feature. Presence of family history may be associated with some clinical conditions, such as uveitis.References:[1]Solmaz, D., et al., Impact of Having Family History of Psoriasis or Psoriatic Arthritis on Psoriatic Disease. Arthritis Care Res (Hoboken), 2020. 72(1): p. 63-68.[2]Zurita Prada, P.A., et al., Influence of smoking and obesity on treatment response in patients with axial spondyloarthritis: a systematic literature review. Clin Rheumatol, 2020.Table 1.Family history in PsA and SpA patientsPsA (n=506)SpA (n=2807)≥ 1 family history, n (%)157 (31.0)774 (27.6)≥1 first-degree relative, n (%)114 (22.5)489 (17.4)≥2 first-degree relatives, n (%)21 (4.2)77 (2.7)≥2 relatives (both first- and second-degree), n (%)45 (8.9)208 (7.4)Family history •Psoriasis, n (%)120 (23.7)155 (5.5) •Psoriatic arthritis, n (%)14 (2.8)9 (0.3) •Spondyloarthritis, n (%)38 (7.5)643 (22.9) •Inflammatory bowel disease, n (%)1 (0.2)10 (0.4) •Uveitis, n (%)02 (0.1)Disclosure of Interests:None declared.

An Unusual Form of Type 1 Diabetes With an Elevated Proinsulin Level

Introduction: Diabetes is one of the most prevalent diseases in the world. We recognize the three most common types of diabetes: type1, type2 and gestational diabetes. It is estimated that around 425 million of people worldwide have diabetes and about 90% of those represent type 2 diabetes. The most common types of diabetes are polygenic -- they are caused by a defect in multiple genes. Monogenic diabetes is caused by a mutation in a single gene. We currently have over 10 different types of monogenic diabetes called MODY (Maturity Onset Diabetes of the Young). Sun et al. states that over the past few years, 30 different insulin gene mutations were reported to cause a new syndrome called MIDY (Mutant INS-gene-induced Diabetes of Youth). Most of these mutations lead to proinsulin misfolding in the endoplasmic reticulum. We present a rare case of a young obese female with an elevated proinsulin level and low C-peptide level diagnosed with type 1 diabetes requiring therapy with insulin. Case Description: A 21 year old female with past medical history of chronic diarrhea initially presented with a complaint of dry mouth, dizziness, excessive urination, and thirst. She was found to have hyperglycemia of 203 mg/dL, A1C 8.3, and negative ketones. Patient had a strong family history of diabetes. She had a family history of: father with type 1 diabetes; mother with a past medical history of gestational diabetes who became diabetic postpartum; and three of the patient’s grandparents with a history of diabetes. Patient was started on the oral hypoglycemic agents metformin and glipizide, but she only had partial response to these medications. Because of her strong family history and incomplete response to oral hypoglycemic agents, additional testing was performed. Patient was found to have a low C-peptide level (1.6 ng/mL), elevated proinsulin (72.9 pmol/L), positive GAD antibody (10.3 units/mL) and negative islet cell autoantibody. Patient had a very good response to insulin and subsequently became insulin dependent. She is currently on an insulin pump. Conclusion: Sun et al. reports that proinsulin misfolding causes beta cell failure. Increased misfolding occurs under certain pathological conditions that are currently unknown. We think that there might be some increased proinsulin misfolding abnormality that might be occurring in this patient. There are most likely many epigenetic modifiers that would trigger certain individuals to be more prone to this phenomena of misfolded proinsulin. Future research in diabetes may one day yield antibodies that would specifically recognize misfolded proinsulin in the plasma. Further research is required to elucidate how defective proinsulin folding may lead to beta cell dysfunction and subsequent evolution of diabetes mellitus.

Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

The impact of a positive family history on clinical and pathologic outcomes of active surveillance for prostate cancer.

225 Background: Active surveillance (AS) is the preferred management strategy for men with low-risk prostate cancer. However, approximately one in three men on AS experience progression of disease leading to treatment within 5 years, highlighting an urgent unmet need to reliably distinguish indolent from aggressive prostate cancer and improve patient selection criteria for AS. Germline genetic testing for DNA repair gene mutations is now recommended for patients with newly diagnosed prostate cancer and a strong family history of prostate cancer or BRCA1/2-related cancers, as such mutations have been associated with more aggressive forms of the disease. Here, we investigated the impact of family history on AS outcomes, under the hypothesis that men at high genetic risk for prostate cancer are at greater risk for progression to treatment on AS. Methods: We retrospectively reviewed detailed family history data of 958 patients from our institutional database of men enrolled in AS between 1997-2019. Data on family history of prostate cancer and hereditary cancer syndrome ( BRCA1/2-related prostate, breast, ovarian and/or pancreatic cancers) were collected and integrated into a composite family history score incorporating the number of relatives with each cancer weighted by degree of relatedness. A strong family history was defined as a composite score representing > 1 first-degree relative equivalent. The primary outcome was biopsy progression and secondary outcomes were adverse pathologic features at prostatectomy and biochemical recurrence. Statistical analysis was conducted using the Kaplan-Meier method and Cox proportional hazards regression. Results: In univariate analysis, a strong family history suggestive of a hereditary cancer syndrome (HR 1.37 [1.03-1.90], P = 0.033) was associated with a significant increased risk of biopsy progression; however, any family history of prostate cancer (HR 1.10 [0.89-1.35], P = 0.38) and a strong family history of prostate cancer (HR 1.35 [0.92-1.98], P = 0.13) were not significant. In multivariate analysis, a strong family history suggestive of a hereditary cancer syndrome remained a statistically significant predictor of biopsy progression (HR 1.42 [1.03-1.96], P = 0.03), after adjusting for age, percent core involvement on initial biopsy and PSA density. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. Conclusions: A positive family history suggestive of a hereditary cancer syndrome is associated with an increased risk of biopsy progression on AS and is an independent predictor of biopsy progression. Men with such a family history may still be safely offered AS but should be counseled about the higher risk of progression. Further work to investigate the underlying genetic factors responsible for this increased risk is warranted.

A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.

Plague Journal

Given a strong family history of early heart attacks, the future has always been an iffy proposition. Miraculously, I have bypassed the early off-ramps and find myself approaching 80, stents in place, considering the very real but previously unimaginable possibility of still more. But what kind of more? With dopamine on the wane and no longer supercharged by the push and shove of unbridled ambition and pride, bigger and grander are out of the question. Tired clichés poke through the widening cracks in my thinking to become uninvited bulletins of compromise and consolation. Be grateful. Relax, reminisce, enjoy sunsets, learn the backyard birds’ names, maybe even sing to them, and count blessings.