Cognitive performance of GBA mutation carriers with early-onset PD: The CORE-PD study

e22154 Background: Recent studies in North American and British series have suggested an association between germline TP53 mutations and early onset HER2-positive breast cancer (BC). Mutations in the TP53 gene are estimated to occur in 1:2,000-1:5,000 individuals of the general population. Among women with BC who are unselected for family history they occur in up to 0.25%. In women with early-onset BC (<30 years) they occur in up to 7%. A specific germline TP53 mutation (c.1010G>A; p.R337H) has been encountered in 0.3% of the general population, in 13.3% of Li-Fraumeni-like families and in 0.5-2.4% of BC-affected women in Brazil. In an exploratory approach, the aim of this study was to investigate, in our series, if there is an association between human epidermal growth factor receptor 2 (HER2) amplification and the germline TP53 p.R337H mutation in a series of BC-affected women. Methods: A series of 718 Brazilian BC-affected women was genotyped in our previous study and 64 (8.9%) were mutation carriers. These cases were recruited from 3 centers and HER2 analysis was performed by immunohistochemistry (IHC) in each center according to validated protocols. Statistical analysis was done using SPSS software. Results: In 47 of 64 mutation carriers (73.5%), BC showed HER expression (either 1+, 2+ or 3+) while among 654 non-carriers, this immunophenotype was observed in 320 (48.9%) (p<0.001). This pattern was still observed after stratification of groups according to age at diagnosis (≤45 and ≥55 years) (p<0.001 and 0.03, respectively) and was independent of recruiting center. Conclusions: These results indicate that BC developing on a background of the founder Brazilian TP53 p.R337H mutation shows more frequently some amplification of HER2, consistent with recent studies showing an association between germline TP53 mutations and BC with HER2 hyperexpression. These findings should be confirmed in larger series to understand the significance of the association. If confirmed, this finding may justify germline TP53 p.R337H mutation testing in all HER2-positive Brazilian BC patients and would have a significant impact on patient and family counseling as well as on treatment.

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PO58 Early onset breast cancer: clinical characteristics and patterns of relapse in BRCA1/2 mutation carriers compared to non-carriers

The Breast ◽

10.1016/s0960-9776(12)70067-x ◽

2012 ◽

Vol 21 ◽

pp. S19-S20

Author(s):

G. Fried ◽

E. Matanis ◽

R. Gershoni-Baruch ◽

E. Dagan

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Clinical Characteristics ◽

Early Onset Breast Cancer ◽

Mutation Carriers

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Contribution of Lynch syndrome to early onset malignancy in Ireland.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.586 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 586-586

Author(s):

Alice Talbot ◽

David James Gallagher

Keyword(s):

Lynch Syndrome ◽

Cancer Diagnosis ◽

Early Onset ◽

Cancer Genetics ◽

Statistical Significance ◽

Hereditary Cancer Syndrome ◽

Carrier Status ◽

Mutation Carriers ◽

Significant Difference ◽

First Diagnosis

586 Background: Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2 -6% of hereditary colorectal cancers. LS is caused by germ-line mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2 or EPCAM. This results in microsatellite instability, a phenotypic hallmark of LS-associated colorectal cancer. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers. Methods: Records were from two of the three existing cancer genetics clinics in Ireland. Clinicopathological data of all probands (n=57) including names, dates of birth and death, carrier status and phenotype were recorded. Death certificates were used to confirm information regarding deceased mutation carriers. An ANOVA test was used to establish statistical significance of variations in age by gene. Length of survival based on stage was assessed using Kaplain Meier curves. Results: 345 affected individuals were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). 138 confirmed carriers were identified: 65 MLH1 (47%), 43 MSH2 (31%), 11 MSH6 (8%), 17 PMS2 (12%), and 2 EPCAM (1%). 22 patients have died since confirmation of Lynch Syndrome, 50% of whom died within 2.5 years of first diagnosis. All deceased carriers had at least one cancer diagnosis and 50% had developed multiple cancers. 59% of deaths were directly related to cancer. 7 of these patients had Stage 4 cancer at diagnosis. There was a significant difference in length of survival based on stage. (p=.048) Phenotype frequencies varied significantly by gene. (see table 1) Median age of first diagnosis of any cancer was 44.5 years (range 23-81). There was no difference in age at presentation by gene mutated. Conclusions: Under-diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset cancer diagnosis with substantial societal impact. A significant number of Lynch Syndrome cases have poor clinical outcomes. Genotype/Phenotype frequencies. [Table: see text]

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Clinical Phenotype and Mutation Spectrum of Alzheimer’s Disease with Causative Genetic Mutation in a Chinese Cohort

Current Alzheimer Research ◽

10.2174/1567205018666210608120339 ◽

2021 ◽

Vol 18 ◽

Author(s):

Chenhui Mao ◽

Jie Li ◽

Liling Dong ◽

Xinying Huang ◽

Dan Lei ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Clinical Phenotype ◽

Genetic Mutation ◽

Mutation Spectrum ◽

Systemic Review ◽

Genetic Mutations ◽

Csf Biomarkers ◽

Mutation Carriers

Background: Alzheimer’s disease with a causative genetic mutation (AD-CGM) is an un- common form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected. Objective: We aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China. Method: Next-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. Results: We studied the following gene mutation variants: 12 AβPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AβPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD. Conclusion: We identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset de- mentia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.

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Pathologic predictors of BRCA1/ BRCA2 (B1/B2) mutations in African-American (AA) women with early-onset breast cancer (BC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10549 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10549-10549

Author(s):

S. M. Domchek ◽

M. S. Simon ◽

C. Hughes Halbert ◽

T. R. Rebbeck ◽

K. L. Nathanson

Keyword(s):

Breast Cancer ◽

African American ◽

Early Onset ◽

Triple Negative ◽

Her2 Overexpression ◽

Her2 Breast Cancer ◽

Mutation Carriers ◽

Myriad Genetics ◽

Brca1 Brca2 ◽

Pathology Reports

10549 Background: African-American (AA) women more frequently have “triple negative” (ER-, PR-, HER2-) breast cancer (BC) and such BC are more frequently associated with B1 mutations; however, the correlation of triple negative BC in the AA population and B1/2 mutations is not known. We were interested in examining the prevalence of B1/2 mutations in a cohort of AA with early-onset breast as well as the associated pathologic characteristics. Methods: 85 unselected AA women diagnosed with 88 BC at or prior to age 40 were enrolled on study and underwent BRCA1/2 genetic testing by full sequencing at Myriad Genetics following informed consent. MLPA screening for large genomic rearrangements also was performed. Pathology reports were obtained and examined. Results: Of the 85 women, 16 (19%) had either a B1 (11) or B2 (5) deleterious mutation, which were associated with 19 BC. 19/85 (22%) women had a variant of unknown significance (VUS); 3 had B1 VUS, 15 had B2 VUS (including 2 with B1 mutations) and 1 had both B1 and B2 VUS. No mutations were detected with MLPA. Of the 14 BC in 11 B1 mutation carriers, 12 were ER- (86%), 13 were PR- (93%) and 3/12 were HER2+ (25%). Of the 5 BC in B2 carriers, 4 were ER- (80%), 1/4 HER2+ (25%). Receptor status was available in 77 of 88 cases (88%). Overall 41 of 77 (53%) cancers were ER-. 15 of 40 women (38%) with any ER- BC had either a B1 (11) or B2 (4) mutation. In contrast, of the 36 ER+ BC, 2 had a B1 and one had a B2 mutation (8%) (p=0.01). Both B1 carriers with ER+ BC also had a contralateral ER- BC. 18 of 65 (27%) cancers were known to be HER2+, of which 4 of 18 (22%) were associated with B1 or B2 mutations (p=NS). Median age of first BC in B1/B2 mutation carriers was 32 vs. 37 in non-carriers. Conclusions: In unselected AA women with early onset BC, B1/2 mutations were common and predominantly found in association with ER- BC. B2 VUS were detected frequently. HER2 overexpression did not predict against B1/2 mutations. No significant financial relationships to disclose.

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Cognitive performance in children with acute early-onset anorexia nervosa

European Child & Adolescent Psychiatry ◽

10.1007/s00787-016-0847-0 ◽

2016 ◽

Vol 25 (11) ◽

pp. 1233-1244 ◽

Cited By ~ 18

Author(s):

Betteke Maria van Noort ◽

Ernst Pfeiffer ◽

Stefan Ehrlich ◽

Ulrike Lehmkuhl ◽

Viola Kappel

Keyword(s):

Anorexia Nervosa ◽

Cognitive Performance ◽

Early Onset

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Cancer Risks For Mismatch Repair Gene Mutation Carriers: A Population-Based Early Onset Case-Family Study

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2006.01.002 ◽

2006 ◽

Vol 4 (4) ◽

pp. 489-498 ◽

Cited By ~ 110

Author(s):

M JENKINS ◽

L BAGLIETTO ◽

J DOWTY ◽

C VANVLIET ◽

L SMITH ◽

...

Keyword(s):

Mismatch Repair ◽

Gene Mutation ◽

Early Onset ◽

Family Study ◽

Population Based ◽

Mismatch Repair Gene ◽

Cancer Risks ◽

Repair Gene ◽

Mutation Carriers ◽

Early Onset Case

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Cannabis use before age 15 and subsequent executive functioning

The British Journal of Psychiatry ◽

10.1192/bjp.bp.110.077479 ◽

2011 ◽

Vol 198 (6) ◽

pp. 442-447 ◽

Cited By ~ 148

Author(s):

Maria Alice Fontes ◽

Karen I. Bolla ◽

Paulo Jannuzzi Cunha ◽

Priscila Previato Almeida ◽

Flávia Jungerman ◽

...

Keyword(s):

Executive Functioning ◽

Cognitive Performance ◽

Early Onset ◽

Impulse Control ◽

Late Onset ◽

Cannabis Use ◽

Neuropsychological Measures ◽

Neuropsychological Tasks ◽

Onset Group ◽

Early Onset Group

BackgroundMany studies have suggested that adolescence is a period of particular vulnerability to neurocognitive effects associated with substance misuse. However, few large studies have measured differences in cognitive performance between chronic cannabis users who started in early adolescence (before age 15) with those who started later.AimsTo examine the executive functioning of individuals who started chronic cannabis use before age 15 compared with those who started chronic cannabis use after 15 and controls.MethodWe evaluated the performance of 104 chronic cannabis users (49 early-onset users and 55 late-onset users) and 44 controls who undertook neuropsychological tasks, with a focus on executive functioning. Comparisons involving neuropsychological measures were performed using generalised linear model analysis of variance (ANOVA).ResultsThe early-onset group showed significantly poorer performance compared with the controls and the late-onset group on tasks assessing sustained attention, impulse control and executive functioning.ConclusionsEarly-onset chronic cannabis users exhibited poorer cognitive performance than controls and late-onset users in executive functioning. Chronic cannabis use, when started before age 15, may have more deleterious effects on neurocognitive functioning.

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