Family History Of Early Onset Research Articles

Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Analysis of Breast Cancer Family History, Estrogen Receptor Status, and Breast Cancer Outcomes in Sweden

ImportanceBreast cancer (BC), the most prevalent cancer among women globally, is a heterogeneous disease, with prognosis differing by estrogen receptor (ER) status. Having a family history of BC increases the risk of BC; however, it is unclear whether family history is associated with the prognosis of overall and ER-specific BC.ObjectiveTo assess whether a family history of BC is associated with the prognosis of overall and ER-specific BC.Design, Setting, and ParticipantsThis cohort study was based on data from several national registers in Sweden. All female residents of Stockholm who were born after 1932; had their first BC diagnosis between January 1, 1991, and December 31, 2019; and had at least 1 identified female first-degree relative (FDR) were included. Women who were diagnosed with other types of cancer before their BC diagnosis, were older than 75 years at diagnosis, or had distant metastasis at diagnosis were excluded. A total of 28 649 women were included. Data were analyzed from January 10, 2022, to December 20, 2022.ExposuresFamily history of BC, defined as 1 or more female FDRs diagnosed with BC.Main Outcomes and MeasuresPatients were followed up until BC-specific death, censoring, or end of follow-up on December 31, 2019. The role of family history in BC-specific mortality was investigated using flexible parametric survival models among the full cohort, ER-positive subgroup, and ER-negative subgroup, adjusting for demographic characteristics, tumor characteristics, and treatments received.ResultsAmong 28 649 patients, the mean (SD) age at BC diagnosis was 55.7 (10.4) years; 19 545 (68.2%) had ER-positive BC, and 4078 (14.2%) had ER-negative BC. Overall, 5081 patients (17.7%) had at least 1 female FDR diagnosed with BC, while 384 (1.3%) had a family history of early-onset BC (FDR diagnosed before age 40 years). During the follow-up period (median [IQR], 8.7 [4.1-15.1] years), 2748 patients (9.6%) died of BC. Multivariable analyses revealed that having a family history of BC was associated with a lower risk of BC-specific death among the full cohort (hazard ratio [HR], 0.78; 95% CI, 0.65-0.95) and the ER-negative subgroup (HR, 0.57; 95% CI, 0.40-0.82) in the first 5 years, after which no association was observed. However, having an early-onset family history was associated with a higher risk of BC-specific death (HR, 1.41; 95% CI, 1.03-2.34).Conclusions and RelevanceIn this study, patients with a family history of BC did not necessarily have a worse prognosis. Those with ER-negative status and a family history of BC had more favorable outcomes in the first 5 years after diagnosis, possibly due to enhanced motivation to receive and adhere to treatment. However, patients with a family history of early-onset BC had worse survival, suggesting that genetic testing of newly diagnosed patients with early-onset family history may provide useful information to aid treatment and future research.

Associations between cancer family history and esophageal cancer and precancerous lesions in high-risk areas of China.

Background:Family clustering of esophageal cancer (EC) has been found in high-risk areas of China. However, the relationships between cancer family history and esophageal cancer and precancerous lesions (ECPL) have not been comprehensively reported in recent years. This study aimed to provide evidence for identification of high-risk populations.Methods:This study was conducted in five high-risk areas in China from 2017 to 2019, based on the National Cohort of Esophageal Cancer. The permanent residents aged 40 to 69 years were examined by endoscopy, and pathological examination was performed for suspicious lesions. Information on demographic characteristics, environmental factors, and cancer family history was collected. Unconditional logistic regression was applied to evaluate odds ratios between family history related factors and ECPL.Results:Among 33,008 participants, 6143 (18.61%) reported positive family history of EC. The proportion of positive family history varied significantly among high-risk areas. After adjusting for risk factors, participants with a family history of positive cancer, gastric and esophageal cancer or EC had 1.49-fold (95% confidence interval [CI]: 1.36–1.62), 1.52-fold (95% CI: 1.38–1.67), or 1.66-fold (95% CI: 1.50–1.84) higher risks of ECPL, respectively. Participants with single or multiple first-degree relatives (FDR) of positive EC history had 1.65-fold (95% CI: 1.47–1.84) or 1.93-fold (95% CI: 1.46–2.54) higher risks of ECPL. Participants with FDRs who developed EC before 35, 45, and 50 years of age had 4.05-fold (95% CI: 1.30–12.65), 2.11-fold (95% CI: 1.37–3.25), and 1.91-fold (95% CI: 1.44–2.54) higher risks of ECPL, respectively.Conclusions:Participants with positive family history of EC had significantly higher risk of ECPL. This risk increased with the number of EC positive FDRs and EC family history of early onset. Distinctive genetic risk factors of the population in high-risk areas of China require further investigation.Trial registration:ChiCTR-EOC-17010553.

Family history of cancer and the risk of childhood solid tumours: a Norwegian nationwide register-based cohort study

Background:It is not clear if family history of cancer increases risk of cancer in children.Methods:We followed-up a total of 2 610 937 children born between 1960 and 2001 for cancer risk, and their parents and siblings. In this period, 2477 primary childhood solid tumours (except lymphoma) were diagnosed. The data from the Norwegian Family and Life Course Study and from the Norwegian Cancer Register were used. Classification of hereditary cancer syndromes was based on tumour histology, pedigrees and Chompret’s criteria.Results:An association between risk of childhood tumours and first-degree family history of early onset of solid tumours was observed for central nervous system tumours (2.3-fold), neuroblastoma (2.3-fold), retinoblastoma (6.1-fold), hepatic tumours (4.0-fold), and melanomas (8.3-fold). Elevated risk was also seen for osteosarcomas (1.5-fold) when considering first-degree family history of cancer diagnosed at any age. The risk of hepatic tumours, neuroblastomas and melanomas remained elevated even after controlling for probable hereditary cancer syndromes.Conclusions:The increased risk for several childhood solid site cancers among those with first-degree relatives diagnosed with solid cancer suggests that genetic or environmental factors are involved. The fact that these associations remained after controlling for hereditary cancer syndromes indicates other genetic mechanisms might be involved.

Diagnosing and Managing Primary Aldosteronism in Hypertensive Patients: a Case-Based Approach

Primary aldosteronism with a prevalence of 8% of hypertension and 20% of pharmacologically resistant hypertension is the most common secondary cause of hypertension. Yet, the diagnosis is missed in the vast majority of patients. Current clinical practice guidelines recommend screening for primary aldosteronism in patients with sustained elevation of blood pressure (BP) ≥150/100mmHg if possible prior to initiation of antihypertensive therapy, and in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, adrenal incidentaloma, obstructive sleep apnea, a family history of early onset of hypertension or cerebrovascular accident <age 40, and first-degree relatives of patients with primary aldosteronism. Clinical and laboratory methods of screening, confirmatory testing, subtype classification, and medical and surgical management are systematically reviewed and illustrated with a clinical case.

Early Vascular Aging: A New Target for Hypertension Treatment.

Vascular aging represents a progressive procedure involving biochemical, enzymatic, and cellular changes of the vascular tree. Early vascular aging (EVA), is defined as the inappropriate for age of vascular damage. Increased for age arterial stiffness is a biomarker that should be considered as a cardiovascular (CV) risk factor that can be manipulated. EVA is a new tool for guidance in everyday clinical praxis for patients at increased CV risk or a positive family history of early onset of cardiovascular events, such as stroke or coronary artery disease. Understanding the mechanisms promoting or protecting from EVA, a process that is in close relationship with CV diseases. The role of hypertension treatment against the development of vascular damage is important and different strategies could have a considerable impact on future vascular health.

Partner and Localizer of BRCA-2 (PALB-2) Mutation Analysis Is Rapidly Being Adopted into Clinical Practice.

To the Editor, Breast-Cancer Risk in Families with Mutations in PALB2: A.C. Antoniou, S. Casadei, T. Heikkinen, et al. N Engl J Med. 2014;371:497-506. In a study published in N Engl J Med. August 2014, researchers from 14 centers in eight countries investigated information from 362 family members from 154 families who had an abnormal partner and localizer of BRCA2 (PALB2) gene, but did not have an abnormal BRCA1 or BRCA2 gene. Their aim was to demonstrate the importance of loss-of-function mutations in PALB2 as a cause of hereditary breast cancer. The study included 311 women with an abnormal PALB2 gene; 229 of these women had been diagnosed with breast cancer and 51 men with an abnormal PALB2 gene; seven of whom had been diagnosed with breast cancer. The researchers compared the breast cancer risk of the study population to the general population. They found out that overall, women with an abnormal PALB2 gene had a risk of breast cancer that was 9.47 times higher than average. Women with an abnormal PALB2 gene had a 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70. The average lifetime risk of breast cancer is about 12%. This increase in risk linked to an abnormal PALB2 gene was dependent on the women’s age and family history. They have demonstrated that the relative risk of breast cancer among PALB2 mutation carriers increased significantly as birth cohort became more recent (P<0.001). In women with an abnormal PALB2 gene, breast cancer risk was eight to nine times higher than average in women aged 20 to 39, six to eight times higher than average in women aged 40 to 60, and five times higher than average in women older than 60 years of age. By the age of 70, women with an abnormal PALB2 gene with no family history of breast cancer had a 33% risk of developing breast cancer whereas women with two or more first-degree relatives with breast cancer at 50 years of age had a 58% risk of developing the disease. The authors concluded that based on their estimates, breast cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. The researchers also reported that this level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2. A Genetic counselor’s perspective Partner and localizer of BRCA2 (PALB) is a gene whose protein facilitates the function of BRCA2 and interacts with BRCA1 to aid in repairing double strand and interstrand cross-link DNA damage. Biallelic PALB2 mutations cause Fanconi Anemia complement group N (FANCN) and monoallellic mutations in the PALB2 gene are associated with increased breast and pancreas cancer risks (1). PALB2 mutations may account for as much as 3% of familial breast cancer risk (2). A recent study of 362 members from PALB2 mutation positive families found that the risk for breast cancer in female mutation carriers ranged between 33% to 58% by age 70, with the higher risks relating to those women with a family history of early onset (<50) breast cancer in 2 first degree family members (3). The study also identified an 8 fold increase in male breast cancer risk and a 2 fold increase in ovarian cancer risk, both of which need to be confirmed in additional studies due a lack of statistical significance. These data suggest that female PALB2 mutation carriers may have breast cancer risks that are similar to those conferred by mutations in the BRCA2 gene. These findings suggest that women who carry PALB2 gene mutations may warrant similar breast cancer screening and prevention strategies as those offered to BRCA2 mutation carriers. PALB2 mutation analysis is available and is rapidly being adopted into clinical practice. As the data continues to accumulate it is likely that PALB2 mutation analysis will become a standard part of genetic testing in the realm of hereditary breast cancer predisposition. Whether testing will be done in addition to BRCA1/2 or as part of a larger breast cancer gene panel remains to be determined. In addition, more data will provide evidence to support the development of specific management guidelines to aid in the care of these at risk patients.

Liddle’s‐Like Syndrome in the Elderly

An 88-year-old woman was undergoing inpatient rehabilitation following hip fracture surgery. Her background history included Alzheimer’s dementia, untreated hypertension, and hypercholesterolemia. There was no family history of early onset or familial hypertension. During her hospital stay, she was hypertensive (systolic blood pressure ranging from 160 to 185 mm Hg) with unexplained hypokalemia (2.5–3.2 mmol/L) and concomitant metabolic alkalosis. Further tests revealed hyporeninemic hypoaldosteronism. Normal urinary cortisol levels and metabolites excluded the diagnosis of hypercortisolism and apparent mineralocorticoid excess. Liddle’s syndrome was considered a probable diagnosis and amiloride was administered with improvement in her serum potassium level and blood pressure. Subsequent genetic testing of ENaC sequences (Liddle’s gene) returned negative results. Liddle’s syndrome is classically associated with early-onset hypertension with hypokalemic metabolic alkalosis and hyporeninemic hypoaldosteronism. Primary sodium retention resulting from enhanced activity of epithelial sodium channels in the cortical collecting duct of the nephrons leads to hypertension and associated hypokalemic metabolic alkalosis. In a recent publication by Tapolyai and colleagues, high prevalence of Liddle’s syndrome phenotype was described in an elderly population. Their study effectively highlighted limited recognition of hypertension associated with hyporeninemic hypoaldosteronism in this age group; however, data regarding genetic testing for Liddle’s syndrome were not provided. A negative gene test in our patient was interesting as it opened up further possibilities such as presence of a previously undescribed genetic defect or a variant of Liddle’s syndrome with possibly different inherited or acquired mutation, which may present in older adults, as does the variant of hypertrophic cardiomyopathy. The second possibility is age- or medication-related dysfunction of epithelial sodium channels leading to a Liddle’s-like biochemical profile. Screening the adult population with hypertension for this Liddle’s-like syndrome could be challenging due to multiple reasons, including polypharmacy, presence of isolated systolic hypertension, dietary habits, presence of renal disease, variability of presence of hypertension and hypokalaemia; however, like many other disorders, we may be looking at only the tip of the iceberg and many older adults thought to have systolic hypertension might actually have this particular type of disorder. This raises the need for criteria to look for the presence of hyporeninemic hypertension in this population. Testing for serum renin and aldosterone, however, should be done following normalizing serum potassium and after withholding relevant medications that might interfere with the results. Our proposed criteria to investigate for hyporeninemic hypoaldosteronism in hypertensive adults is presented in the Table. Monitoring and reviewing other family members may also be important. Lastly, the defect that causes this Liddle’s-like profile could be similar to the epithelial Na channel mutants that cause Liddle’s syndrome; however, the mechanism involved and its initiation could be different from Liddle’s syndrome, which may warrant further research.

Population-Based Estimate of the Contribution of TP53 Mutations to Subgroups of Early-Onset Breast Cancer: Australian Breast Cancer Family Study

Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal. We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer. Germline TP53 mutation status was assessed by DNA sequencing, screening for heterozygous single-nucleotide polymorphisms, and Multiplex Ligation-Dependent Probe Amplification analyses. From an Australian population-based series of invasive breast cancers, we studied (a) 52 women diagnosed before age 30 years unselected for family history [very early-onset (VEO)] and (b) 42 women diagnosed in their 30s with two or more first- or second-degree relatives with breast or ovarian cancer [early-onset family history (EO-FH)]. Of the VEO group, two (4%) had a mutation: G13203A (exon 6 missense) in a 24-year-old and a large 5,338-bp genomic deletion in a 26-year-old. Neither had a family cancer history that met Li-Fraumeni criteria. Of the EO-FH group, three (7%) had a mutation: T13240G (a known intron 5 splicing mutation) in a 36-year-old from a classic Li-Fraumeni family; G12299A (exon 4 missense) in a 33-year-old from a Li-Fraumeni-like family; and 14058delG (exon 7 frame-shift) in a 39-year-old with a family cancer history that did not meet Li-Fraumeni criteria. Germline TP53 mutations play a larger role in early-onset breast cancer than previously thought, and in this context, can be evident outside clinically defined Li-Fraumeni families.

Preimplantation genetic diagnosis for BRCA1 exon 13 duplication mutation using linked polymorphic markers resulting in a live birth

The risk of breast cancer associated with inheriting a BRCA1 mutation is extremely high, in addition, there is a 50% chance of transmitting this familial cancer mutation to any offspring. A 31-year-old woman with a strong maternal family history of early onset of breast cancer had experienced 3 years of primary infertility. Presymptomatic testing confirmed the woman had inherited a 6 kb duplication of exon 13 (ins6KbEx13) in BRCA1 from her mother. Neither gamete donation or adoption were acceptable options for this infertile couple, and as termination of pregnancy after prenatal diagnosis following in vitro fertilization (IVF) was not ethically acceptable, preimplantation genetic diagnosis (PGD) was sought. A single-cell PCR protocol for PGD for the breast and ovarian cancer predisposing BRCA1 exon 13 duplication mutation was developed which involved amplification of three specific gene regions, including the BRCA1 mutation (ins6KbEx13), an intragenic marker (D17S855) and a flanking marker (D17S1185). In the first cycle of IVF, three embryos were analyzed and two were determined to be at low risk of having inherited the maternal BRCA1 mutation. Following the transfer of both embryos on day 5, a singleton pregnancy resulted. Declining confirmatory prenatal diagnosis, a male baby was subsequently delivered at term. Successful PGD for BRCA1 resulted in the delivery of a live-born male. PGD using linked polymorphic markers provides an alternate option for reproduction for couples with or at risk of having inherited a BRCA1 mutation.

Relations of plasma fibrinogen level in children to measures of obesity, the (G-455-->A) mutation in the beta-fibrinogen promoter gene, and family history of ischemic heart disease: the Columbia University BioMarkers Study.

Higher plasma fibrinogen levels are associated with increased risk of myocardial infarction in adults, but little is known about factors that influence fibrinogen levels in childhood. The authors examined the associations of measures of obesity, presence of the (G-455-->A) allele in the beta-fibrinogen promoter gene, and family history of early onset of ischemic heart disease with plasma fibrinogen levels in children. Children (n = 299) were recruited during 1994-1997 from 276 families living in a racially mixed area of New York City. The mean age of the study children was 9.9 years; 79% were Hispanic. The frequency of the (G-455-->A) allele was lower in Hispanics than in non-Hispanic Whites (15.5% vs. 28.3% in children (p < 0.01) and 13.9% vs. 28.3% in parents (p < 0.001)). Graded relations of children's plasma fibrinogen levels were found with tertiles of body mass index (weight (kg)/height (m)2) and sum of skinfolds (tests for linear trend: p < 0.001). Plasma fibrinogen levels in the children were not related to race/ethnicity, presence of the (G-455-->A) allele, or family history. Multiple linear regression analyses adjusting plasma fibrinogen levels for age, sex, race/ethnicity, the (G-455-->A) allele, and family history of early onset of heart disease showed a significant association with either body mass index or sum of skinfolds (p < 0.001 for both models) but not with the other variables.