Hereditary Cases Research Articles

Genetic testing for hereditary cancer syndromes in Tunisian patients: Impact on health system

IntroductionCancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases is crucial to improve clinical management and preventive care in these settings. This study aims to explore the clinicopathological features and genetic factors associated with hereditary cancer in Tunisia, a North African country with a rising cancer burden Materials and methodsClinicopathological features and personal/family history of cancer were explored in 521 patients. Genetic analysis using Sanger and next-generation sequencing was performed for a set of patients ResultsHereditary breast and ovarian cancer syndrome was the most frequent cluster in which 36 BRCA mutations were identified. We described a subgroup of patients with likely ‘’breast cancer-only syndrome’’ among this cluster. Two cases of Li-Fraumeni syndrome with distinct TP53 mutations namely c.638G>A and c.733G>A have been identified. Genetic investigation also allowed the identification of a new BLM homozygous mutation (c.3254dupT) in one patient with multiple primary cancers. Phenotype-genotype correlation suggests the diagnosis of Bloom syndrome. A recurrent MUTYH mutation (c.1143_1144dup) was identified in three patients with different phenotypes ConclusionOur study calls for comprehensive genetic education and the implementation of genetic screening in Tunisia and other African countries health systems, to reduce the burden of hereditary diseases and improve cancer outcomes in resource-stratified settings.

Cribiform and intraductal carcinoma in hereditary prostate cancer: clinical and pathological analysis of 20 cases.

Cribiform and intraductal carcinoma are patterns of aggressive prostate carcinoma. This study investigated the clinical and pathological features of hereditary prostate cancer. Twenty cases of hereditary prostate cancer from 11 family lines treated at the First Affiliated Hospital of Zhejiang University School of Medicine between 2016-2022 were included to summarize the clinical and pathological features by analyzing clinical information including follow up the survival of the patients and pathological features. Of the 20 hereditary prostate cancer cases, 19 were radical prostate specimens and 1 was a biopsy specimen. The mean age at diagnosis of the patients was 67.55 years and the mean PSA was 15.44 ng/ml, of which 10 cases had PSA ≥ 10 ng/ml and 5 cases had PSA ≥ 20 ng/ml. Of the 19 radical prostate specimens, Gleason cribriform pattern (Gleason grade 4) of PCa is observed in 15 cases (78.95%), and intraductal carcinoma, usually a rare form, is seen in 9 cases (47.3%). Two cases demonstrated pelvic lymph node metastasis, and 7 cases (35%) belonged to high-risk or very high-risk PCa. One case (5.26%) showed partial deletion of expression of RB1, and 13 cases (68.42%) showed deletion of expression of PTEN. Follow-up was 4-90 months, 2 cases had biochemical recurrence and 1 case died from prostate cancer. The mean age at diagnosis of this group of patients with hereditary prostate cancer was 67.55 years, the mean preoperative PSA was 15.44 ng/ml, and their histomorphology was characterized by a high percentage of intraductal carcinoma and cribriform pattern of the prostate.

Immunohistochemistry staining for DNA mismatch repair proteins in endoscopic biopsies and the corresponding surgical specimen in colorectal cancer.

Microsatellite instability is found in 15% of sporadic colorectal cancers (CRC) and 95% of hereditary CRC cases. Lynch syndrome (LS) diagnosis begins with the analysis of the surgical specimen using methods such as immunohistochemistry (IHC), which identifies changes in the nuclear expression of DNA mismatch repair (MMR) proteins. However, IHC analysis on endoscopic biopsies could provide substantial benefits. Our goal was to assess the accuracy of MMR IHC status on endoscopic biopsies in comparison to corresponding surgical specimen in a series of CRC. We retrospectively selected patients who had undergone CRC surgery between February 2011 and January 2020 and had IHC testing for MMR proteins on the surgical specimen. The study was then performed on the corresponding endoscopic biopsies and results were compared. MMR IHC staining on surgical specimens were available for 361 CRC patients and only in 154 cases for preoperative endoscopic biopsies. The concordance between MMR IHC status of the endoscopic biopsy and the surgical specimen analysis was 98.6% for the MLH1/PMS2 proteins and 100% for MSH2/MSH6. In conclusion, endoscopic biopsies of colorectal tumors serve as a suitable tissue source for the immunohistochemical analysis of DNA repair proteins. The correlation with results from the surgical specimen was notably high and discrepancies were primarily as a result of intratumoral heterogeneity within the same sample. The features of MMR protein loss in endoscopic biopsies can provide clinicians with valuable information for specific therapeutic approaches and genetic counseling.

Enhanced Recovery after Surgery Applied to Pediatric Laparoscopic Cholecystectomy for Simple Cholelithiasis: Feasibility and Teaching Insights.

Same-day discharge after a cholecystectomy is a common practice in the adult population and has been demonstrated as safe and viable for children as well. However, there is a lack of comprehensive teaching models for pediatric cholecystectomy. Drawing inspiration from standardized outpatient procedures, this study aimed to assess the clinical outcomes and feasibility of teaching programs and an Enhanced Recovery After Surgery (ERAS) protocol following ambulatory laparoscopic cholecystectomy in pediatric patients. In 2015, an ERAS pathway for laparoscopic cholecystectomy (LC) was implemented, focusing on admission procedures, surgery timing, anesthetic choices, analgesia, postoperative feeding, mobilization, and pain assessment. Day-case surgery was not applicable for acute cholecystitis, choledochal lithiasis, sickle cell disease, and hereditary spherocytosis cases. The protocol was employed for a group of attending surgeons and fellows, as well as a group of residents under the supervision of experienced surgeons. A retrospective analysis was conducted to evaluate the feasibility and effectiveness of ambulatory cholecystectomy in children and its utilization in training pediatric surgical trainees. Between 2015 and 2020, a total of 33 patients were included from a cohort of 162 children who underwent LC, with 15 children operated on by senior surgeons and 18 by young surgeons. The primary diagnoses were symptomatic gallbladder lithiasis (n = 32) and biliary dyskinesia (n = 1). The median age at the time of surgery was 11.3 years (interquartile range (IQR) 4.9-18), and the median duration of surgery was 54 min (IQR 13-145). One intraoperative complication occurred, involving gallbladder rupture and the dissemination of lithiasis into the peritoneal cavity. Three patients (9%) required an overnight stay, while no postoperative complications or readmissions within 30 days were observed. ERAS was successfully implemented in 30 patients (91%). No significant differences in surgical outcomes were noted between senior and young surgeons. At an average follow-up of 55 months, no long-term sequelae were identified. These findings align with the current trend of increasing use of outpatient laparoscopic cholecystectomy and underscore its feasibility in the pediatric population. The application of a structured ERAS protocol appears viable and practical for training the next generation of pediatric surgeons. Level III.

Identification and characterization of ATM founder mutation in BRCA-negative breast cancer patients of Arab ethnicity

Breast cancer (BC) is the most prevalent malignancy among women worldwide with germline pathogenic variants/likely pathogenic variants (PVs/LPVs) in BRCA1/2 accounting for a large portion of hereditary cases. Recently, heterozygous PVs/LPVs in the ATM serine/threonine kinase or Ataxia-telangiectasia mutated gene (ATM) has been identified as a moderate susceptibility factor for BC in diverse ethnicities. However, the prevalence of ATM PVs/LPVs in BC susceptibility in Arab populations remains largely unexplored. This study investigated the prevalence of ATM PVs/LPVs among BC patients from Saudi Arabia, employing capture-sequencing technology for ATM PVs/LPVs screening in a cohort of 715 unselected BC patients without BRCA1/2 PVs/LPVs. In addition, founder mutation analysis was conducted using the PHASE program. In our entire cohort, four unique PVs/LPVs in the ATM gene were identified in six cases (0.8%). Notably, one recurrent LPV, c.6115G > A:p.Glu2039Lys was identified in three cases, for which haplotype analysis confirmed as a novel putative founder mutation traced back to 13 generations on average. This founder mutation accounted for half of all identified mutant cases and 0.4% of total screened cases. This study further reveals a significant correlation between the presence of ATM mutation and family history of BC (p = 0.0127). These findings underscore an approximate 0.8% prevalence of ATM germline PVs/LPVs in Arab BC patients without BRCA1/2 PVs/LPVs and suggest a founder effect of specific recurrent ATM mutation. These insights can help in the design of a genetic testing strategy tailored to the local population in Saudi Arabia, thereby, enabling more accurate clinical management and risk prediction.

Microsatellite instability screening in colorectal carcinoma: immunohistochemical analysis of MMR proteins in correlation with clinicopathological features and Ki-67 protein expression

BackgroundDefects in mismatch repair (MMR) system or microsatellite instability (MSI) and detected in colorectal carcinoma (CRC), both in sporadic and more frequently in hereditary cases. Immunohistochemistry (IHC) is the most frequent method for MMR protein deficiency screening in CRCs. In this study, we aimed to evaluate immunohistochemical expression of MMR and Ki-67 in colorectal carcinoma with clinicopathological features.MethodsIn this study, we evaluated the immunohistochemical expression of MMR proteins including MSH6, MSH2, PMS2 and MLH1 in 50 resection materials with colorectal carcinoma. Their expression is correlated with clinicopathological features of patients together, with Ki-67 protein expression in attempt to screen the most significant predictor of microsatellite instability.ResultsOf the 50 cases of cancer colon, 28% were classified as MSI-H, 20% were MSI-L, and 52% were MSS. The most frequent pattern in MSI-H tumors was concurrent loss of MSH6 and PMS2 proteins. There was a significant correlation between MMR protein expression pattern with tumor size, grade, T-classification and stage (0.015, 0.0515, 0.0162 and 0.0391), respectively. MSI-H tumors were located more frequently in right colon, early TNM stage and poorly differentiated and infrequent distant metastases. There was a significant correlation between Ki-67 high expression and MSI status patterns in their common biological aspects distinct from MSI-negative tumors.ConclusionsMismatch repair defective colorectal carcinoma has characteristics clinicopathological features different from MSS tumors. The role of immunohistochemistry (IHC) for MSI evaluation is the easiest and effective way for evaluation of MMR deficiency in colorectal carcinoma.

High frequency of WNT-activated medulloblastomas with CTNNB1 wild type suggests a higher proportion of hereditary cases in a Latin-Iberian population.

Medulloblastomas are the most common primary malignant brain tumors in children. They are divided into molecular subgroups: WNT-activated, SHH-Activated, TP53 mutant or wild type, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated medulloblastomas are usually caused by mutations in the CTNNB1 gene (85%-90%), and most remaining cases of CTNNB1 wild type are thought to be caused by germline mutations in APC. So far, the frequencies of CTNNB1 have been reported mainly in North American and European populations. The aim of this study was to report the frequency of CTNNB1 mutations in WNT-activated medulloblastomas in a Latin-Iberian population and correlate with their clinicopathological characteristics. A total of 266 medulloblastomas from seven different institutions from Brazil (n=211), Portugal (n=38), and Argentina (n=17) were evaluated. Following RNA and DNA isolation from formalin-fixed, paraffin-embedded (FFPE) tumor tissues, the molecular classification and CTNNB1 mutation analysis were performed by nCounter and Sanger sequencing, respectively. WNT-activated medulloblastomas accounted for 15% (40/266) of the series. We observed that 73% of WNT-activated medulloblastomas harbored CTNNB1 mutations. CTNNB1 wild-type cases (27%) were more prevalent in female individuals and suggested to be associated with a worse outcome. Among the CTNNB1 wild-type cases, the available analysis of family history revealed two cases with familiar adenomatous polyposis, harboring APC germline variants. We observed a lower incidence of CTNNB1 mutations in WNT-activated medulloblastomas in our Latin-Iberian cohort compared to frequencies previously described in other populations. Considering that CTNNB1 wild-type cases may exhibit APC germline mutations, our study suggests a higher incidence (~30%) of hereditary WNT-activated medulloblastomas in the Latin-Iberian population.

-PERPENDICULAR WIDE SUBCATEGORIES

Abstract Let $\Lambda $ be a finite-dimensional algebra. A wide subcategory of $\mathsf {mod}\Lambda $ is called left finite if the smallest torsion class containing it is functorially finite. In this article, we prove that the wide subcategories of $\mathsf {mod}\Lambda $ arising from $\tau $ -tilting reduction are precisely the Serre subcategories of left-finite wide subcategories. As a consequence, we show that the class of such subcategories is closed under further $\tau $ -tilting reduction. This leads to a natural way to extend the definition of the “ $\tau $ -cluster morphism category” of $\Lambda $ to arbitrary finite-dimensional algebras. This category was recently constructed by Buan–Marsh in the $\tau $ -tilting finite case and by Igusa–Todorov in the hereditary case.

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility.

Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

Recent trends in hereditary breast cancer incidence by race and age in KwaZulu-Natal, South Africa: An 11-year single-centre retrospective study (2011-2021).

Breast cancer incidence has increased globally in the last decade, especially in low- and middle-income countries. In Sub-Saharan Africa, breast cancer trends have been described only in a few populations owing to the scarcity of population-specific data. Using data collected between 2011 and 2021 at Inkosi Albert Luthuli Central Hospital, this retrospective study describes demographic and genetic trends for hereditary breast cancer patients in the KwaZulu-Natal province, South Africa. Six hundred and forty-five patients were included, of whom 44.3% were Black, 36.8% Indian, 15.6% White and 3.2% Coloured. The number of annual new cases increased from eight in 2011 to 145 in 2021, with a notable increase among Blacks. The mean onset age was 46 years, and Black patients were diagnosed ~10 years earlier than White and Indian patients. Triple-negative breast cancers accounted for 20.3% of hereditary cases, and 51.1% of them were Black. Bilateral and recurrent breast cancers constituted 7.4%, while pathogenic sequence variants in BRCA1/2 were reported in 10.4% of all patients, and the majority were Blacks and Indians. Overall, the KwaZulu-Natal province has seen an increase in hereditary breast cancer incidence in the past decade. Despite testing negative for pathogenic sequence variants, Black women frequently presented with breast cancers that are BRCA1-like, while Indians presented with extensive family history. This suggests that South African patients may require unique approaches to interventions, such as early detection and awareness programs among Blacks and increased genetic screening among Indians.

Iron overload leading to cirrhosis in a patient with hereditary spherocytosis and heterozygosity for H63D mutation in the HFE gene

Hereditary spherocytosis (HS) refers to a group of autosomal dominantly inherited heterogeneous hereditary haemolytic anaemias (HHA). Significant iron overload in HS is uncommon. Iron overload has been described as a complication of HS when there is co-inheritance of hereditary haemochromatosis (HH). H63D mutation accounts for a minority of hereditary hemochromatosis cases and does not cause iron overload in an otherwise healthy heterozygous carrier state. We present a 64-year-old man , diagnosed with HS presenting with cirrhosis without significant on-going haemolysis. He had a markedly high serum ferritin and transferrin saturation. Magnetic Resonance Imaging for liver iron concentration revealed haemochromatosis of the liver. HFE genotyping showed heterozygosity for the H63D mutant allele. Haemolysis in HS does not usually result in clinically significant iron excess leading to haemochromatosis and the presence of H63D heterozygous mutation will increase the risk of clinically significant iron overload which can lead to hepatic iron deposition and fibrosis. Therefore, if a patient with H63D mutation demonstrates clinically significant iron overload, clinicians should search for other factors that increase iron excess such as on-going haemolysis, alcohol abuse and presence of metabolic syndrome.

From Circulating Tumor Cells to Mirna: New Challenges in the Diagnosis and Prognosis of Medullary Thyroid Cancer.

Medullary thyroid carcinoma (MTC) is a malignant tumor that arises from parafollicular C cells, which are responsible for producing calcitonin. The majority (75%) of MTC cases are sporadic forms, while the remaining (25%) have a hereditary component. In these hereditary cases, MTC can occur in conjunction with other endocrine disorders (i.e., pheochromocytoma) or as an isolated condition known as familial medullary thyroid carcinoma. The primary genetic mutation associated with the development of MTC, regardless of its hereditary or sporadic nature, is a point mutation in the RET gene. Evaluation of serum calcitonin levels represents the most reliable and sensitive marker for both the initial diagnosis and the postsurgical monitoring of MTC. Unfortunately, most patients do not achieve normalization of postsurgical serum calcitonin (CT) levels after surgery. Therefore, there is a need to find new biomarkers to be used with serum CT in order to increase test sensitivity and specificity. In this review, we summarize the literature from 2010 to 2023 to review the role of circulating tumor cells, cell-free DNA, and miRNA and their application in diagnosis, outcome of MTC, and response to treatments.

Association of single nucleotide polymorphisms (4G/5G) of plasminogen activator inhibitor-1 and the risk factors for placenta-related obstetric complications.

Placenta-related obstetric complications (PROCs) such as miscarriage, fetal growth restriction, preeclampsia, and preterm birth are the major causes of maternal and fetal morbidity and mortality. The objective of this study was to search the relevance of plasminogen activator inhibitor-1 (PAI-1) polymorphisms and co-morbidities and the risk factors for PROCs such as miscarriage, fetal growth restriction, preeclampsia, and preterm birth. This retrospective study analyzed the PAI-1 genotype in a cohort of 268 multiparous women with poor obstetric history. Poor obstetric history was defined as the presence of at least one of the PROCs and/or poor gestational outcomes at the previous pregnancy/pregnancies. 5G allele frequency was higher than the 4G allele frequency in the cohort (0.767 vs. 0.233). The frequencies of having at least one risk factor are relatively similar among the different PAI-1 genotypes (P > 0.05). However, the presence of MTHFR polymorphisms (homozygous and compound heterozygous forms of C677T and A1298G) and hereditary thrombophilia (Factor V Leiden and prothrombin G20210A gene mutations, and FXIII deficiency) were found to be associated with PAI 4G/4G (P = 0.048) and 5G/5G (P = 0.022) genotypes, respectively. Significant differences were not observed in other risk factors and co-morbidities such as autoimmune disorders, chronic inflammatory diseases, history of venous thromboembolism, carbohydrate metabolism disorders, hyperlipidemia, cardiovascular and cerebrovascular diseases depending on PAI-1 genotypes (P > 0.05). MTHFR polymorphisms were found to be associated with PAI 4G/4G genotype, while 5G/5G genotype was observed more frequently in hereditary thrombophilia cases.

Arthur Conan Doyle, Sherlock Holmes, and gout.

Arthur Conan Doyle, the creator of Sherlock Holmes, was an experienced physician who treated gouty patients. A gouty character appears in The Adventure of the Missing Three-Quarter, a Sherlock Holmes novel. This offers the possibility of discussing gout from the peculiar perspective of a medical writer in light of the historical-medical context of the time. This study was conducted using Conan Doyle's autobiographical, scientific, and literary primary sources, as well as past and current medical literature. The Adventure of the Missing Three-Quarter was autobiographical. Conan Doyle himself was a rugby player and his wife died of tuberculosis. Furthermore, in 1884, in The Lancet, he described the hereditary case of a female gouty patient, presenting with ocular manifestations. In agreement with the concept of rich man's gout, the gouty patient of Sherlock Holmes' story, Lord Mount James, was a rich irascible noble but he was not addicted to the pleasures of food and sex. Following the usual funny representation of gouty patients, Conan Doyle made fun of Lord Mount James, but he misquoted a true case of gout cited in the literature. In his scientific and literary production on gout, Conan Doyle stuck to the most updated medical concepts of the time, demonstrating an uncommon knowledge of scientific literature.

The Correlation between Tumour Location, Clinicopathological Characteristics and Mismatch Repair Protein (MMR) Status of Colorectal Cancer In Egyptian Patients

Background: Colorectal cancer (CRC) is considered one of the most common cancers worldwide. By the year of 2035, it is predicted that there will be a dramatic rise of colonic and rectal cancers of 60% and 71.5% respectively. It has been reported that microsatellite instability (MSI) is a genetic target in hereditary nonpolyposis colorectal cancer cases however recent studies have shown that it is also implicated in the development of sporadic cases. MSI/MMR mutations can stimulate tumourigenesis by inactivating tumour suppressor genes and cases with high or deficient MMR (dMMR) have shown a better clinical outcome and response to programmed cell death 1 (PD-1) inhibitors in many studies. Furthermore, right and left sided colon cancers have different clinicopathological features and may display a different MMR status. Aim of the work: This work aimed to examine immunohistochemical expression of MMR proteins in colorectal tumours of Egyptian patients and their correlation with the age, sex, tumour grade, histological type and TNM stage to implicate possible therapeutic and prognostic potential. Material and Methods: This retrospective study was conducted on 409 cases of archived, formalin fixed paraffin embedded tissue blocks and immunohistochemical staining was performed using monoclonal antibodies against (MLH1, PMS2, MSH2 and MSH6). Results: MMR protein expression revealed intact expression (MMR-proficient status) in (84.4%) of the cases while (15.6%) of the cases showed lost protein expression. MMR protein loss was seen more frequently in patients with right side colon cancer compared to left side counterparts and this was statistically highly significant (p=0.001*). MLH1/PMS2 loss was the most frequent pattern while MSH2/MSH6 loss was less frequent. Moreover, a statistically significant correlation was demonstrated between loss of MLH1 and PMS2 among right-side tumours, while left-side CRC tumours revealed obvious loss MSH2 and MSH6. In regards to age and gender, a statistically significant correlation was seen regarding loss of MSH2 (p=0.008*) and MSH6 (p=0.002*). In thirty-eight cases, PMS2 was lost and showed a positive correlation regarding grade (p=0.045*). These results have shown the difference in MMR status of right and left sided colorectal cancers and the potential prognostic and therapeutic impact. Conclusion: The frequency of mismatch repair deficiency (dMMR) status in this cohort study carried on Egyptians’ CRC cases was 15.6%. It showed varying expression in right sided CRC in comparison to Left sided ones. The different biological factors regarding right and left sided colonic cancers may be used to identify cases who needs screening and further management.

Identification of a Biallelic Missense Variant in Gasdermin D (c.823G > C, p.Asp275His) in a Patient of Atypical Gorham-Stout Disease in a Consanguineous Family.

Gorham-Stout disease (GSD), also called vanishing bone disease, is a rare osteolytic disease, frequently associated with lymphangiomatous tissue proliferation. The causative genetic background has not been noted except for a case with a somatic mutation in KRAS. However, in the present study, we encountered a case of GSD from a consanguineous family member. Whole-exome sequencing (WES) analysis focusing on rare recessive variants with zero homozygotes in population databases identified a homozygous missense variant (c.823G > C, p.Asp275His) in gasdermin D (GSDMD) in the patient and heterozygous in his unaffected brother. Because this variant affects the Asp275 residue that is involved in proteolytic cleavage by caspase-11 (as well as -4 and -5) to generate an activating p30 fragment required for pyroptotic cell death and proinflammation, we confirmed the absence of this cleavage product in peripheral monocytic fractions from the patient. A recent study indicated that a shorter p20 fragment, generated by further cleavage at Asp88, has a cell-autonomous function to suppress the maturation of osteoclasts to resorb bone matrix. Thus, the present study suggests for the first time the existence of hereditary GSD cases or novel GSD-like diseases caused by GSDMD deficiency. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The APOBEC3B c.783delG Truncating Mutation Is Not Associated with an Increased Risk of Breast Cancer in the Polish Population.

The APOBEC3B gene belongs to a cluster of DNA-editing enzymes on chromosome 22 and encodes an activation-induced cytidine deaminase. A large deletion of APOBEC3B was associated with increased breast cancer risk, but the evidence is inconclusive. To investigate whether or not APOBEC3B is a breast cancer susceptibility gene, we sequenced this gene in 617 Polish patients with hereditary breast cancer. We detected a single recurrent truncating mutation (c.783delG, p.Val262Phefs) in four of the 617 (0.65%) hereditary cases by sequencing. We then genotyped an additional 12,484 women with unselected breast cancer and 3740 cancer-free women for the c.783delG mutation. The APOBEC3B c.783delG allele was detected in 60 (0.48%) unselected cases and 19 (0.51%) controls (OR = 0.95, 95% CI 0.56-1.59, p = 0.94). The allele was present in 8 of 1968 (0.41%) familial breast cancer patients from unselected cases (OR = 0.80, 95% CI 0.35-1.83, p = 0.74). Clinical characteristics of breast tumors in carriers of the APOBEC3B mutation and non-carriers were similar. No cancer type was more frequent in the relatives of mutation carriers than in those of non-carriers. We conclude the APOBEC3B deleterious mutation p.Val262Phefs does not confer breast cancer risk. These data do not support the hypothesis that APOBEC3B is a breast cancer susceptibility gene.

P-304 CDH1 and CTNNA1 negative hereditary diffuse gastric carcinoma cases: Genetic susceptibility variants and their potential impacts

P-304 CDH1 and CTNNA1 negative hereditary diffuse gastric carcinoma cases: Genetic susceptibility variants and their potential impacts

Functional Study of SAMD9L in Familial Gastric Cancer.

Familial aggregation occurs in approximately 10% of cases of gastric cancer. The genetic predisposition or cause of the disease in only about 40% of hereditary gastric cancer cases is known, while the genetic factors of the remaining cases remain to be studied. Samples were collected from a family with gastric cancer, including 3 gastric cancer and 17 healthy samples. Whole-exome sequencing was performed on samples from 3 patients with gastric cancer and 1 sample from healthy peripheral blood. SAMD9L was knocked down using small interfering RNAs and short hairpin RNA. The expression of SAMD9L was detected by quantitative real-time polymerase chain reaction and Western blot in SGC-7901 cells. CCK-8 assay was used to detect the proliferation of gastric cancer cells. The migration and invasion of gastric cancer cells were detected by Transwell assay and scratch assay. The cell apoptosis was detected by flow cytometry. Twelve single-nucleotide variants and 9 insertions/deletions mutation sites were identified as candidate genes. Among them, SAMD9L regulates cell proliferation as a tumor suppressor gene. The experiments of knocking down SAMD9L in SGC-7901 cells revealed that reduced expression of SAMD9L significantly enhanced the proliferation, migration, and invasion of SGC-7901 cells. These results suggest that SAMD9L inhibits the proliferation of gastric cancer cells, thereby increasing the risk of gastric cancer in people with SAMD9L downregulation. Therefore, SAMD9L may represent a susceptibility gene of this gastric cancer family.

A dominant variant in apoptosis-related gene XKR8 is relevant to hereditary auditory neuropathy

BackgroundAuditory neuropathy is an unusual type of hearing loss. At least 40% of patients with this disease have underlying genetic causes. However, in many hereditary auditory neuropathy cases, etiology remains undetermined.MethodsWe collected data and blood samples from a four-generation Chinese family. After excluding relevant variants in known deafness-related genes, exome sequencing was conducted. Candidate genes were verified by pedigree segregation, transcript/protein expression in the mouse cochlea, and plasmid expression studies in HEK 293T cells. Moreover, a mutant mouse model was generated and underwent hearing evaluations; protein localization in the inner ear was also assessed.ResultsThe clinical features of the family were diagnosed as auditory neuropathy. A novel variant c.710G > A (p.W237X) in apoptosis-related gene XKR8 was identified. Genotyping of 16 family members confirmed the segregation of this variant with the deafness phenotype. Both XKR8 mRNA and XKR8 protein were expressed in the mouse inner ear, predominantly in regions of spiral ganglion neurons; Moreover, this nonsense variant impaired the surface localization of XKR8 in cells. Transgenic mutant mice exhibited late-onset auditory neuropathy, and their altered XKR8 protein localization in the inner ear confirmed the damaging effects of this variant.ConclusionsWe identified a variant in the XKR8 gene that is relevant to auditory neuropathy. The essential role of XKR8 in inner ear development and neural homeostasis should be explored.