Germline Mutation Carriers Research Articles

Clinical Value of Genetic Susceptibility Genes for Myeloid Neoplasm in Myeloproliferative Neoplasm

To investigate the influence of genetic susceptibility genes for myeloid tumors on the clinical characteristics of patients with myeloproliferative neoplasm (MPN). Two hundred and thirty-two patients with MPN diagnosed at the Second Hospital of Tianjin Medical University from September 2017 to December 2021 were collected, myeloid neoplasm-related genes were detected by targeted next-generation sequencing, and germline mutations were verified. The clinical characteristics and prognosis of MPN patients with germlines mutations in the genetic susceptibility gene for myeloid neoplasm were analyzed. The germline mutation carrier rate of myeloid neoplasm genetic susceptibility gene in MPN patients was 21.6% (50/232), and the PV, ET and PMF patients carrying germline mutations of genetic susceptibility gene for myeloid neoplasm were 25/114 (21.9%), 8/69 (11.6%) and 17/49 (34.7%), respectively, among which PMF patients had the highest carrier rate (P=0.01) and were older (P=0.02). The incidence of chromosomal abnormalities in MPN patients carrying the genetic susceptibitity genes for myeloid neoplasm was higher than that in the non-carrier group (26.5% vs 11.8%, P=0.05). Germline mutations in the genetic susceptibility gene of myeloid neoplasm in MPN patients were mainly concentrated in the RAS pathway, and patients with germline mutations in the genetic susceptibility gene of myeloid neoplasm associated with the RAS pathway had shorter survival without AML progression (P<0.0001). The overall survival time in MPN patients with CBL and TP53 germline mutations was shorter than that of non-carrier group (P=0.001; P=0.043). In MPN, PMF patients are more likely to carry germline mutations in the genetic susceptibility gene for myeloid neoplasm. MPN patients with germline mutations carring the genetic susceptibility gene for myeloid neoplasm are prone to chromosomal abnormalities; Patients with MPN who have germline mutations in the genetic susceptibility gene for myeloid neoplasm in the RAS pathway are more likely to develop AML; CBL and TP53 germline mutations affect the overall survival of MPN patients.

Vitamin C boosts DNA demethylation in TET2 germline mutation carriers

BackgroundAccurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation.MethodsIn a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members.ResultsWe show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals.ConclusionsThese results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations.Trial registration: This trial was registered at EudraCT with reference number of 2018-000155-41 (01.04.2019).Graphical

Relative Risk of Bladder and Kidney Cancer in Lynch Syndrome: Systematic Review and Meta-Analysis.

Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane’s tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as “low” due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.

Routine genetic testing in patients with pancreatic cancer - worth it?

Background: Approximately 5-10% of patients with pancreatic adenocarcinoma (PDAC) carry germline mutations that contributed to the development of their cancer. Recently, the National Comprehensive Cancer Network (NCCN) began recommending that all pancreatic cancer patients and first-degree relatives undergo genetic testing. For patients who were previously unaware of their germline mutation, such findings may have significant impact on the patient’s family and family planning. The aim of this study was to investigate the frequency of new diagnoses of germline mutations in pancreatic cancer and characterize their oncologic outcomes.

Re-recognition of BMPR1A-related polyposis: beyond juvenile polyposis and hereditary mixed polyposis syndrome.

Bone morphogenetic protein receptor type 1A (BMPR1A) is responsible for two individual Mendelian diseases: juvenile polyposis syndrome and hereditary mixed polyposis syndrome 2, which have overlapping phenotypes. This study aimed to elucidate whether these two syndromes are just two subtypes of a single syndrome rather than two isolated syndromes. We sequenced the BMPR1A gene in 186 patients with polyposis and colorectal cancer, and evaluated the clinicopathological features and phenotypes of the probands and their available relatives with BMPR1A mutations. BMPR1A germline mutations were found in six probands and their three available relatives. The numbers of frameshift, nonsense, splice-site, and missense mutations were one, one, two, and two, respectively; two of the six mutations were novel. Typical juvenile polyps were found in only three patients. Two patients had colorectal cancer rather than any polyps. Diseases in BMPR1A germline mutation carriers vary from mixed polyposis to sole colorectal cancer, and typical juvenile polyps do not always occur in these carriers. The variety of phenotypes reflected the features of BMPR1A-mutation carriers, which should be recognized as a spectrum of one syndrome. Genetic testing may be a good approach to identifying BMPR1A-related syndromes.

Prophylactic and Early Thyroidectomy in RET Germline Mutation Carriers in Pediatric and Adult Population: Long-Term Outcomes of a Series of 63 Patients

Prophylactic and early thyroidectomy in RET germline mutation carriers allows the removal of the thyroid before medullary thyroid carcinoma (MTC) develops, or while it is still confined to the gland. This study was aimed to assess the clinicopathological features in RET carriers according to the age at surgery and the long-term outcomes after prophylactic and early thyroidectomy. A retrospective analysis of 63 operated asymptomatic RET carriers diagnosed after familial genetic screening was performed. Twenty-one RET carriers were operated at pediatric (<18 yrs) and 42 at adult (≥18 yrs) age. Serum preoperative calcitonin levels were significantly lower in pediatric compared to adult patients (p = 0.04); moreover, adult RET carriers had a greater frequency of microMTC at pathology (p = 0.009). Permanent postoperative morbidity occurred in 9.5% of patients, without differences between the two groups. Biochemical postoperative cure was achieved in all patients. At a median follow-up of 14 years, all C-cell hyperplasia patients are disease-free; conversely, biochemical, and structural recurrence of disease occurred in three adults and one pediatric patient with microMTC. The independent predictive factors of MTC were the age at surgery, the preoperative calcitonin level and the RET mutational risk profile (p < 0.02). In conclusion, prophylactic and early thyroidectomy are safe and effective procedures in achieving definitive cure in most RET carriers. However, since recurrences may occur at long-term in case of microMTC, thyroidectomy should be possibly performed earlier to prevent microMTC development.

Development of Human Pituitary Neuroendocrine Tumor Organoids to Facilitate Effective Targeted Treatments of Cushing's Disease.

(1) Background: Cushing's disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient's tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.

Human induced pluripotent stem cells generated from a patient with a homozygous mutation in the Lyn kinase gene

We have successfully generated induced pluripotent stem cells (iPSC) from dermal fibroblasts of the patient with a germline mutation in the coding region of the LYN kinase gene. This gain of function (GOF) mutation eliminates the inhibitory tyrosine (Y) at the position p.Y508, with an unknown established disease etiology. The iPSC carrying germline mutation in LYN are phenotypically normal, and they have capacity to differentiate toward the three germ layers. These iPSCs are critical for studying this unknown disease etiology and to the further understand the role of Lyn kinases in autoimmune disease.

Local treatment in patients with hereditary breast cancer: decision-making process in low-, moderate-, high-penetrance pathogenic germline mutation carriers.

We summarize recent evidence regarding commonly tested breast cancer susceptibility genes and review indications derived from recently published guidelines regarding management of carriers affected by early breast cancer (BC). Management of affected women with a known genetic predisposition to BC was matter of debate at the most relevant international conferences, such as St. Gallen International Consensus Conference and San Antonio Breast Cancer Symposium held both in 2021. At the same time, a joint Experts Panel from American Society of Clinical Oncology/American Society for Radiation Oncology/Society of Surgical Oncology (ASCO/ASTRO/SSO) convened to develop recommendations to support clinical decision-making in this specific setting and results about administration of new systemic therapies such as poly adenosine diphosphate-ribose polymerase (PARP) inhibitors became available. Population of patients affected by BC and carriers of mutations in susceptibility genes is progressively increasing, but new mutations identified do not always have a clear clinical impact.To date, we have data to support consideration of different local management choices for affected patients carrying specific mutations, but some issues especially relating to breast-conserving surgery or administration of radiotherapy in these patients, still need to be better addressed. Opinions about the best way to treat these patients are still heterogeneous and information deriving from different sources seems to be conflicting at times. Our purpose is to offer a synopsis of the different evidence available that may be helpful in clinical decision making.

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

BackgroundHigh-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown.MethodWe performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers).ResultsExploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions.ConclusionThese results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer.

Simple SummaryIn this study, we identified germline mutations that contribute to prostate cancer development in men who have multiple relatives with prostate cancer (and other cancers). We correlated the genetic mutations found in each patient with the resulting prostate cancer characteristics. Mutations found in ATM and CHEK2 genes were associated with aggressive prostate cancer. More data is needed to confirm the prevalence and impact of these germline mutations in prostate cancer.Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions: ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.

The role of prophylactic prostatectomy as a primary prevention strategy in high-risk germline mutation carriers.

Men with high-risk germline mutations are at significantly higher risk of developing and dying from prostate cancer. Current screening and treatment paradigms may lead to missed opportunities for cure. Herein we review the current literature on prevention, screening and treatment of these carriers and explore the potential role of prophylactic prostatectomy in primary prevention of prostate cancer mortality. Prostate-specific antigen (PSA)-based screening has demonstrated marginal benefits in prostate cancer (PCa) survival and uncertainty remains on its true benefit among high-risk carriers. Recent results indicate that PCa in BRCA 2 carriers occurs at a higher incidence, younger age and progresses more rapidly compared with noncarriers. An intensified screening protocol of MRI and PSA in young carriers demonstrated how using PSA values alone may be insufficient. Current evidence indicates that high-risk carriers have worse survival outcomes after undergoing radical treatment for screening detected disease when compared with noncarriers. Prophylactic prostatectomy within the context of a clinical trial is a reasonable primary prevention option for discussion with high-risk carriers, especially BRCA2 carriers during the shared decision-making process. Limitations exist in the current strategies of early PSA screening followed by radical treatment in this group.

Tissue methylated DNA markers for sporadic pancreatic cancer are strongly associated with familial and genetically predisposed pancreatic cancer

High-risk individuals (HRIs) with familial and genetic predisposition to pancreatic ductal adenocarcinoma (PDAC) are eligible for screening. There is no accurate biomarker for detecting early-stage PDAC. We previously demonstrated that a panel of methylated DNA markers (MDMs) accurately detect sporadic PDAC. In this study we compared the distribution of MDMs in DNA extracted from tissue of PDAC cases who carry germline mutations and non-carriers with family history, with control tissue and demonstrate high discrimination like that seen in sporadic PDAC. These results provide scientific rationale for examining plasma MDMs in HRIs with the goal of developing a minimally-invasive early detection test.

Abstract 5872: Investigation on the prevalence of germline and somatic mutations in gynecological malignancies: Implications for risk assessment and therapeutic decision-making

Abstract Introduction: Heritable mutations in cancer predisposition genes increase the relative risk of developing malignant gynecological tumors, whereas actionable somatic mutations could serve as biomarker for therapeutic decision-making. Our study explored the prevalence of germline pathogenic/likely-pathogenic (P/LP) mutations and actionable somatic mutations to understand the clinical utility of next-generation sequencing (NGS) in gynecological malignancies. Methods: Genomic data was retrospectively analyzed for 1,610 women with various stages of gynecological malignancies including ovarian (OC, n=945), cervical (CC, n=358), and endometrial cancers (EC, n=307). Genomic data were derived from targeted NGS of paired white blood cell and other biological samples using a 520-gene panel that included 62 cancer predisposition genes. Genomic signatures including tissue-based tumor mutation burden (tTMB) and microsatellite instability (MSI) were also estimated from somatic mutation profiles. Results: The prevalence of germline P/LP mutations in cancer predisposition genes was 20.6% for OC, 13.4% for EC, and 6.4% for CC. OC had the highest mutation rate in genes involved in the homologous recombination repair pathway (18.8%, 178/945), while EC had the highest mutation rate in genes involved in mismatch repair (MMR) pathway (5.5%, 17/307). The frequency of actionable germline P/LP mutations was 19.8% for OC, 11.7% for EC, and 5.0% for CC. The detection rate for actionable somatic mutations were comparable between carrier and non-carrier of germline mutations (OC, 80.5% vs 76.3%, p=0.2; EC, 73.2% vs 80.5%, p=0.4; and CC, 56.5% vs 63.0%, p=0.7). tTMB was also comparable and generally low among carrier and non-carrier of germline mutations (OC, 3.0 [range: 2.0-5.0] vs 3.0 [2.0-5.0], p=0.9; EC, 6.2 [4.8-45.1] vs. 4.8 [2.8-13.2], p=0.1; and CC, 4.8 [2.4-6.0] vs 4.0 [2.4-7.9], p=0.8). The proportion of MSI-H was comparable for OC patients with or without germline mutations (2.6% vs 1.2%, p=0.2); however, the proportion of MSI-H was significantly higher for EC (29.3% vs 11.7%, p=0.019) and CC (13.0% vs 1.2%, p&amp;lt;0.001) who were carriers of germline mutations than non-carriers. The proportion of MSI-H was comparable between EC patients with germline (n=5) and somatic (n=29) MMR gene mutations (40.0%, 2/5 vs 48.3%, 14/29; p=1). EC patients with MSI-H were more likely to have high tTMB (cut-off ≥7 mutations/Mb) (p&amp;lt;0.001). Conclusions: The comparable frequency of actionable somatic mutations in women with or without germline mutations indicates that both populations could benefit from NGS testing. Our findings raise the importance of NGS-based genetic testing with a large gene panel as part of gynecological cancer screening and diagnosis to explore heritable and acquired mutation status for risk assessment and therapeutic decision-making. Citation Format: Hao Wen, Qin Xu, Xiujie Sheng, Huawen Li, Xipeng Wang, Xiaohua Wu. Investigation on the prevalence of germline and somatic mutations in gynecological malignancies: Implications for risk assessment and therapeutic decision-making [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5872.

Abstract 1434: Molecular characteristics of breast cancer patients subjected to screening for germline predisposition in a population-based observational study

Abstract An estimated 5-10% of breast cancer cases carry germline mutations in genes associated with a moderate to strong breast cancer risk, like BRCA1 and BRCA2. These mutations can influence disease onset, progression, biology of the tumor, potential for therapy, risk of recurrence and cancer risk of close relatives. This warrants clinical germline screening for such gene variants according to national guidelines on patient selection. In this study we aimed to molecularly and clinicopathologically contrast clinically screened patients and their tumors against unscreened patients. For this we used a population-based breast cancer cohort from southern Sweden with 6660 patients (14% of which had been screened) with accompanying RNA-sequencing and clinicopathological registry data. Screening subsets were analyzed within five clinically relevant breast cancer subgroups based on hormone receptor and lymph node status. Among other features, we investigated clinicopathological characteristics, risk of tumor recurrence, survival outcomes, tumor proliferation markers, immune cell content, genes differentially expressed and the pathways in which they were involved. Most differences were found in the triple negative breast cancer (TNBC) subgroup: when compared to patients that had not been screened, the screened subset contained younger individuals showing better overall survival, more proliferative tumors with upregulated genes that belong to DNA replication and double-strand break repair processes, lower proportion of M2 macrophages and higher proportion of T-helper 2 cells. As so, Swedish screening guidelines divide TNBC cases into two separate subsets possibly by selecting distinct underlying biological and mutational mechanisms associated with DNA repair deficiency (e.g., through BRCA1/2-deficiency), a disparity not seen in other breast cancer clinical subgroups. Understanding the molecular landscape of defined screening populations may improve future guideline updates, which in turn would also improve patient and resource handling. Citation Format: Deborah F. Nacer de Oliveira, Johan Vallon-Christersson, Hans Ehrencrona, Anders Kvist, Åke Borg, Johan Staaf. Molecular characteristics of breast cancer patients subjected to screening for germline predisposition in a population-based observational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1434.

Germline Mutations in Patients With Early-Onset Prostate Cancer.

ObjectiveTo investigate the inherited mutations and their association with clinical features and treatment response in young-onset prostate cancer patients.MethodTargeted gene sequencing on 139 tumor susceptibility genes was conducted with a total of 24 patients diagnosed with PCa under the age of 63 years old. Meanwhile, the related clinical information of those patients is collected and analyzed.ResultsSixty-two germline mutations in 45 genes were verified in 22 patients. BRCA2 (20.8%) and GJB2 (20.8%) were found to be the most frequently mutated, followed by CHEK2, BRCA1, PALB2, CDKN2A, HOXB13, PPM1D, and RECQL (8.3% of each, 2/24). Of note, 58.3% (14/24) patients carry germline mutations in DNA repair genes (DRGs). Four families with HRR (homologous recombination repair)-related gene mutations were described and analyzed in detail. Two patients with BRCA2 mutation responded well to the combined treatment of androgen deprivation therapy (ADT) and radiotherapy/chemotherapy.ConclusionMutations in DRGs are more prevalent in early-onset PCa with advanced clinical stages, and these patients had shorter progression-free survival. ADT Combined with either radiotherapy or chemotherapy may be effective in treating PCa caused by HRR-related gene mutations.

Breast Cancer Risk in Women from Ghana Carrying Rare Germline Pathogenic Mutations.

Risk estimates for women carrying germline mutations in breast cancer susceptibility genes are mainly based on studies of European ancestry women. We investigated associations between pathogenic variants (PV) in 34 genes with breast cancer risk in 871 cases [307 estrogen receptor (ER)-positive, 321 ER-negative, and 243 ER-unknown] and 1,563 controls in the Ghana Breast Health Study (GBHS), and estimated lifetime risk for carriers. We compared results with those for European, Asian, and African American ancestry women. The frequency of PV in GBHS for nine breast cancer genes was 8.38% in cases and 1.22% in controls. Relative risk estimates for overall breast cancer were: (OR, 13.70; 95% confidence interval (CI), 4.03-46.51) for BRCA1, (OR, 7.02; 95% CI, 3.17-15.54) for BRCA2, (OR, 17.25; 95% CI, 2.15-138.13) for PALB2, 5 cases and no controls carried TP53 PVs, and 2.10, (0.72-6.14) for moderate-risk genes combined (ATM, BARD1, CHEK2, RAD51C, RAD52D). These estimates were similar to those previously reported in other populations and were modified by ER status. No other genes evaluated had mutations associated at P &lt; 0.05 with overall risk. The estimated lifetime risks for mutation carriers in BRCA1, BRCA2, and PALB2 and moderate-risk genes were 18.4%, 9.8%, 22.4%, and 3.1%, respectively, markedly lower than in Western populations with higher baseline risks. We confirmed associations between PV and breast cancer risk in Ghanaian women and provide absolute risk estimates that could inform counseling in Ghana and other West African countries. These findings have direct relevance for breast cancer genetic counseling for women in West Africa.

Territorial manifestation features of multiple primary malignant neoplasms in carriers of germline mutations in the BRCA 1 gene in Republic of Bashkortostan.

e22523 Background: Recent advances in the diagnostic and therapeutic fields of oncology have increased the life expectancy of cancer patients, and therefore carriers of germline mutations, who are at high risk of developing a malignant neoplasm, also have a higher risk of developing a second synchronous or metachronous malignant tumor. The aim of this work is to study the features of the development of primary multiple malignant neoplasms in patients with germline mutations in the repair genes. Methods: Among all treated in the Republican Clinical Oncological Dispensary patients germline mutations in the repair genes were detected in 225 persons. Mutations were determined by polymerase chain reaction (PCR). The material of the study was a sample of venous blood taken from a patient on an empty stomach. A diagnostic panel was used to detect the most common mutations in Russia in the BRCA1 (5382insC, 4153delA, 300T &gt; G, 185delAG, 2080delA, 3819delGTAAA) and BRCA2 (6174delT) genes. In the absence of a mutation, the study was carried out by the next generation sequencing (NGS) method. Results: After a molecular genetic study from 2014 to 2021, we determined the spectrum of germline mutations in residents of the Republic of Bashkortostan: BRCA 1 - c.5266dupC, c.3143delG, c.5161C &gt; T, c.5382 insC, c.3819delGTAAA, c. 300T &gt; G, c.5136G &gt; A, 185delAG, 4153delA, 2080delA; BRCA 2 - c.6621_6622del, p.39-1_39delGA, c.961_962insAA. Among carriers of germinal mutations, primary multiple cancer was registered in 14.6% (33/225) of patients with mutations in the BRCA 1 genes. The following mutations were identified in patients with primary multiple malignant neoplasms: c.5382 insC and c.3819delGTAAA in the BRCA gene 1. The first primary breast cancer was registered in 10.6% (24/225) of patients, ovarian cancer in 1.8% (4/225), gastric cancer in 0.4% (1/225), primary multiple synchronous breast and ovarian cancer in 1.8% (4/225). In carriers of germinal mutations, manifestations of the first primary cancer were observed at the age of 29 to 60 years. The manifestation of the second primary cancer was registered in 2-18 years after the manifestation of the first primary cancer. Twenty-two patients subsequently developed a second primary breast cancer and 11 patients developed ovarian cancer. Also, 6 patients had a manifestation of the third primary cancer of the breast, ovaries or stomach in 8-26 years after the manifestation of the second primary cancer. Conclusions: Primary multiple cancer in carriers of germline mutations in the Republic of Bashkortostan was observed in 14.6% (33/225) of patients with mutations in the BRCA 1 genes. The period of manifestation of a secondary malignant tumor ranged from 2 to 18 years. This study plays an important role in the process of optimizing screening for multiple primary malignant neoplasms for carriers of germline mutations.

Prevalence and clinical significance of pathogenic germline mutations in homologous recombination repair genes in Chinese lung cancer patients.

e20547 Background: There is accumulating evidence indicating that pathogenic germline mutations may contribute to lung cancer susceptibility besides environmental factors. The prevalence and clinical significance of pathogenic germline mutations in homologous recombination repair genes on lung cancer susceptibility has not been systematically investigated. Methods: We used real-world HaploX genomic data from patients (pts) with lung cancer to determine the prevalence of pathogenic germline mutations in homologous recombination repair genes from July 2020 to January 2022. Results: Out of the 766 patients screened, 5.5% (42/766) of the patients harbored the pathogenic germline mutations：12 with ATM, 12 with FANCA, 8 with ATR, 7 with BRCA1, and 3 with BRCA2. Conclusions: A proportion of 5.5% of patients carrying germline mutations in homologous recombination repair genes may be potentially linked to increased susceptibility to lung cancer. Our study has demonstrated that pathogenic germline mutations in homologous recombination repair genes are a risk factor for lung cancer.

Telomere-mediated lung disease.

Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange.