Double Hit in Clear-Cell Renal Cell Carcinoma With Germline Pathogenic ATM Mutation and Somatic VHL Mutation.

While renal cell carcinoma (RCC) is often linked to smoking, obesity, and hypertension, hereditary forms also account for about 3% of RCC cases. Notably, NCCN guidelines identify 7 major hereditary syndromes associated with an increased RCC risk. Inherited mutations in DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of various cancers. Biallelic pathogenic mutations in ATM cause Ataxia-Telangiectasia (A-T) syndrome, while heterozygous germline pathogenic ATM mutations, present in about 1% of the population, also elevate cancer risk. RCC has not traditionally been associated with germline pathogenic ATM mutations, only limited retrospective analyses have identified such mutations. This case report presents a 68-year-old woman with a germline pathogenic ATM mutation (c.8786+1 G>A) who developed high-risk clear cell RCC followed by an acquired somatic VHL mutation in RCC and a 3-cm serous cystadenoma, illustrating the double-hit phenomenon. Her brother, who shares the same germline pathogenic mutation, was diagnosed with pancreatic cancer and prostate cancer. This case highlights the potential use for enhanced screening protocols for RCC in patients who have germline pathogenic ATM mutations and the importance of research in targeted treatments for tumors driven by dual genetic mechanisms. Increased awareness and vigilant screening for RCC are crucial in managing hereditary cancer syndromes effectively.

Nodule-specific NRF2-targeted upregulation in patients with KEAP1 mutations and familial nontoxic multinodular goiter.

CONTEXT: Kelch-like ECH-associated protein 1 (KEAP1) is associated with nuclear factor erythroid-2 related factor 2 (NRF2) and promotes NRF2 degradation in normal conditions. Genetic abnormality in KEAP1 is a rare disease and presents with familial multinodular goiter. OBJECTIVE: This study assessed the clinical and molecular findings concerning nodular formation in the thyroid gland of patients harboring KEAP1 germline mutations. METHODS: Next-generation sequencing analysis targeting goiter-associated genes was performed on 39 patients with familial multinodular goiter. The expression of NRF2-targeted genes from surgical thyroid specimens of patients with KEAP1 mutations were analyzed using a whole transcript expression array and immunohistochemistry. RESULTS: We found five probands with pathogenic heterozygous mutations in KEAP1 (p.Q86*, p.L136P, p.V411fs, p.R415C, and p.R483H), which had no meaningful concomitance with mutations of other goiter-associated genes in germline and somatic levels. Their common histopathological features showed multinodular goiters in the entire thyroid gland with few degenerative lesions or complications of malignancy and slow proliferation indicating < 1% at the Ki-67 labeling index. Among 42 NRF2-targeted genes, antioxidant genes were most frequently upregulated (11/12) in the nodule, followed by detoxification genes (6/11). Immunohistochemical analysis showed relatively high expression of glutathione peroxidase 2 and NAD(P)H quinone oxidoreductase 1 (representative NRF2-targeted genes) in the nodules of various patients harboring KEAP1 mutations. CONCLUSION: KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.

Clinical relevance of protein-truncating variants of germline DNA repair genes in prostate cancer.

BACKGROUND: Interpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied. METHODS: We collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy. RESULTS: We identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients. CONCLUSIONS: PTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

Detection of Germline Variants in Patients With Localized and Metastatic Prostate Cancer Through Guideline-Based Testing.

PURPOSE: There is increasing awareness that patients with prostate cancer frequently harbor germline variants that may carry important implications for them and their family members. Given the variable clinical guidelines, there remains a need to better understand which patients with prostate cancer are likely to harbor pathogenic or likely pathogenic (P/LP) germline variants. We sought to understand factors associated with P/LP germline variants in patients with metastatic or localized prostate cancer qualifying for National Comprehensive Cancer Network genetic testing criteria. MATERIALS AND METHODS: Patients diagnosed with prostate cancer were offered genetic testing in accordance with National Comprehensive Cancer Network guidelines. Patient-level factors, including demographic, clinical, and pathologic data, were tracked in a prospectively collected registry. The association of the presence of a P/LP variant in germline testing results with patient-level factors was assessed using univariate and multivariate logistic regression. Variables were tested for overall significance with chi-squared tests. RESULTS: Five hundred five patients underwent germline testing and had clinical data available. Rates of P/LP germline variants were 7.6% (20/264) in patients with metastatic disease and 11.2% (27/241) in patients with localized disease. The most prevalent P/LP variants were CHEK2 (34%), BRCA2 (22%), ATM (10%), and HOXB13 (10%). CONCLUSIONS: In this cohort of patients undergoing guideline-informed germline testing, P/LP germline variants were found in similar proportions across all age ranges and clinical characteristics. Only age at genetic testing for patients with metastatic disease was demonstrated to be predictive of the presence of a P/LP germline variant, highlighting the challenges associated with refining current clinical testing guidelines.

Whole exome sequencing in relapsed or refractory childhood cancer: case series.

Background: The prognosis for relapsed or refractory childhood cancer is approximately 20%. Genetic alterations are one of the significant contributing factors to the prognosis of patients. Objective: To investigate the molecular profile of relapsed or refractory childhood cancers in Thai cases. Methods: The study design is a descriptive study of patients <18 years old, suspected or diagnosed of relapsed or refractory childhood cancer who underwent whole exome sequencing (WES). Results: WES was successfully performed in both the tumor and the blood or saliva samples obtained from 4 unrelated patients. Six different variants were identified in the NCOR2, COL6A3, TP53, and SMAD4 genes. These alterations were found to be associated with tumor aggressiveness. Conclusion: This study is the first one to demonstrate genetic alterations by using WES in relapsed or refractory childhood cancer in Thai cases.

Genetic profiles and clinical features in subcutaneous panniculitis-like T-cell lymphomas.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare peripheral T-cell lymphoma characterized by cutaneous lesions and immunologic manifestations. The five-year survival rate of SPTCL has been reported to be over 80%, indicating a favorable prognosis. Recent studies have uncovered recurrent germline variants in HAVCR2, encoding an immunomodulator. In this study, we integrated whole-exome sequencing data from 60 samples collected from 36 SPTCL patients, encompassing six patients of our cohort and 30 patients of publicly available data. We identified 138 somatic mutations in skin tumors of 24 patients and HAVCR2 germline mutations in 23 of 29 patients. HAVCR2 p.Tyr82Cys mutations were identified in four of six Japanese patients. During the clinical courses of four patients, cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone were administered to all patients, but it resulted in incomplete responses in all four patients. However, disease conditions of all patients remained stable with additional treatment, including autologous peripheral blood stem cell transplantation. Over a 7.5-year median follow-up, one patient developed autoimmune-related diseases, while one developed other hematological malignancy, resulting in death. To our knowledge, this is the first report of recurrent HAVCR2 germline mutations in Japanese patients, suggesting the necessity for long-term follow-up.

Constitutional Mutation of PIK3CA: A Variant of Cowden Syndrome?

We present a family in which four individuals have been identified with the same likely pathogenic genetic alteration in the PIK3CA gene at the germinal level; specifically, c.1145G>A p.(Arg382Lys) missense type. The index case patient was diagnosed with multinodular goiter and breast cancer at 61 years old. Among the other three carrier relatives: one has been diagnosed with serous cystadenoma of the ovary and a thyroid nodule with no radiological suspicion of malignancy; the other two present multinodular goiter. Additionally, a sister of three of the carriers suffered from an ovarian teratoma, follicular thyroid carcinoma on multinodular goiter, and high-grade serous ovarian carcinoma. No direct mutation study was performed on her as she had died due to ovarian carcinoma. This finding suggests that the PIK3CA gene should be considered in Cowden-like families when no other gene mutations have been found. Furthermore, this report contributes to characterization of the clinical phenotype caused by mutations in PIK3CA, which may be shared with other hereditary breast and ovarian cancer syndromes.

Mutational analysis of the RB1 gene in patients with unilateral retinoblastoma.

Purpose: Retinoblastoma, a childhood cancer originating in the retina, is primarily attributed to pathogenic RB1 mutations The aim of this study is to conduct a mutational analysis of the RB1 gene in cases of unilateral Retinoblastoma among individuals within the Jordanian population. Methods: In this study, the peripheral blood of 50 unilateral Rb patients was collected, genomic DNA was extracted, and mutations were identified using Next Generation Sequencing (NGS) analysis. Results: In this cohort of 50 unrelated patients with unilateral Rb, the median age at diagnosis was eight months (mean, 12 months; range; 2 weeks to 54 months). Twenty-eight (56%) were males, 29 (58%) had the disease in the right eye, 3 (6%) had a positive family history of Rb, and 20 (40%) were diagnosed within the first year of life. RB1 gene pathogenic mutations were detected in 14 out of 50 (28%) patients, indicating germline disease. Among unilateral non-familial cases, 11 out of 47 (23%) were found to have germline RB1 mutations. Overall, five (36%) of the germline cases had the same mutation detected in one of the parents consistent with an inherited disease (four (80%) were of paternal origin); 3 (60%) of these had affected carrier parent, two (40%) had an unaffected carrier parent. Nine (64%) patients had the nonsense mutation, and six (43%) had the mosaic mutation. The significant prognostic factors for positive genetic testing were positive family history (p = 0.018) and age at diagnosis less than 12 months (p = 0.03). At a median of 54 months follow-up, two (4%) patients were dead from distant metastasis. The overall eye salvage rate was 44% (n = 22/50) eyes; 100% for groups A, B, and C, 60% for group D, and none for group E eyes. There was no correlation between the presence of germline mutation and outcome in terms of eye salvage, metastasis, and survival. Conclusion: In this study, 28% of patients with unilateral Rb had germline RB1 mutations, of which 43% were inherited, and one-third presented beyond their first year of life. Therefore, molecular screening is critical for genetic counseling regarding the risk for inherited Rb in unilateral cases, including those with no family history, regardless of the age at diagnosis. However, germline mutations did not appear to significantly predict patient outcomes regarding eye salvage, metastasis, and survival.

Clinical characteristics and genomic profiling of outpatients with endometrial cancer at a Chinese tertiary cancer center.

OBJECTIVE: Endometrial cancer is stepping into the era of precision therapy. Genomic test is recommended for newly diagnostic patients. However, outpatients displayed more complex characteristics. Here, we elucidated the clinical characteristics and genomic profiling of outpatients with endometrial cancer at our institution. METHODS: Between 2018 and 2023, 68 endometrial cancer received genomic tests at outpatient department of Fudan University Shanghai Cancer Center. Data, including age, pathological histology, FIGO stage and treatment strategy were collected. Germline mutations, molecular subtypes and other somatic mutations were also summarized. RESULTS: Overall, 72.1% (49/68) of patients receive genomic tests at primary diagnosis, while 27.9% (19/68) of patients received tests at recurrence. Nine patients had deleterious germline mutations, including BRCA1(2), MLH1(1), MSH2(2, including one with co-mutation of RAD50), MSH6(2), FANCA(1), MUTYH(1). Molecular subtypes were recognized among 62 patients, as POLE super-mutation(4, 6.5%), MSI-H(7, 11.3%), CN-Low(36, 58.1%) and CN-High(15, 24.2%). Ten patients received anti-PD1 monotherapy or in combination with chemotherapy or anti-angiogenic therapy, with the duration of disease control of 1 to 35 months. The ORR rate was 30%, and six patients had stable disease. The median (range) follow-up time was 18(2-160) months. 23(33.8%) relapses were recorded, and CN-High subtype displayed worst PFS compared with other subtypes (P < 0.01). 6 deaths were reported including 2(5.6%) of CN-Low and 4(26.7%) of CN-High. CONCLUSION: Outpatients department gathered a considerable proportion of recurrent patients with complex genomic features. Patients with worse prognosis could be well studied, and anti-PD1 therapy was a promising salvage therapy in the real world.

The Spectrum of Disease-Associated Alleles in Countries with a Predominantly Slavic Population.

There are more than 260 million people of Slavic descent worldwide, who reside mainly in Eastern Europe but also represent a noticeable share of the population in the USA and Canada. Slavic populations, particularly Eastern Slavs and some Western Slavs, demonstrate a surprisingly high degree of genetic homogeneity, and, consequently, remarkable contribution of recurrent alleles associated with hereditary diseases. Along with pan-European pathogenic variants with clearly elevated occurrence in Slavic people (e.g., ATP7B c.3207C>A and PAH c.1222C>T), there are at least 52 pan-Slavic germ-line mutations (e.g., NBN c.657_661del and BRCA1 c.5266dupC) as well as several disease-predisposing alleles characteristic of the particular Slavic communities (e.g., Polish SDHD c.33C>A and Russian ARSB c.1562G>A variants). From a clinical standpoint, Slavs have some features of a huge founder population, thus providing a unique opportunity for efficient genetic studies.

Mutation Spectrum Comparison between Benign Breast Lesion Cohort, Unselected Cancer Cohort and High-Risk Breast Cancer Cohort.

Mutation study for high-risk breast and ovarian cancer (HBOC) has been extensively studied in patients of different ethnicities. Here we compared the germline mutation rate and mutation spectrum of patients (n = 4341) with benign breast diseases or breast cancers, with and without other risk factors. Three cohorts of Chinese patients were recruited. The first cohort, high-risk cohort (HR, n = 3935) included high-risk breast cancer patients fulfilling high-risk HBOC criteria and who are recruited at our genetics clinic. The second cohort, unselected cancer cohort (CC, n = 307) was from general recruitment of patients with breast cancer at breast surgery clinics. The third cohort, benign breast lesion cohort (NC, n = 99) comprised 99 patients with benign breast diseases such as fibroadenoma, fibroadenomatoid hyperplasia, and intraductal papilloma. Thirty HBOC related genes were sequenced on the above-mentioned patient cohorts. The germline mutation rates of HR, CC, and NC cohort were 11.9%, 6.5%, and 8.1%, respectively. In the CC cohort, 29.3% (90/307) of patients fulfilled the National Comprehensive Cancer Network (NCCN) high-risk genetic test criteria 2022 v.2. The mutation rate for this group of patients was 11.1%, similar to that of the HR cohort, while the mutation rate for those not fulfilling testing criteria was 4.6%, like that of the NC cohort. High penetrance genes (BRCA1/2, CDH1, PALB2, PTEN, and TP53) mutations were only found in the HR (10.6%) and CC (3.3%) cohorts but were not found in the NC cohort. ATM, BRIP1, RAD51C, and RAD51D mutations were identified in all cohorts. RAD51C and RAD51D mutations showed conflicting penetrance. An unexpectedly high mutation rate of total 2% was found in the NC cohort but it was only 0.3% and 0.5% in the HR cohort and CC cohort, respectively. Our results show a clinical need to enhance genetic testing of unselected breast cancer patients to identify the high-risk patients.

BRCA1-associated-protein-1 inactivated melanocytic tumours: characterisation of the clinicopathological spectrum and immunohistochemical expression pattern of preferentially expressed antigen in melanoma.

AIMS: BRCA1-associaed protein-1 (BAP1) inactivated tumours (BIMT) are rare melanocytic tumours that may be mistaken for Spitz tumours or melanoma. They occur sporadically or in association with the BAP1 tumour predisposition syndrome (BAP1-TPDS), which may be complicated by uveal or cutaneous melanoma, mesothelioma, basal cell carcinoma and renal cell carcinoma. The aim of this study was to characterise the clinicopathological features and the immunohistochemical expression pattern of preferentially expressed antigen in melanoma (PRAME) of BIMT in a large patient cohort. METHODS AND RESULTS: Ethical approval was obtained, haematoxylin and eosin-stained slides were reviewed, PRAME immunohistochemistry was performed and clinical follow-up was obtained from patient records. Sixty-five BIMT from 38 patients (F:M = 4.4:1) were identified. BIMT were typically located on the trunk and head and neck (median size = 0.5 cm). Seven patients with BAP1-TPDS (range = 16-66 years, median = 25) had multiple BIMT (median = 5), while sporadic BIMT were solitary (median patient age = 39 years). One of seven patients with BAP1-TPDS developed additional malignancies (mesothelioma and cutaneous spindle cell melanoma) and died of complications of mesothelioma. All other patients are alive without recurrence of BIMT (median follow-up = 42 months). BIMT presented as intradermal, nodular aggregates of epithelioid melanocytes with low mitotic activity and moderate to severe cytological atypia in 63% of cases. A background conventional naevus was present in 64%. PRAME immunohistochemistry showed negative or weakly patchy positive staining in all BIMT. CONCLUSIONS: BIMT are more common in a sporadic setting and behave indolently, despite worrying cytological atypia. PRAME immunohistochemistry is a reassuring tool in distinguishing BIMT from melanoma.

Familial Acute Promyelocytic Leukemia: A Case Report and Review of the Literature.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation t (15;17) (q24;q21), which leads to the fusion of PML and RARα genes known as PML-RARα fusion. A few cases of potentially hereditary leukemia-related genes in APL have been reported, but no instances of familial aggregation of APL have been documented. Here, we describe a family in whom two members successively affected by APL。The potential familial association observed in these two cases of APL highlights the need for further investigation and more definitive genetic lineage tracing in order to understand the genetic basis of this disease.

Identification and functional validation of a novel pathogenic POT1 germline variant p.G95V in familial melanoma.

POT1 variants have been identified in familial melanoma (FM) as well as a number of other germline and somatic malignancies. The functional validation of variants identified from the screening of patients with melanoma gene susceptibility panels is key to understanding the clinical significance of identified variants. Here we report a novel, likely pathogenic POT1 missense variant (p.G95V) in FM and investigate its functional impact. We demonstrate loss of function owing to the inability of the mutant POT1 protein to bind telomeric DNA compared to its wild-type counterpart. This study provides important functional validation of a novel POT1 variant in FM.

The guidelines for clinical practice for carriers of germline mutations in hereditary breast, ovarian, prostate, and pancreatic cancer predisposition genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 (4.2024).

The Guidelines for Clinical Practice for carriers of pathogenic variants in clinically relevant cancer predisposition genes define the steps of primary and secondary prevention that should be provided to these individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyne Czech Medical Society (SLG CLS JEP) in cooperation with the representatives of oncology and oncogynecology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.

Atypical noncontiguous TSC2/PKD1 gene deletions presenting as tuberous sclerosis/polycystic kidney disease contiguous gene syndrome.

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct disorders typically associated with pathogenic variants in TSC1 and TSC2 for the former and PKD1 and PKD2 for the latter. TSC2 and PKD1 lie adjacent to each other, and large deletions comprising both genes lead to TSC2/PKD1 contiguous gene deletion syndrome (CGS). In this study, we describe a young female patient exhibiting symptoms of TSC2/PKD1 CGS in which genetic analysis disclosed two noncontiguous partial gene deletions in TSC2 and PKD1 that putatively are responsible for the manifestations of the syndrome. Further analysis revealed that both deletions appear to be de novo on the maternal chromosome, presumably with a germline origin. Despite extensive analysis, no maternal chromosomal rearrangement triggering these pathogenic variants was detected. This case elucidates a unique pathogenesis for TSC2/PKD1 CGS, diverging from the common contiguous deletions typically observed, marking the first reported instance of TSC2/PKD1 CGS caused by independent, functionally significant partial gene deletions.

Single nucleotide variants in lung cancer.

Germline genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), account for interpatient heterogeneity. In the past several decades, genome-wide association studies (GWAS) have identified multiple lung cancer-associated SNVs in Caucasian and Chinese populations. These variants either reside within coding regions and change the structure and function of cancer-related proteins or reside within non-coding regions and alter the expression level of cancer-related proteins. The variants can be used not only for cancer risk assessment and prevention but also for the development of new therapies. In this review, we discuss the lung cancer-associated SNVs identified to date, their contributions to lung tumorigenesis and prognosis, and their potential use in predicting prognosis and implementing therapeutic strategies.

Germline RAD51C and RAD51D Mutations in High-Risk Chinese Breast and/or Ovarian Cancer Patients and Families.

BACKGROUND: RAD51C and RAD51D are crucial in homologous recombination (HR) DNA repair. The prevalence of the RAD51C and RAD51D mutations in breast cancer varies across ethnic groups. Associations of RAD51C and RAD51D germline pathogenic variants (GPVs) with breast and ovarian cancer predisposition have been recently reported and are of interest. METHODS: We performed multi-gene panel sequencing to study the prevalence of RAD51C and RAD51D germline mutations among 3728 patients with hereditary breast and/or ovarian cancer (HBOC). RESULTS: We identified 18 pathogenic RAD51C and RAD51D mutation carriers, with a mutation frequency of 0.13% (5/3728) and 0.35% (13/3728), respectively. The most common recurrent mutation was RAD51D c.270_271dupTA; p.(Lys91Ilefs*13), with a mutation frequency of 0.30% (11/3728), which was also commonly identified in Asians. Only four out of six cases (66.7%) of this common mutation tested positive for homologous recombination deficiency (HRD). CONCLUSIONS: Taking the family studies in our registry and tumor molecular pathology together, we concluded that this relatively common RAD51D variant showed incomplete penetrance in our local Chinese community. Personalized genetic counseling emphasizing family history for families with this variant, as suggested at the UK Cancer Genetics Group (UKCGG) Consensus meeting, would also be appropriate in Chinese families.

Single Center Experience of Genetic Testing in Patients Undergoing Breast Cancer Treatment.

BACKGROUND: Breast cancer remains the most frequently diagnosed cancer in female population worldwide. However, germline mutations are responsible for a small proportion of these cases. The aim of our study is to assess how germline mutations influence the management and outcome of these patients taken into consideration both their cancer diagnosis and genetic assessment. METHODS: We performed a retrospective analysis in a women's single-center during a period of six years to assess the contribution of germline mutation in the treatment, prognosis and survival of breast cancer patients. Statistics were collected from both the patients' medical records and genetics department. RESULTS: From the total number of patients treated for breast cancer in our department between 2017 and 2022, 243 were eligible for genetic testing, comprising either BRCA1/2 or extended panel, taking into consideration their personal and family history. Of all subjects included in our study cohort, 5% were carriers of a pathogenic(P) or likely pathogenic(LP) variant of cancer susceptibility gene, of which 78% were diagnosed before the age of 50; triple negative disease was diagnosed in the majority of cases, and therefore, 62% of patients started treatment with systemic neoadjuvant chemotherapy and 32% of subjects underwent upfront surgery. Prophylactic surgery for contralateral breast and bilateral salpingo-oophorectomy was considered and performed for 20% of patients. Less than 2% of cases had metastatic disease and received PARP inhibitors, with excellent treatment response and a very low rate of mortality in the study group. CONCLUSION: Carriers of pathogenic variants with breast cancer diagnosis may have a greater benefit from a tailored approach, including both surgical and oncological treatment, with better long-term outcomes.

Case report: TP53 c.848G>A germline mutation as a possible screening target at initial diagnosis for acute lymphoblastic leukemia.

BACKGROUD: Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear. CASE PRESENTATION: We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free. CONCLUSION: This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.