De novo deletions and duplications at recombination hotspots in mouse germlines.

Numerous DNA double-strand breaks (DSBs) arise during meiosis to initiate homologous recombination. These DSBs are usually repaired faithfully, but here, we uncover a distinct type of mutational event in which deletions form via joining of ends from two closely spaced DSBs (double cuts) within a single hotspot or at adjacent hotspots on the same or different chromatids. Deletions occur in normal meiosis but are much more frequent when DSB formation is dysregulated in the absence of the ATM kinase. Events between chromosome homologs point to multi-chromatid damage and aborted gap repair. Some deletions contain DNA from other hotspots, indicating that double cutting at distant sites creates substrates for insertional mutagenesis. End joining at double cuts can also yield tandem duplications or extrachromosomal circles. Our findings highlight the importance of DSB regulation and reveal a previously hidden potential for meiotic mutagenesis that is likely to affect human health and genome evolution.

Identifying somatic fingerprints of cancers defined by germline and environmental risk factors.

Numerous studies over the past generation have identified germline variants that increase specific cancer risks. Simultaneously, a revolution in sequencing technology has permitted high-throughput annotations of somatic genomes characterizing individual tumors. However, examining the relationship between germline variants and somatic alteration patterns is hugely challenged by the large numbers of variants in a typical tumor, the rarity of most individual variants, and the heterogeneity of tumor somatic fingerprints. In this article, we propose statistical methodology that frames the investigation of germline-somatic relationships in an interpretable manner. The method uses meta-features embodying biological contexts of individual somatic alterations to implicitly group rare mutations. Our team has used this technique previously through a multilevel regression model to diagnose with high accuracy tumor site of origin. Herein, we further leverage topic models from computational linguistics to achieve interpretable lower-dimensional embeddings of the meta-features. We demonstrate how the method can identify distinctive somatic profiles linked to specific germline variants or environmental risk factors. We illustrate the method using The Cancer Genome Atlas whole-exome sequencing data to characterize somatic tumor fingerprints in breast cancer patients with germline BRCA1/2 mutations and in head and neck cancer patients exposed to human papillomavirus.

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes.

The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

An oocyte-specific Cas9-expressing mouse for germline CRISPR/Cas9-mediated genome editing.

Cas9 transgenes can be employed for genome editing in mouse zygotes. However, using transgenic instead of exogenous Cas9 to produce gene-edited animals creates unique issues including ill-defined transgene integration sites, the potential for prolonged Cas9 expression in transgenic embryos, and increased genotyping burden. To overcome these issues, we generated mice harboring an oocyte-specific, Gdf9 promoter driven, Cas9 transgene (Gdf9-Cas9) targeted as a single copy into the Hprt1 locus. The X-linked Hprt1 locus was selected because it is a defined integration site that does not influence transgene expression, and breeding of transgenic males generates obligate transgenic females to serve as embryo donors. Using microinjections and electroporation to introduce sgRNAs into zygotes derived from transgenic dams, we demonstrate that Gdf9-Cas9 mediates genome editing as efficiently as exogenous Cas9 at several loci. We show that genome editing efficiency is independent of transgene inheritance, verifying that maternally derived Cas9 facilitates genome editing. We also show that paternal inheritance of Gdf9-Cas9 does not mediate genome editing, confirming that Gdf9-Cas9 is not expressed in embryos. Finally, we demonstrate that off-target mutagenesis is equally rare when using transgenic or exogenous Cas9. Together, these results show that the Gdf9-Cas9 transgene is a viable alternative to exogenous Cas9.

Risk-reducing surgeries for breast cancer in Brazilian patients undergoing multigene germline panel: impact of results on decision making.

PURPOSE: To assess the behavior change of high-risk breast cancer patients regarding the intention to undergo risk-reducing mastectomies (RRM) before and after genetic testing results and to identify the main influencing factors in decision-making. METHODS: Prospective cohort study conducted between November 2021 and October 2022 with women under follow-up at the high-risk outpatient clinic of the State University of Campinas (UNICAMP). Patients were referred for genetic testing, followed by counseling according to the test result. RESULTS: A total of 373 women were included. In the pre-genetic testing analysis, 54.1% of patients intended to undergo RRMs. After testing, 42.2% opted for the procedure. Behavior change occurred in 26.2%, mainly from "yes" to "no/don't know" (72,6%) (p < 0.001). The genetic test result was positive (LPV or PV) in 29.7% of patients. Among the 90 patients with positive results, 62 (68.9%) agreed to RRM, while 22 (24.4%) remained unwilling to accept RRM, regardless of the positive test. Significant influencing factors for behavior change pre- and post-genetic testing (in favor of surgery) in multivariate analysis were: positive genetic test result (OR 2.94, p < 0.001), personal cancer history (OR 2.7, p = 0.008), and ages between 40 and 49 years (OR 2.07, p = 0.008) and ≥ 50 years (OR 3.47, p < 0.001). CONCLUSION: In a Brazilian population at high-risk for breast cancer and users of the public health system, it was observed that most desired RRM, however, when genetic testing and counseling were performed, behavior change was observed, especially when the result was positive.

Germline genetic mutations in a multi-center cohort of 248 phyllodes tumors.

PURPOSE: Germline genetic mutations in women with phyllodes tumors (PT) are understudied, although some describe associations of PT with various mutations. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in women with PT. METHODS: A 6-site multi-center study of women with a PT was initiated, then expanded nationally through an online "Phyllodes Support Group." All women underwent 84-gene panel testing. We defined eligibility for testing based on select NCCN (National Comprehensive Cancer Network) criteria (v1.2022). Logistic regression was used to estimate the association of covariates with the likelihood of a P/LP variant. RESULTS: 274 women were enrolled: 164 (59.9%) through multi-center recruitment and 110 (40.1%) via online recruitment. 248 women completed testing; overall 14.1% (N = 35) had a P/LP variant, and over half (N = 19) of these individuals had a mutation in genes associated with autosomal dominant (AD) cancer conditions. The most common AD genes with a P/LP variant included CHEK2, ATM, and RAD51D. A quarter of participants (23.8%) met NCCN criteria for testing, but we found no difference in prevalence of a P/LP variant based on eligibility (p = 0.54). After adjustment, the presence of P/LP variants was not associated with age, NCCN testing eligibility, or PT type (all p > 0.05). CONCLUSION: Our study demonstrates that 7.7% of women with PT harbor germline P/LP variants in genes associated with AD cancer conditions. Early identification of these variants has implications for screening, risk reduction, and/or treatment. National guidelines for women with PT do not currently address germline genetic testing, which could be considered.

HLA gene polymorphism is a modifier of age-related breast cancer penetrance in carriers of BRCA1 pathogenic alleles.

PURPOSE: Female carriers of germline BRCA1 mutations almost invariably develop breast cancer (BC); however, the age at onset is a subject of variation. We hypothesized that the age-related penetrance of BRCA1 mutations may depend on inherited variability in the host immune system. METHODS: Next-generation sequencing was utilized for genotyping of HLA class I/II genes (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5) in patients with BRCA1-associated BC with early (< / = 38 years, n = 215) and late (> / = 58 years, n = 108) age at onset. RESULTS: HLA-DQB1*06:03P prevalence was higher in the late-onset group due to the excess of allele carriers [25/108 (23.1%) vs. 22/215 (10.2%); OR 2.96, p < 0.001]. For all HLA-I loci, there was a trend toward an increase in the number of homozygotes in the early-onset group. This trend reached statistical significance for the HLA-A [14.4% vs. 6.5%, p = 0.037; OR 2.4, p = 0.042]. The frequencies of HLA-DPB1, HLA-DQB1, and HLA-DRB1/3/4/5 homozygous genotypes did not differ between young-onset and late-onset patients. The maximum degree of homozygosity detected in this study was 6 out of 7 HLA class I/II loci; all six carriers of these genotypes were diagnosed with BC at the age < / = 38 years [OR 6.97, p = 0.187]. CONCLUSION: HLA polymorphism may play a role in modifying the penetrance of BRCA1 pathogenic variants. Certain HLA alleles or HLA homozygosity may modify the risk of BC in BRCA1 carriers.

Precision therapy for cancer prevention by targeting carcinogenesis.

Cancer represents a major global public health burden, with new cases estimated to increase from 14 million in 2012 to 24 million by 2035. Primary prevention is an effective strategy to reduce the costs associated with cancer burden. For example, measures to ban tobacco consumption have dramatically decreased lung cancer incidence and vaccination against human papillomavirus can prevent cervical cancer development. Unfortunately, the etiological factors of many cancer types are not completely clear or are difficult to actively control; therefore, the primary prevention of such cancers is not practical. In this review, we update the progress on precision therapy by targeting the whole carcinogenesis process, especially for three high-risk groups: (1) those with chronic inflammation, (2) those with inherited germline mutations, and (3) those with precancerous lesions like polyps, gastritis, actinic keratosis or dysplasia. We believe that attenuating chronic inflammation, treating precancerous lesions, and removing high-risk tissues harboring germline mutations are precision methods for cancer prevention.

The Role of Demographic and Clinical Factors in Germline Mutation Testing for Patients with Primary Hyperparathyroidism.

INTRODUCTION: Guidelines recommending genetic counseling in primary hyperparathyroidism (PHPT) vary. To further delineate current recommendations, this study examined genetic counseling referral patterns and rates of mutations in surgical patients with PHPT. PATIENTS AND METHODS: A single-institution review was performed of adult patients who underwent parathyroidectomy for presumed sporadic PHPT. Genetic testing indications of hypercalcemia onset ≤ 40 years, multigland disease (MGD), family history (FHx) of PHPT, or other clinical indications suspicious for a PHPT-related endocrinopathy were examined by demographics and mutation detection rates. RESULTS: Genetic counseling was performed in 237 (37.9%) of 625 patients. Counseling was discussed but not performed in 121 (19.4%) patients. No evidence was noted of genetic referral discussion in the remaining 267 (42.7%). Of these groups, patients who received genetic counseling were youngest, p < 0.001 [median age 55.3 (IQR 43.2, 66.7) years]. The majority of patients with indications of age ≤ 40 years (65.7%), FHx (78.0%), and other clinical indications (70.7%) underwent genetic counseling, while most with MGD (57.0%) did not. Eight mutations were detected in 227 patients (3.5%). Mutations included: MEN1 (n = 2), CDC-73 (n = 4), and CASR (n = 2). Detection was most common in patients with FHx (4/71, 5.6%), then age ≤ 40 years (3/66, 4.5%), and other clinical indications (3/80, 3.8%). No mutations were identified in 48 patients tested solely for MGD. CONCLUSIONS: Most patients with onset of hypercalcemia age ≤ 40 years, positive FHx, or other clinical concerns underwent genetic counseling, while most with MGD did not. As no germline mutations were identified in patients with MGD alone, further investigation of MGD as a sole indication for genetic counseling may be warranted.

Blood-based molecular and cellular biomarkers of early response to neoadjuvant PD-1 blockade in patients with non-small cell lung cancer.

BACKGROUND: Despite the improved survival observed in PD-1/PD-L1 blockade therapy, a substantial proportion of cancer patients, including those with non-small cell lung cancer (NSCLC), still lack a response. METHODS: Transcriptomic profiling was conducted on a discovery cohort comprising 100 whole blood samples, as collected multiple times from 48 healthy controls (including 43 published data) and 31 NSCLC patients that under treatment with a combination of anti-PD-1 Tislelizumab and chemotherapy. Differentially expressed genes (DEGs), simulated immune cell subsets, and germline DNA mutational markers were identified from patients achieved a pathological complete response during the early treatment cycles. The predictive values of mutational markers were further validated in an independent immunotherapy cohort of 1661 subjects, and then confirmed in genetically matched lung cancer cell lines by a co-culturing model. RESULTS: The gene expression of hundreds of DEGs (FDR p < 0.05, fold change < -2 or > 2) distinguished responders from healthy controls, indicating the potential to stratify patients utilizing early on-treatment features from blood. PD-1-mediated cell abundance changes in memory CD4 + and regulatory T cell subset were more significant or exclusively observed in responders. A panel of top-ranked genetic alterations showed significant associations with improved survival (p < 0.05) and heightened responsiveness to anti-PD-1 treatment in patient cohort and co-cultured cell lines. CONCLUSION: This study discovered and validated peripheral blood-based biomarkers with evident predictive efficacy for early therapy response and patient stratification before treatment for neoadjuvant PD-1 blockade in NSCLC patients.

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil. METHODS: A cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes. RESULTS: The prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time. CONCLUSION: One in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

The role of genetic factors in pediatric myelodysplastic syndromes with different outcomes.

BACKGROUND: Pediatric myelodysplastic syndromes (MDS) are rare disorders with an unrevealed pathogenesis. Our aim is to explore the role of genetic factors in the pathogenesis of MDS in children with different outcomes and to discover the correlation between genetic features and clinical outcomes as well as disease characteristics. METHODS: We conducted an analysis of archived genetic data from 26 patients diagnosed with pediatric MDS at our institution between 2015 and 2021, examining the association between different genetic characteristics and clinical manifestations as well as prognosis. Additionally, We presented three cases with distinct genetic background and outcomes as examples to elaborate the role of genetic factors in pediatric MDS with different prognoses. RESULTS: Genetic variations were detected in 13 out of the 26 patients, including 8 patients with co-occurrence of somatic and germline mutations (CSGMs) and 5 patients with somatic mutations alone. Our analysis revealed that advanced MDS (4/8, 50% vs. 1/5, 20% and 4/11, 36.4%), PD (3/8, 37.5% vs. 1/5, 20% and 1/11 9.1%), and TD (6/8, 75% vs. 2/5, 40% and 2/11, 18.2%) were more common in patients with CSGMs than those with somatic mutations alone or without any mutations. We also found out in our study that 8 patients with CSGMs had evidently different clinical outcomes, and we presented 3 of them as examples for elaboration. Case 1 with germline and somatic mutations of unknown significance had a relatively slow disease course and a good prognosis. Case 2 with compound heterozygous germline SBDS variants and somatic mutations like del20q had a stable disease course and a reversed outcome. Case 3 with a germline GATA2 variant and somatic mutations including - 7 had a rapidly progressive disease course and a worst prognosis. CONCLUSION: Our findings indicate that genetic background of pediatric MDS is closely linked with disease characteristics as well as outcomes and that CSGMs may lead to disease progression. It should be emphasized that the interaction between certain germline variants and somatic mutations, such as SBDS and del20q, may result in hematopoietic stem cell adaptation (improved hematopoiesis) and reversed clinical outcomes, which can facilitate the development of targeted therapy.

The clinical phenotype of germline RUNX1 mutations in relation to the accompanying somatic variants and RUNX1 isoform expression.

Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, abnormal bleeding, and an elevated risk of developing myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML) at young age. However, it is not known why or how germline carriers of RUNX1 mutations have a particular propensity to develop myeloid hematologic malignancies, but the acquisition and composition of somatic mutations are believed to initiate and determine disease progression. We present a novel family pedigree that shares a common germline RUNX1R204* variant and exhibits a spectrum of somatic mutations and related myeloid malignancies (MM). RUNX1 mutations are associated with inferior clinical outcome; however, the proband of this family developed MDS with ring sideroblasts (MDS-RS), classified as a low-risk MDS subgroup. His relatively indolent clinical course is likely due to a specific somatic mutation in the SF3B1 gene. While the three main RUNX1 isoforms have been ascribed various roles in normal hematopoiesis, they are now being increasingly recognized as involved in myeloid disease. We investigated the RUNX1 transcript isoform patterns in the proband and his sister, who carries the same germline RUNX1R204* variant, and has FPDMM but no MM. We demonstrate a RUNX1a increase in MDS-RS, as previously reported in MM. Interestingly, we identify a striking unbalance of RUNX1b and -c in FPDMM. In conclusion, this report reinforces the relevance of somatic variants on the clinical phenotypic heterogeneity in families with germline RUNX1 deficiency and investigates a potential new role for RUNX1 isoform disequilibrium as a mechanism for development of MM.

M-FISH evaluation of chromosome aberrations to examine for historical exposure to ionising radiation due to participation at British nuclear test sites.

Veterans of the British nuclear testing programme represent a population of ex-military personnel who had the potential to be exposed to ionising radiation through their participation at nuclear testing sites in the 1950s and 1960s. In the intervening years, members of this population have raised concerns about the status of their health and that of their descendants, as a consequence. Radiation dose estimates based on film badge measurements of external dose recorded at the time of the tests suggest any exposure to be limited for the majority of personnel, however, only ∼20% of personnel were monitored and no measurement for internalised exposure are on record. Here, to in-part address families concerns, we assay for chromosomal evidence of historical radiation exposure in a group of aged nuclear test (NT) veterans, using multiplexin situhybridisation (M-FISH), for comparison with a matched group of veterans who were not present at NT sites. In total, we analysed 9379 and 7698 metaphase cells using M-FISH (24-colour karyotyping) from 48 NT and 38 control veteran samples, representing veteran servicemen from the army, Royal Airforce and Royal Navy. We observed stable and unstable simple- and complex-type chromosome aberrations in both NT and control veterans' samples, however find no significant difference in yield of any chromosome aberration type between the two cohorts. We do observe higher average frequencies of complex chromosome aberrations in a very small subset of veterans previously identified as having a higher potential for radiation exposure, which may be indicative of internalised contamination to long-lived radionuclides from radiation fallout. By utilising recently published whole genome sequence analysis data of a sub-set of the same family groups, we examined for but found no relationship between paternal chromosome aberration burden, germline mutation frequency and self-reported concerns of adverse health in family members, suggesting that the previously reported health issues by participants in this study are unlikely to be associated with historical radiation exposure. We did observe a small number of families, representing both control and NT cohorts, showing a relationship between paternal chromosome aberrations and germline mutation sub-types which should be explored in future studies. In conclusion, we find no cytogenetic evidence of historical radiation exposure in the cohort of nuclear veterans sampled here, offering reassurance that attendance at NTs sites by the veterans sampled here, was not associated with significant levels of exposure to radiation.

Exome Sequencing: the Search for Mutations Associated with Hereditary Breast and Ovarian Cancers in the Tuvan Ethnic Group (A Pilot Study).

Whole exome sequencing of peripheral blood samples from Tuvan females diagnosed with breast and ovarian cancers (BC/OC) was performed to search for new genes involved in BC/OC pathogenesis. Considering the high cost of whole exome sequencing and study material requirements, 9 samples were selected from 61 genomic DNA samples. A mutation in the LGR4 gene (rs34804482) involved in the tumor-mediated Wnt signaling pathway and a mutation in the BRWD1 gene (rs147211854) involved in chromatin remodeling were identified in BC patients. A mutation in the CITED2 gene (rs77963348) involved in the pathogenesis of primary ovarian insufficiency was identified in a patient with OC and a history of infertility. A mutation in the PDGFRA gene (rs2291591) was identified in two BC/OC patients. LRG4, BRWD1, PDGFRA, and CITED2 germline pathogenic mutations were discovered in Tuvan women diagnosed with BC/OC for the first time.

Pleomorphic/solid lobular carcinoma of male breast with PALB2 germline mutation: case report and literature review.

Male breast cancer (MBC) accounts for approximately 1% of all breast cancers and among these infiltrating lobular carcinomas (ILC) represents only 1-2% of all MBC cases. Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of ILC with only eight cases reported until now in males. Up to 10% of MBC cases have a germline pathogenic variant in a predisposing gene such as BRCA1 and BRCA2 genes. Mutations in PALB2 (partner and localizer of BRCA2) have been reported in men with breast cancer, with a frequency that ranges from 0.8 to 6.4%, but it has never been reported in male ILC. Here, we report a rare and interesting case of an invasive pleomorphic/solid lobular carcinoma, which carries a pathogenic variant in PALB2 gene, and a family history of breast cancer without other well defined risk factors for developing this type of neoplasia. In addition, we review the current literature.

A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia.

PURPOSE: Pathogenic variants (PVs) in BRCA1 and BRCA2 genes are essential biomarkers of an increased breast and ovarian cancer risk and tumor sensitivity to poly ADP ribose polymerase inhibitors. In Russia, eight PVs were thought to be the most common, among which BRCA1 c.5266dup is the most frequently identified one. METHODS: We show the distribution of BRCA1/2 PVs identified with quantitative PCR and targeted next-generation sequencing in 1399 ovarian cancer patients recruited into the study from 72 Russian regions in 2015-2021. RESULTS: The most abundant PVs were c.5266dup (41.0%), c.4035del (7.0%), c.1961del (6.3%), c.181 T > G (5.2%), c.3756_3759del (1.8%), c.3700_3704del (1.5%), and c.68_69del (1.5%), all found in BRCA1 and known to be recurrent in Russia. Several other frequent PVs were identified: c.5152 + 1G > T (1.2%), c.1687C > T (1.0%), c.4689C > G (0.9%), c.1510del (0.6%), c.2285_2286del (0.6%) in the BRCA1 gene; and c.5286 T > G (1.2%), c.2808_2811del (0.8%), c.3847_3848del (0.8%), c.658_659del (0.7%), c.7879A > T (0.6%), in the BRCA2 gene. For the most common PV in the BRCA2 gene c.5286 T > G, we suggested that it arose about 700 years ago and is a new founder mutation. CONCLUSION: This study extends our knowledge about the BRCA1 and BRCA2 pathogenic variants variability.

Prognostic impact of germline BRCA1/2 pathogenic variants in breast cancer.

PURPOSE: This study investigates the impact of different subtypes of pathogenic BRCA variants on the prognosis and on the survival of breast cancer (BC) patients. METHODS: Associations between BRCA1/2 pathogenic variants (PVs) mutations, clinicopathological features, locoregional tumor reappearance, and survival data were analyzed. The Gray's test was used to test difference of the cumulative incidence of local relapse between missense/splicing and other mutations, taking into of competing events. The multivariate proportional hazard model was used to assess the independent association between type of mutation and local relapse, after adjustment for other prognostic factors and clinicopathological characteristics. RESULTS: Out of 482 patients, 285 presented 98 different BRCA1 PVs and 201 harbored 103 different BRCA2 PVs. Missense mutations were found in 46 BC patients (9.5%), splicing mutations in 42 (8.6%), deletions in 206 (42.4%), insertions in 73 (15%), indel mutations in 6 (1.2%), nonsense mutations in 86 (17.7%), and large rearrangements in 27 (5.6%). Kalbfleisch and Prentice cumulative incidence curves analysis showed a significantly lower locoregional recurrence incidence in the missense/splicing group (Gray-test P-value = 0.011). We found that the risk of local relapse was 58% less likely in women carrying missense/splicing variants than in those with other PV subtypes (HR 95% CI 0.42 [0.21-0.82]; P-value = 0.0108). No significant differences were observed in overall survival (OS) in all groups. CONCLUSIONS: Having been found to be associated with a lower risk of BC reappearance, germline BRCA1/2 PVs of the missense/splicing subtypes can be used as prognostic predictors and are likely to improve BC patients' management.

Germline mutations directions are different between introns of the same gene: case study of the gene coding for amyloid-beta precursor protein.

Amyloid-beta precursor protein (APP) is highly conserved in mammals. This feature allowed us to compare nucleotide usage biases in fourfold degenerated sites along the length of its coding region for 146 species of mammals and birds in search of fragments with significant deviations. Even though cytosine usage has the highest value in fourfold degenerated sites in APP coding region from all tested placental mammals, in contrast to marsupial mammals with the bias toward thymine usage, the most frequent germline and somatic mutations in human APP coding region are C to T and G to A transitions. The same mutational AT-pressure is characteristic for germline mutations in introns of human APP gene. However, surprisingly, there are several exceptional introns with deviations in germline mutations rates. The most of those introns surround exons with exceptional biases in nucleotide usage in fourfold degenerated sites. Existence of such fragments in exons 4 and 5, as well as in exon 14, can be connected with the presence of lncRNA genes in complementary strand of DNA. Exceptional nucleotide usage bias in exons 16 and 17 that contain a sequence encoding amyloid-beta peptides can be explained either by the presence of yet unmapped lncRNA(s), or by the autonomous expression of a short mRNA that encodes just C-terminal part of the APP providing an alternative source of amyloid-beta peptides. This hypothesis is supported by the increased rate of T to C transitions in introns 16-17 and 17-18 of Human APP gene relatively to other introns.

Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer.

The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting.