RESUMO
Background: Identifying germline predisposition in CNS malignancies is of increasing clinical importance, as it contributes to diagnosis and prognosis, and determines aspects of treatment. The inclusion of germline testing has historically been limited due to challenges surrounding access to genetic counseling, complexity in acquiring a germline comparator specimen, concerns about the impact of findings, or cost considerations. These limitations were further defined by the breadth and scope of clinical testing to precisely identify complex variants as well as concerns regarding the clinical interpretation of variants including those of uncertain significance. Methods: In the course of conducting an IRB-approved protocol that performed genomic, transcriptomic and methylation-based characterization of pediatric CNS malignancies, we cataloged germline predisposition to cancer based on paired exome capture sequencing, coupled with computational analyses to identify variants in known cancer predisposition genes and interpret them relative to established clinical guidelines. Results: In certain cases, these findings refined diagnosis or prognosis or provided important information for treatment planning. Conclusions: We outline our aggregate findings on cancer predisposition within this cohort which identified 16% of individuals (27 of 168) harboring a variant predicting cancer susceptibility and contextualize the impact of these results in terms of treatment-related aspects of precision oncology.
RESUMO
BACKGROUND: Choroid plexus carcinomas (CPCs) are rare malignant tumors primarily affecting pediatric patients and often co-occur with Li-Fraumeni Syndrome (LFS), an inherited predisposition to early-onset malignancies in multiple organ systems. LFS is closely linked to TP53 mutations, with germline TP53 gene mutations present in approximately 75% of Li-Fraumeni syndrome families and 25% of Li-Fraumeni-like syndrome families. Individuals with TP53 mutations also have an elevated probability of carrying mutations in BRCA1 and BRCA2 genes. OBJECTIVE: To investigate the structural and functional implications of the TP53: 799C > T, p. (Arg267Trp) missense mutation, initially identified in a Saudi family, and understand its impact on TP53 functionality and related intermolecular interactions. METHODS: Computational analyses were conducted to examine the structural modifications resulting from the TP53: 799C > T, p. (Arg267Trp) mutation. These analyses focused on the mutation's impact on hydrogen bonding, ionic interactions, and the specific interaction with Cell Cycle and Apoptosis Regulator 2 (CCAR2), as annotated in UniProt. RESULTS: The study revealed that the native Arg267 residue is critical for a salt bridge interaction with glutamic acid at position 258. The mutation-induced charge alteration has the potential to disrupt this ionic bonding. Additionally, the mutation is located within an amino acid region crucial for interaction with CCAR2. The altered properties of the amino acid within this domain may affect its functionality and disrupt this interaction, thereby impacting the regulation of catalytic enzyme activity. CONCLUSIONS: Our findings highlight the intricate intermolecular interactions governing TP53 functionality. The TP53: 799C > T, p. (Arg267Trp) mutation causes structural modifications that potentially disrupt critical ionic bonds and protein interactions, offering valuable insights for the development of targeted mutants with distinct functional attributes. These insights could inform therapeutic strategies for conditions associated with TP53 mutations.
Assuntos
Neoplasias do Plexo Corióideo , Síndrome de Li-Fraumeni , Mutação de Sentido Incorreto , Proteína Supressora de Tumor p53 , Síndrome de Li-Fraumeni/genética , Humanos , Neoplasias do Plexo Corióideo/genética , Proteína Supressora de Tumor p53/genética , Carcinoma/genética , Feminino , Mutação em Linhagem Germinativa , MasculinoRESUMO
TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1-69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2-54)-19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.
RESUMO
PURPOSE: Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer. MATERIALS AND METHODS: A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low- or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancerâspecific death. RESULTS: Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of 14.9 years, participants with favorable-risk prostate cancer with a positive family history had a significantly higher risk of prostate cancerâspecific death (HR 1.95, 95% CI 1.15-3.32, P = .014) compared to those without any family history. The rs2735839 (19q13) risk allele was associated with prostate cancerâspecific death (HR 1.81 per risk allele, 95% CI 1.04-3.17, P = .037), whereas the polygenic risk score was not. Combined family history and rs2735839 risk allele were each associated with an additive risk of prostate cancerâspecific death (HR 1.78 per risk factor, 95% CI 1.25-2.53, P = .001). CONCLUSIONS: Family history of prostate, breast, or pancreatic cancer and/or a 19q13 germline risk allele are associated with an elevated risk of prostate cancerâspecific death among favorable-risk patients. These findings have implications for how family history and germline genetic risk SNPs should be factored into clinical decision-making around favorable-risk prostate cancer.
Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Medição de Risco , Seguimentos , PrognósticoRESUMO
OBJECTIVES: Multidisciplinary hereditary tumor clinics are a collaborative format to identify and treat patients with genetic cancer predispositions. The hereditary renal cancer clinic at Indiana University is comprised of a urologic oncologist, medical oncologist, clinical geneticist, and genetic counselor. The clinic holds regular tumor board meetings, where patient histories, pedigrees, imaging, pathology, and management plans are collectively reviewed and discussed. Here we report the contemporary experience for our hereditary renal cancer clinic, with description and analysis of referral patterns, patient profiles, and genetic testing outcomes. MATERIALS AND METHODS: A retrospective review of an IRB-approved, prospectively maintained database of patients seen in the hereditary renal cancer clinic was performed. Patient characteristics, genetic testing results, and disease characteristics were reported and analyzed. RESULTS: A total of 142 patients seen in clinics from January 2018 to June 2023 were included. Patient's median age was between 40 and 49 years old, and 88.7% were Caucasian. The most common reasons for referral were early-onset renal tumors (40%), known hereditary renal cancer syndrome (29%), and hereditary renal cancer syndrome screening (13%). Of those with a tissue diagnosis of renal cell carcinoma, 46.2% were clear cell subtype. The presence of nonrenal syndromic features concerning for hereditary renal tumor syndrome was predictive of pathogenic mutation identification (OR 13.45, P < 0.0001). Patient race and presence of multifocal tumors were not predictive of pathogenic mutation identification. When restricting analysis to patients with an established renal malignancy, high-grade tumor histology was predictive of a pathogenic mutation (OR 8.17, Pâ¯=â¯0.012), though higher pathologic stage and nonclear cell histology were not. Referral for early-onset renal tumor (age < 45 years) predicted lower likelihood of pathogenic mutations (OR 0.10, Pâ¯=â¯0.0002). FH gene mutations were the most commonly identified pathogenic mutations. Genetic testing of family members (cascade testing) was recommended to 9 patients seen in clinic; a pathogenic mutation was subsequently identified in all but one of these families. CONCLUSIONS: These findings are useful for referring physicians and patients in determining patient referral to hereditary cancer clinics, and for counseling patients undergoing genetic testing. Data from non-Caucasian patients and evolving implications of variants of unclear significance (VUS) may represent future research directions for hereditary renal cancer clinics.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Síndromes Neoplásicas Hereditárias , Humanos , Adulto , Pessoa de Meia-Idade , Carcinoma de Células Renais/patologia , Testes Genéticos , Neoplasias Renais/patologia , Mutação , Síndromes Neoplásicas Hereditárias/genética , Predisposição Genética para Doença , Encaminhamento e ConsultaRESUMO
Lynch syndrome is one of the most common hereditary cancer sensitivity syndromes and is caused by autosomal-dominant germline mutations in DNA mismatch repair genes. In patients affected by this syndrome, pre-implantation genetic testing for monogenic disorders (PGT-M) could be the elective technique used to prevent the transmission of this hereditary syndrome to offspring. Notably, despite the severity of the condition, some authors have observed a markedly lower demand for PGT-M in these patients compared to those with other hereditary conditions. A 34-year-old woman with a medical history of Lynch syndrome associated with endometrial cancer came to the Villa Mafalda fertility center in Rome in order to conceive a healthy baby. In a pre-implantation genetic testing for aneuploidy (PGT-A) + PGT-M cycle, eight blastocysts were formed. Six out of eight blastocysts were affected by the same mother syndrome. One of the other two was aneuploid and the other one was a mosaic embryo, which resulted in a healthy pregnancy. The aim of this report is to emphasize the importance of a multidisciplinary approach to managing patients with this condition. In vitro fertilization (IVF), specifically PGT-M, is a tool that allow patients to conceive biological children with lower risk of inheriting the disease.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Diagnóstico Pré-Implantação , Gravidez , Feminino , Criança , Humanos , Adulto , Diagnóstico Pré-Implantação/métodos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Testes Genéticos/métodos , Fertilização in vitro/métodos , Implantação do Embrião , Blastocisto , AneuploidiaRESUMO
Genetic factors play significant roles in the tumorigenicity of lung cancer; however, there is lack of systematic and large-scale characterization of pathogenic germline variants for lung cancer. In this study, germline variants in 146 preselected cancer-susceptibility genes were detected in 17 904 Chinese lung cancer patients by clinical next-generation sequencing. Among 17 904 patients, 1738 patients (9.7%) carried 1840 pathogenic/likely pathogenic (P/LP) variants from 87 cancer-susceptibility genes. SBDS (SBDS ribosome maturation factor) (1.37%), TSHR (thyroid stimulating hormone receptor) (1.20%), BLM (BLM RecQ like helicase) (0.62%), BRCA2 (BRCA2 DNA repair associated) (0.62%), and ATM (ATM serine/threonine kinase) (0.45%) were the top five genes with the highest overall prevalence. The top mutated pathways were all involved in DNA damage repair (DDR). Case-control analysis showed SBDS c.184A>T(p.K62*), TSHR c.1574T>C(p.F525S), BRIP1 (BRCA1 interacting helicase 1) c.1018C>T(p.L340F), and MUTYH (mutY DNA glycosylase) c.55C>T(p.R19*) were significantly associated with increased lung cancer risk (q value < 0.05). P/LP variants in certain genes were associated with early onset of lung cancer. Our study indicates that Chinese lung cancer patients have a higher prevalence of P/LP variants than previously reported. P/LP variants are distributed in multiple pathways and dominated by DNA damage repair-associated pathways. The association between identified P/LP variants and lung cancer risk requires further studies for verification.
RESUMO
Background: Only 5 to 10% of cancers are hereditary, but they are particularly important since they can be passed down from generation to generation, and family members are at elevated risk. Although screening methods are one of the essential strategies for dealing with hereditary cancers, they do not have high specificity and sensitivity. The emergence of whole-exome sequencing (WES) causes a significant increase in the diagnostic rate of cancer-causing variants in at-risk families. Materials and Methods: We performed WES on the proband's DNA sample from an Iranian family with multiple cancer-affected members to identify potential causative variants. Multiple in silico tools were used to evaluate the candidate variants' pathogenicity and their effects on the protein's structure, function, and stability. Moreover, the candidate variants were co-segregated in the family with Sanger sequencing. Results: The WES data analysis identified two pathogenic variants (CHEK2: NM_007194.4: c.538C>T, p.Arg180Cys and MLH1: NM_000249.4, c.844G>A, p.Ala282Thr). Sanger sequencing data showed each of the variants was incompletely segregated with phenotype, but both of them explained the patient's phenotype together. Also, the structural analysis demonstrated that due to the variant (c.538C>T), a salt bridge between arginine 180 and glutamic acid 149 was lost. Indeed, several protein stability tools described both variants as destabilizing. Conclusion: Herein, we interestingly identify two distinct deleterious causative variants (CHEK2: NM_007194.4: c.538C>T, p.Arg180Cys and MLH1: NM_000249.4, c.844G>A, p.Ala282Thr) in a family with several cancer-affected members. Furthermore, this study's findings established the utility of WES in the genetic diagnostics of cancer.
RESUMO
Traditionally, gynecological cancers have been classified based on histology. Since remarkable advancements in next-generation sequencing technology have enabled the exploration of somatic mutations in various cancer types, comprehensive sequencing efforts have revealed the genomic landscapes of some common forms of human cancer. The genomic features of various gynecological malignancies have been reported by several studies of large-scale genomic cohorts, including The Cancer Genome Atlas. Although recent comprehensive genomic profiling tests, which can detect hundreds of genetic mutations at a time from cancer tissues or blood samples, have been increasingly used as diagnostic clinical biomarkers and in therapeutic management decisions, germline pathogenic variants associated with hereditary cancers can also be detected using this test. Gynecological cancers are closely related to genetic factors, with approximately 5% of endometrial cancer cases and 20% of ovarian cancer cases being caused by germline pathogenic variants. Hereditary breast and ovarian cancer syndrome and Lynch syndrome are the two major cancer susceptibility syndromes among gynecological cancers. In addition, several other hereditary syndromes have been reported to be associated with gynecological cancers. In this review, we highlight the genes for somatic mutation and germline pathogenic variants commonly seen in gynecological cancers. We first describe the relationship between clinicopathological attributes and somatic mutated genes. Subsequently, we discuss the characteristics and clinical management of inherited cancer syndromes resulting from pathogenic germline variants in gynecological malignancies.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias dos Genitais Femininos , Feminino , Humanos , Neoplasias dos Genitais Femininos/genética , Mutação , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Colorretais Hereditárias sem Polipose/genéticaRESUMO
Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity.
Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Doença de von Hippel-Lindau , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Sequência de Bases , Carcinoma/genética , MutaçãoRESUMO
Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.
Assuntos
Neoplasias Colorretais , Neoplasias Nasofaríngeas , Humanos , Arábia Saudita , Sequenciamento de Nucleotídeos em Larga Escala , Prevalência , Predisposição Genética para DoençaRESUMO
We sought to determine whether there are racial disparities in cascade testing rates and whether providing testing at no-charge impacts rates in Black and White at-risk-relatives (ARR). Probands with a pathogenic/likely pathogenic germline variant in a cancer predisposition gene were identified up to one year before and up to one year after cascade testing became no-charge in 2017. Cascade testing rates were measured as the proportion of probands who had at least one ARR obtain genetic testing through one commercial laboratory. Rates were compared between self-reported Black and White probands using logistic regression. Interaction between race and cost (pre/post policy) was tested. Significantly fewer Black probands than White probands had at least one ARR undergo cascade genetic testing (11.9% versus 21.7%, OR 0.49, 95% CI 0.39-0.61, p < 0.0001). This was seen both before (OR 0.38, 95% CI 0.24-0.61, p < 0.001) and after (OR 0.53, 95% CI 0.41-0.68, p < 0.001) the no-charge testing policy. Rates of an ARR undergoing cascade testing were low overall, and significantly lower in Black versus White probands. The magnitude of difference in cascade testing rates between Blacks and Whites did not significantly change with no-charge testing. Barriers to cascade testing in all populations should be explored in order to maximize the benefits of genetic testing for both treatment and prevention of cancer.
Assuntos
Testes Genéticos , Neoplasias , Humanos , Grupos Populacionais , Neoplasias/genética , Disparidades em Assistência à SaúdeRESUMO
The complexity of genetic variant interpretation means that a proportion of individuals who undergo genetic testing for a hereditary cancer syndrome will have their test result reclassified over time. Such a reclassification may involve a clinically significant upgrade or downgrade in pathogenicity, which may have significant implications for medical management. To date, few studies have examined the psychosocial impact of a reclassification in a hereditary cancer syndrome context. To address this gap, semi-structured telephone interviews were performed with eighteen individuals who had a BRCA1, BRCA2 or Lynch syndrome-related (MLH1, MSH2, MSH6 or PMS2) gene variant reclassified. The interviews were analysed utilising an inductive, qualitative approach and emergent themes were identified by thematic analysis. Variable levels of recall amongst participants were found. Common motivations for initial testing included a significant personal and/or family history of cancer and a desire to "find an answer". No individual whose uncertain result was upgraded reported negative psychosocial outcomes; most reported adapting to their reclassified result and appraised their genetic testing experience positively. However, individuals whose likely pathogenic/pathogenic results were downgraded reported feelings of anger, shock and sadness post reclassification, highlighting that additional psychosocial support may be required for some. Genetic counselling issues and recommendations for clinical practice are outlined.
RESUMO
AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.
Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias da Próstata , Masculino , Feminino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Autopsia , Genes BRCA1 , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Mutação , Predisposição Genética para DoençaRESUMO
Background and Aims: Tumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC. Methods: We assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results. Results: The PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic. Conclusions: Among patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification.
RESUMO
Hereditary cancer syndromes predispose to several types of cancer due to inherited pathogenic variants in susceptibility genes. We describe the case of a 57-year-old woman, diagnosed with breast cancer, and her family. The proband belongs to a family with a suspected tumor syndrome, due to other cancer cases in her family from the paternal and maternal sides. After oncogenetic counseling, she was subjected to mutational analysis with an NGS panel analyzing 27 genes. The genetic analysis showed two monoallelic mutations in low penetrance genes, c.1187G>A (p.G396D) in MUTYH and c.55dup (p.Tyr19Leufs*2) in BRIP1. One of the mutations was inherited from the maternal side and the other from the paternal side, suggesting two different cancer syndrome types in the family. MUTYH mutation was related to the onset of cancers on the paternal side, as confirmed by the occurrence of the same mutation in the proband's cousin. BRIP1 mutation was found in the proband's mother, indicating that it was related to the cancer cases observed on the maternal side, including breast cancer and sarcoma. Advances in NGS technologies have allowed the identification of mutations in families with hereditary cancers in genes other than those related to a specific suspected syndrome. A complete oncogenetic counseling, together with molecular tests that enable a simultaneous analysis of multiple genes, is essential for the identification of a correct tumor syndrome and for clinical decision-making in a patient and his/her family. The detection of mutations in multiple susceptibility genes allows the initiation of early risk-reducing measures for identified mutation carriers among family members and to include them in a proper surveillance program for specific syndromes. Moreover, it may enable an adapted treatment for the affected patient, permitting personalized therapeutic options.
Assuntos
Neoplasias da Mama , Síndromes Neoplásicas Hereditárias , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Predisposição Genética para Doença , Mutação , Síndromes Neoplásicas Hereditárias/genética , Neoplasias da Mama/genética , FamíliaRESUMO
The hamartomatous polyposis syndromes are a set of clinically distinct disorders characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Although each of the syndromes has distinct phenotypes, the hamartomatous polyps can be challenging to differentiate histologically. Additionally, each of these syndromes is associated with increased lifetime risks of gene-specific and organ-specific cancers, including those outside of the gastrointestinal tract. Germline pathogenic variants can be identified in a subset of individuals with these syndromes, which facilitates molecular diagnosis and subsequent gene-enabled management in the setting of genetic counseling. Although the malignant potential of hamartomatous polyps remains elusive, timely recognition of these syndromes is important and enables presymptomatic cancer surveillance and management before symptom exacerbation. Presently, there are no standard agents to prevent the development of polyps and cancers in the hamartomatous polyposis syndromes.
Assuntos
Síndrome do Hamartoma Múltiplo , Hamartoma , Síndromes Neoplásicas Hereditárias , Síndrome de Peutz-Jeghers , Humanos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Hamartoma/diagnóstico , Hamartoma/genética , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/genética , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Pólipos IntestinaisRESUMO
Pathogenic germline mutations in VHL gene cause von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome associated with high penetrance of benign and malignant neoplasms, including clear cell renal cell carcinoma (ccRCC), central nervous system haemangioblastomas (CNS-HB), retinal angiomas, phaeochromocytomas and pancreatic neuroendocrine tumours (pNET). Management of VHL disease involves lifelong radiological and biochemical surveillance, often leading to repeat surgical intervention causing significant morbidity and mortality. Systemic therapy that prevents or reduces the need for surgical intervention could improve clinical outcomes and quality of life for affected individuals. Belzutifan is a second-generation small molecule hypoxia-inducible factor 2α (HIF-2α) inhibitor recently approved by US and UK regulators for the treatment of VHL (disease)-associated ccRCC, CNS-HB and pNET. While this is a welcome step forward, it is vital that we consider in what circumstances these drugs are recommended and how they fit into the overall management of VHL disease. In this personal view article, we reflect on the history of the use of systemic therapy in localised VHL disease and consider open questions relating to the use of HIF-2α inhibitors, including the need to involve medical oncologists in the multidisciplinary team moving forward. Indeed, VHL disease is the perfect paradigm for similar settings in the future.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Tumores Neuroectodérmicos Primitivos , Doença de von Hippel-Lindau , Humanos , Carcinoma de Células Renais/patologia , Qualidade de Vida , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Neoplasias Renais/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genéticaRESUMO
The diagnosis of a hereditary cancer syndrome can be psychologically stressful and influence family planning. This study aimed to gain insights into the relationship between the desire for children and the distress of female carriers. Women (N = 255) with different hereditary cancer syndromes were assessed from November 2019 to July 2021 at genetic counseling centers, the centers of the German HBOC-Consortium and the centers of the German HNPCC-Consortium regarding their distress levels with the NCCN Distress Thermometer (DT). The desire for children was measured by self-developed questions. Levels of distress and desire for children were evaluated descriptively. Factors influencing the desire for children and distress were calculated using binary logistic regression: 56% (n = 51) of 18- to 39-year-old participants reported a desire to have children; 70.6% of the carriers with a desire for children indicated a need for advice from their physicians regarding family planning. The diagnosis led 61.5% to postpone the timing of family planning, and the majority (68.8%) opted for an earlier birth. Carriers had higher levels of distress. Younger carriers (p = 0.037) and those living in poorer economic circumstances (p = 0.011) were more distressed. The diagnosis of hereditary cancer syndrome affects family planning. The results emphasize the importance of physicians addressing family planning in their counseling sessions.
Assuntos
Síndromes Neoplásicas Hereditárias , Criança , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Síndromes Neoplásicas Hereditárias/genética , Aconselhamento Genético/psicologia , Serviços de Planejamento Familiar , Educação Sexual , Modelos LogísticosRESUMO
Cancer is a clonal disease that develops as a result of the changes on the genetic material by various factors in micro/macro environment. It has a multi-step development process. In some cancer types, genetic factors allow this multi-step process to proceed easily. These cancer types are also called hereditary cancer syndromes. Targeted gene panels are important diagnostic methods in hereditary cancer syndromes to detect the causative variants associated with these hereditary cancer syndromes. We reviewed the data of 94 patients who applied to Ankara City Hospital Genetic Diseases Evaluation Center from March 2019 to July 2021. Qiagen familial cancer susceptibility gene panel kit was used for next generation sequencing to detect the single nucleotide variants for the targeted genes. Sixty-one genes which are associated with increased cancer risk or well characterized hereditary cancer syndromes were included to this panel. Twenty five patients (27%), including 8 males and 17 females, had pathogenic/likely pathogenic variants in 13 of the 61 genes analyzed. Forty patients (43%) had variants which were assessed as variant of unknown significant. In our study, targeted multi-gene panel was diagnostic in nearly one third of the patients with personal/familial cancer syndromes. Molecular diagnosis in familial cancer syndromes is important in terms of predictive diagnosis and family screening, as well as patient follow-up and early prophylactic surgery. The predisposition for hereditary cancer syndromes can be determined according to pre-test evaluation, figuring out the inheritance type with pedigree analysis, cancer type and the genetic analysis for appropriate susceptibility genes.