ABSTRACT
MUTYH encodes a glycosylase involved in the base excision repair of DNA. Biallelic pathogenic germline variants in MUTYH cause an autosomal recessive condition known as MUTYH-associated adenomatous polyposis and consequently increase the risk of colorectal cancer. However, reports of increased cancer risk in individuals carrying only one defective MUTYH allele are controversial and based on studies involving few individuals. Here, we describe a comprehensive investigation of monoallelic pathogenic MUTYH germline variants in 10,389 cancer patients across 33 different tumour types and 117,000 healthy individuals. Our results indicate that monoallelic pathogenic MUTYH germline variants can lead to tumorigenesis through a mechanism of somatic loss of heterozygosity of the functional MUTYH allele in the tumour. We confirmed that the frequency of monoallelic pathogenic MUTYH germline variants is higher in individuals with cancer than in the general population, although this frequency is not homogeneous among tumour types. We also demonstrated that the MUTYH mutational signature is present only in tumours with loss of the functional allele and found that the characteristic MUTYH base substitution (C>A) increases stop-codon generation. We identified key genes that are affected during tumorigenesis. In conclusion, we propose that carriers of the monoallelic pathogenic MUTYH germline variant are at a higher risk of developing tumours, especially those with frequent loss of heterozygosity events, such as adrenal adenocarcinoma, although the overall risk is still low. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/genetics , DNA Glycosylases/genetics , Germ-Line Mutation , Neoplasms/genetics , Case-Control Studies , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Databases, Genetic , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Loss of Heterozygosity , Neoplasms/enzymology , Neoplasms/pathology , Phenotype , Prognosis , Risk Assessment , Risk FactorsABSTRACT
In southern and southeastern Brazil, the TP53 founder variant c.1010G>A (R337H) has been previously documented with a prevalence of 0.3% within the general population and linked to a heightened incidence of lung adenocarcinomas (LUADs). In the present investigation, we cover clinical and molecular characterizations of lung cancer patients from the Brazilian Li-Fraumeni Syndrome Study (BLISS) database. Among the 175 diagnosed malignant neoplasms, 28 (16%) were classified as LUADs, predominantly occurring in females (68%), aged above 50 years, and never-smokers (78.6%). Significantly, LUADs manifested as the initial clinical presentation of Li-Fraumeni Syndrome in 78.6% of cases. Molecular profiling was available for 20 patients, with 14 (70%) revealing EGFR family alterations. In total, 23 alterations in cancer driver genes were identified, comprising 7 actionable mutations and 4 linked to resistance against systemic treatments. In conclusion, the carriers of TP53 R337H demonstrate a predisposition to LUAD development. Furthermore, our results indicate that environmental pollution potentially impacts the carcinogenesis of lung tumors in the carriers of TP53 R337H.
Subject(s)
Adenocarcinoma of Lung , Li-Fraumeni Syndrome , Lung Neoplasms , Female , Humans , Aged , Li-Fraumeni Syndrome/genetics , Brazil/epidemiology , Tumor Suppressor Protein p53/genetics , Lung Neoplasms/epidemiology , Lung Neoplasms/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , Carcinogenesis , Adenocarcinoma of Lung/genetics , Germ Cells/pathologyABSTRACT
BACKGROUND: The microphthalmia-associated transcription factor gene (MITF) belongs to the MYC supergene family and plays an important role in melanocytes' homeostasis. Individuals harboring MITF germline pathogenic variants are at increased risk of developing cancer, most notably melanoma and renal cell carcinoma. CASE PRESENTATION: We describe a cohort of ten individuals who harbor the same MITF c.952G > A (p.Glu 318Lys), or p.E318K, germline pathogenic variant. Six carriers developed at least one malignancy (4 cases of breast cancer; 1 cervical cancer; 1 colon cancer; 1 melanoma; 1 ovarian/fallopian tube cancer). A significant phenotypic heterogeneity was found among these individuals and their relatives. Breast cancer was, overall, the most frequent malignancy observed in this case series, with 13 occurrences of 60 (21.67 %) total cancer cases described among the probands and their relatives. CONCLUSIONS: Our retrospective analysis data raise the hypothesis of a possible association of the MITF p.E318K pathogenic variant with an increased risk of breast cancer.
ABSTRACT
Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53-specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.
Subject(s)
Breast Neoplasms/genetics , Germ-Line Mutation , Tumor Suppressor Protein p53/genetics , Adult , Breast Neoplasms/diagnosis , Female , Guidelines as Topic , Humans , Middle Aged , Phenotype , Receptor, ErbB-2/geneticsABSTRACT
Li-Fraumeni Syndrome (LFS) is a hereditary disorder that confers an approximately 90% lifetime risk of cancer and requires comprehensive lifetime cancer screening. We explored healthcare roles for managing LFS-related cancer risks and treatments that were assumed by parents, adolescents, and adult children. Semi-structured interviews were conducted with 23 families. Family groupings were comprised of 2-5 members, with the younger generation in each family ranging in age from 7 to 40 years. Using grounded theory methods, we conducted open and focused coding of interview transcript content. Family members described how the role of health leader was implemented in their family, as well as factors such as maturation of a child or death of a member that determined who assumed particular roles and how these roles shifted over time. They often expressed collective responsibility for helping relatives understand LFS and implement appropriate cancer risk management. Members demonstrated their health role by attending others' medical appointments for support or information gathering. The health leader role was intergenerational and provided the family necessary support in navigating complicated healthcare decisions. Our findings provide insight into healthcare providers regarding how LFS patients and their relatives develop unique medical decision-making and caring roles influenced by the hereditary nature of LFS, and how these roles change over time. Providers who are attuned to family role dynamics may be better able to meet relatives' psychosocial and medical needs by understanding how living with LFS influences the family system's functioning and facilitating members' support for each other.
El síndrome de Li-Fraumeni (LFS) es un trastorno hereditario que concede aproximadamente un 90 % de riesgo durante toda la vida de contraer cáncer y exige exámenes completos para la detección del cáncer de por vida. Analizamos los roles sanitarios a la hora de manejar los riesgos y los tratamientos de cáncer relacionados con el LFS que asumieron los padres, los adolescentes y los hijos adultos. Se realizaron entrevistas semiestructuradas con 23 familias. Los agrupamientos familiares estaban compuestos por entre 2 y 5 familiares, donde la edad de la generación más joven de cada familia oscilaba entre 7 y 40 años. Utilizando los métodos de la teoría fundamentada, realizamos una codificación abierta y centrada del contenido de la transcripción de la entrevista. Los miembros de la familia describieron cómo se implementó el rol de jefe de la salud en su familia, así como factores como la maduración de un niño o la muerte de un miembro que determinaron quiénes asumieron roles particulares y cómo estos roles cambiaron con el tiempo. Con frecuencia ellos expresaron la responsabilidad colectiva de ayudar a los familiares a comprender el LFS y a implementar el manejo adecuado del riesgo de contraer cáncer. Los familiares demostraron sus roles sanitarios asistiendo a citas médicas de los demás para recibir apoyo u obtener información. El rol de jefe sanitario fue intergeneracional y proporcionó a la familia el apoyo necesario para manejarse ante decisiones complicadas sobre la asistencia sanitaria. Nuestros resultados brindan información para los prestadores de servicios médicos con respecto a cómo los pacientes de LFS y sus familiares desarrollan roles únicos para la toma de decisiones médicas y el cuidado influenciados por la índole hereditaria del LFS, y cómo estos roles cambian con el tiempo. Es posible que los prestadores que estén acostumbrados a la dinámica de roles familiares sean más capaces de satisfacer las necesidades psicosociales y médicas de los familiares si comprenden cómo vivir con LFS influye en el funcionamiento del sistema familiar y si facilitan el apoyo mutuo de los familiares.
Subject(s)
Family Health , Family , Leadership , Li-Fraumeni Syndrome , Role , Adolescent , Adult , Female , Humans , Male , Young Adult , Family/psychology , Family Characteristics , Grounded Theory , Health Behavior , Li-Fraumeni Syndrome/psychology , Qualitative ResearchABSTRACT
BACKGROUND: Ovarian carcinomas presenting homologous recombination deficiency (HRD), which is observed in about 50% of cases, are more sensitive to platinum and PARP inhibitor therapies. Although platinum resistant disease has a low chance to be responsive to platinum-based chemotherapy, a set of patients is retreated with platinum and some of them are responsive. In this study, we evaluated copy number alterations, HR gene mutations and HR deficiency scores in ovarian cancer patients with prolonged platinum sensitivity. METHODS: In this retrospective study (2005 to 2014), we selected 31 patients with platinum resistant ovarian cancer retreated with platinum therapy. Copy number alterations and HR scores were evaluated using the OncoScan® FFPE platform in 15 cases. The mutational profile of 24 genes was investigated by targeted-NGS. RESULTS: The median values of the four HRD scores were higher in responders (LOH = 15, LST = 28, tAI = 33, CS = 84) compared with non-responders (LOH = 7.5, LST = 17.5, tAI = 23, CS = 47). Patients with high LOH, LST, tAI and CS scores had better response rates, although these differences were not statistically significant. Response rate to platinum retreatment was 22% in patients with CCNE1 gains and 83.5% in patients with no CCNE1 gains (p = 0.041). Furthermore, response rate was 54.5% in patients with RB1 loss and 25% in patients without RB1 loss (p = 0.569). Patients with CCNE1 gains showed a worse progression free survival (PFS = 11.1 months vs 3.7 months; p = 0.008) and a shorter overall survival (OS = 39.3 months vs 7.1 months; p = 0.007) in comparison with patients with no CCNE1 gains. Patients with RB1 loss had better PFS (9.0 months vs 2.6 months; p = 0.093) and OS (27.4 months vs 3.6 months; p = 0.025) compared with cases with no RB1 loss. Four tumor samples were BRCA mutated and tumor mutations were not associated with response to treatment. CONCLUSIONS: HR deficiency was found in 60% of our cases and HRD medium values were higher in responders than in non-responders. Despite the small number of patients tested, CCNE1 gain and RB1 loss discriminate patients with tumors extremely sensitive to platinum retreatment.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cyclin E/genetics , Drug Resistance, Neoplasm/genetics , Oncogene Proteins/genetics , Ovarian Neoplasms/genetics , Platinum Compounds/pharmacology , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brazil/epidemiology , Child, Preschool , DNA Copy Number Variations/genetics , DNA Mutational Analysis , Female , Homologous Recombination/genetics , Humans , Middle Aged , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Platinum Compounds/therapeutic use , Progression-Free Survival , Retreatment , Retrospective Studies , Survival AnalysisABSTRACT
PURPOSE: Li-Fraumeni Syndrome (LFS) is an inherited tumor predisposition syndrome with lifetime cancer risks approaching 100% and evolving risk-management strategies. This study evaluated couples' coping with LFS-related burdens. RESEARCH APPROACH: Constructivist grounded theory and anticipatory loss frameworks guided design and analysis. SAMPLE AND METHODS: Twenty-six individuals enrolled in the NCI LFS Family Study completed semi-structured interviews with their partner during annual screening visits. An interdisciplinary team completed open and focused coding to identify patterns of coping and adaptation. FINDINGS: Couples described living with ambiguous danger, a state of chronic apprehension resulting from LFS-associated uncertainties. Most couples communicated openly and alternated shouldering the burden, while others engaged in protective buffering to shield each other from distress and sustain the appearance of normalcy. INTERPRETATION: Optimally, coping reduces shared psychosocial distress, yet some strategies may inadvertently increase disconnection. IMPLICATIONS: Mental health support is critical for both partners coping with LFS, together and separately.
Subject(s)
Adaptation, Psychological , Interpersonal Relations , Li-Fraumeni Syndrome/psychology , Mass Screening/psychology , Spouses/psychology , Uncertainty , Adult , Aged , Female , Humans , Li-Fraumeni Syndrome/diagnosis , Male , Middle Aged , Psychological Distress , Qualitative Research , Spouses/statistics & numerical data , Young AdultABSTRACT
Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear, most likely due to biased selection of cancer affected families. The aim of this study was to estimate the population prevalence of potentially pathogenic TP53 exonic variants in three sequencing databases, totaling 63,983 unrelated individuals. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, suggested clinical significance, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131 out of 63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA-binding domain of TP53, with an enrichment for specific variants that were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalence of potentially pathogenic TP53 variants may be up to 10 times higher than previously estimated from family-based studies. These results point to the need for further studies aimed at evaluating cancer penetrance modifiers as well as the risk associated between cancer and rare TP53 variants.
Subject(s)
Databases, Genetic , Exome/genetics , Genetic Variation , Li-Fraumeni Syndrome/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Family , Female , Genotype , Germ-Line Mutation , Humans , Middle Aged , Penetrance , Prevalence , Exome SequencingABSTRACT
The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.
Subject(s)
Anticipation, Genetic , Genetic Heterogeneity , Genetic Predisposition to Disease , Li-Fraumeni Syndrome/genetics , Neoplasms/genetics , Adult , Age of Onset , Animals , Child , Chromosome Segregation/genetics , Comparative Genomic Hybridization , DNA Copy Number Variations/genetics , Exome/genetics , Family Characteristics , Female , Genome, Human/genetics , Germ-Line Mutation/genetics , Heterozygote , Humans , Male , Mice, Knockout , Middle Aged , Pedigree , Phenotype , Sequence Analysis, DNA , Tumor Suppressor Protein p53/geneticsABSTRACT
A growing understanding of the molecular pathology of tumours combined with a surge of new drugs and associated diagnostic technologies (ie, precision medicine) has translated into substantial improvements in survival for patients with cancer. However, to achieve the promise that precision medicine has to offer will require overcoming hurdles within a national health-care system in which it is to be implemented. Brazil is one such nation, an emerging middle-income country with a very complex health-care system. To address the challenges associated with implementing precision medicine into a country such as Brazil, a group of experts convened (Nov 16-18, 2015, Miami) to discuss challenges related to precision medicine within an oncology setting. Complex regulatory hurdles, a shortage of human and technical resources, and the complexities of a two-tiered health-care delivery system were all identified as the main shortcomings to effectively implementing this new field of medicine. A path forward was proposed that relies on active collaboration between clinicians, private organisations, and government. It seems entirely possible that, despite many intrinsic economic and political problems, Brazil can readily emerge as a model for other countries in Latin America for the potential benefits of precision medicine and companion diagnostics.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Delivery of Health Care/legislation & jurisprudence , Health Policy , Molecular Diagnostic Techniques/standards , Molecular Targeted Therapy/standards , Neoplasm Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Humans , Neoplasms/metabolism , Neoplasms/pathology , Precision MedicineABSTRACT
PURPOSE: CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America. METHODS: CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained. RESULTS: Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients. CONCLUSION: The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first- or second-degree relatives.Genet Med 18 7, 727-736.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p18/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Receptor, Melanocortin, Type 1/genetics , Adult , Aged , Cyclin-Dependent Kinase Inhibitor p16 , Female , Genetic Counseling , Germ-Line Mutation , Humans , Male , Melanoma/diagnosis , Melanoma/epidemiology , Melanoma/pathology , Middle Aged , Risk Factors , SpainABSTRACT
AIM: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition. PATIENTS & METHODS: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays. RESULTS: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2). CONCLUSION: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.
Subject(s)
DNA Copy Number Variations/genetics , Genetic Predisposition to Disease/genetics , Melanoma/genetics , Skin Neoplasms/genetics , Adult , Female , Germ-Line Mutation , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Real-Time Polymerase Chain Reaction , Retrospective StudiesABSTRACT
OBJECTIVES: Secondary cytoreductive surgery (SCS) is an option for treating patients with recurrent ovarian cancer. Three ongoing randomized trials are comparing SCS plus chemotherapy with chemotherapy alone, and few comparative studies have been published. MATERIALS AND METHODS: We performed a retrospective review of data on 209 patients with recurrent ovarian carcinoma who were treated at a single institution from 2000 to 2013. We analyzed prognostic factors in the recurrence setting to determine the value of SCS in a multivariate model, including propensity score, by prognostic group. RESULTS: In the univariate analysis, younger than 65 years, personal or family history of breast or ovarian cancer, stage I-II at diagnosis, residual disease 10 mm or less after primary debulking surgery, performance status 1 or less, CA125 less than 100, only 1 metastatic site of recurrence, platinum-free interval of more than 12 months, and SCS correlated with better overall survival. In the multivariate model, including propensity score, SCS remained associated with a 66% decrease in the risk of death (hazard ratio, 0.34; 95% CI, 0.15-0.76, P = 0.008). Secondary cytoreductive surgery was also linked to longer progression-free survival (hazard ratio, 0.50; 95% CI, 0.30-0.84, P = 0.008). There was no evidence of a benefit of SCS in patients with unfavorable prognosis (P for interaction = 0.654). CONCLUSIONS: Our results confirm the benefit of SCS in progression-free survival and overall survival in the recurrent setting and suggest that it exists not only for patients with a good prognosis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cystadenocarcinoma, Serous/surgery , Cytoreduction Surgical Procedures , Neoplasm Recurrence, Local/surgery , Neoplasm, Residual/surgery , Ovarian Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/pathology , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Neoplasm, Residual/drug therapy , Neoplasm, Residual/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Prognosis , Proportional Hazards Models , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Interval debulking surgery (IDS) is an option for treating patients with advanced ovarian carcinoma. Two randomized trials have shown similar survival rates for primary debulking surgery (PDS) and IDS. One of the concerns with IDS is the potentially higher risk of inducing platinum resistance when treating patients with greater disease volume. METHODS: A retrospective review of data on 237 patients with stage IIIC and IV ovarian carcinoma who were treated at a single institution from 2000 to 2013. We analyzed the association of IDS with time to first platinum resistant relapse (TTPR); platinum-resistant disease at first relapse, defined as a platinum-free interval (PFI) after first-line chemotherapy of <6 months; and overall response rate (ORR) to chemotherapy at first platinum-sensitive relapse. RESULTS: The TTPR was 60 months, and the median TTPR was longer for the PDS (80.8 months) versus IDS group (39.3 months; p = 0.012) and for patients with residual disease (RD) ≤10 mm (80.8 months) compared with those with RD >10 mm (26.1 months; p < 0.001). In the multivariate analysis, IDS [hazard ratio (HR) 1.92; p = 0.009] and RD >10 mm (HR 1.65; p < 0.001) retained an increased risk of developing platinum-resistant disease. IDS was not associated with a greater risk of PFI <6 months at first relapse, and the ORR to platinum-based chemotherapy at first platinum-sensitive relapse was 87.2 % for patients who were treated with PDS compared with 68.0 % for those who underwent IDS (p = 0.051). CONCLUSIONS: IDS correlates with a higher risk of the development of platinum resistance.
Subject(s)
Cytoreduction Surgical Procedures , Drug Resistance, Neoplasm , Neoplasm Recurrence, Local/pathology , Neoplasm, Residual/pathology , Ovarian Neoplasms/pathology , Platinum/therapeutic use , Adenocarcinoma, Clear Cell/pathology , Adenocarcinoma, Clear Cell/therapy , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Mucinous/therapy , Chemotherapy, Adjuvant , Combined Modality Therapy , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/therapy , Endometrial Neoplasms/pathology , Endometrial Neoplasms/therapy , Female , Follow-Up Studies , Humans , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Neoplasm, Residual/therapy , Ovarian Neoplasms/therapy , Prognosis , Retrospective Studies , Risk Factors , Survival RateABSTRACT
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by DNA repair defects that cause photophobia, sunlight-induced cancers, and neurodegeneration. Prevalence of germline mutations in the nucleotide excision repair gene XPA vary significantly in different populations. No Brazilian patients have been reported to carry a germline mutation in this gene. In this study, the germline mutational status of XPA was determined in Brazilian patients exhibiting major clinical features of XP syndrome. The study was conducted on 27 unrelated patients from select Brazilian families. A biallelic inactivating transition mutation c.619C>T (p.Arg207Ter) was identified in only one patient with a history of neurological impairment and mild skin abnormalities. These findings suggest that XP syndrome is rarely associated with inherited disease-causing XPA mutations in the Brazilian population. Additionally, this report demonstrates the effectiveness of genotype-phenotype correlation as a valuable tool to guide direct genetic screening.
Subject(s)
Xeroderma Pigmentosum Group A Protein/genetics , Xeroderma Pigmentosum/genetics , Adolescent , Brazil , DNA Mutational Analysis , Female , Germ-Line Mutation , Humans , Male , Prevalence , Xeroderma Pigmentosum/epidemiologyABSTRACT
Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3' flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3' flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers.
Subject(s)
Age of Onset , G-Quadruplexes , Genes, p53 , Genetic Carrier Screening , Neoplasms/genetics , Polymorphism, Genetic , Base Sequence , DNA , Humans , Molecular Sequence DataABSTRACT
Melanoma is a highly aggressive cancer, accounting for up to 75% of skin cancer deaths. A small proportion of melanoma cases can be ascribed to the presence of highly penetrant germline mutations, and approximately 40% of hereditary melanoma cases are caused by CDKN2A mutations. The current study sought to investigate whether the presence of germline CDKN2A mutations or the occurrence of cutaneous melanoma would result in constitutive genome-wide DNA methylation changes. The leukocyte methylomes of two groups of melanoma patients (those with germline CDKN2A mutations and those without CDKN2A mutations) were analyzed together with the profile of a control group of individuals. A pattern of DNA hypomethylation was detected in the CDKN2A-negative patients relative to both CDKN2A-mutated patients and controls. Additionally, we delineated a panel of 90 CpG sites that were differentially methylated in CDKN2A-mutated patients relative to controls. Although we identified a possible constitutive epigenetic signature in CDKN2A-mutated patients, the occurrence of reported SNPs at the detected CpG sites complicated the data interpretation. Thus, further studies are required to elucidate the impact of these findings on melanoma predisposition and their possible effect on the penetrance of CDKN2A mutations.
Subject(s)
DNA Methylation/genetics , Genes, p16 , Germ-Line Mutation , Leukocytes , Melanoma/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Male , Oligonucleotide Array Sequence AnalysisABSTRACT
Despite the high prevalence of TP53 pathogenic variants (PV) carriers in the South and Southeast regions of Brazil, germline genetic testing for hereditary breast cancer (HBC) is not available in the Brazilian public health system, and the prevalence of Li-Fraumeni syndrome (LFS) is not well established in other regions of Brazil. We assessed the occurrence of TP53 p.R337H carriers among women treated for breast cancer (BC) between January 2021 and January 2022 at public hospitals of Brasilia, DF, Brazil. A total of 180 patients who met at least one of the NCCN criteria for HBC underwent germline testing; 44.4% performed out-of-pocket germline multigene panel testing, and 55.6% were tested for the p.R337H variant by allelic discrimination PCR. The median age at BC diagnosis was 43.5 years, 93% had invasive ductal carcinoma, 50% had estrogen receptor-positive/HER2 negative tumors, and 41% and 11% were diagnosed respectively at stage III and IV. Two patients (1.11%) harbored the p.R337H variant, and cascade family testing identified 20 additional carriers. The TP53 p.R337H detection rate was lower than that reported in other studies from south/southeast Brazil. Nonetheless, identifying TP53 PV carriers through genetic testing in the Brazilian public health system could guide cancer treatment and prevention.
Subject(s)
Breast Neoplasms , Genetic Predisposition to Disease , Germ-Line Mutation , Tumor Suppressor Protein p53 , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/epidemiology , Brazil/epidemiology , Adult , Tumor Suppressor Protein p53/genetics , Middle Aged , Genetic Testing/methods , Public Health , Li-Fraumeni Syndrome/genetics , Li-Fraumeni Syndrome/epidemiology , AgedABSTRACT
BACKGROUND: A recent large, well-annotated international cohort of patients with Li-Fraumeni syndrome and early-stage breast cancer was examined for shared features. METHODS: This multicenter cohort study included women with a germline TP53 pathogenic or likely pathogenic variant and nonmetastatic breast cancer diagnosed between 2002 and 2022. Clinical and genetic data were obtained from institutional registries and clinical charts. Descriptive statistics were used to summarize proportions, and differences were assessed using χ2 or Wilcoxon rank sum tests. Metachronous contralateral breast cancer risk, radiation-induced sarcoma risk, and recurrence-free survival were analyzed using the Kaplan-Meier methodology. RESULTS: Among 227 women who met study criteria, the median age of first breast cancer diagnosis was 37 years (range = 21-71), 11.9% presented with bilateral synchronous breast cancer, and 18.1% had ductal carcinoma in situ only. In total, 166 (73.1%) patients underwent mastectomies, including 67 bilateral mastectomies as first breast cancer surgery. Among those patients with retained breast tissue, the contralateral breast cancer rate was 25.3% at 5 years. Among 186 invasive tumors, 72.1% were stages I to II, 48.9% were node negative, and the most common subtypes were hormone receptor-positive/HER2-negative (40.9%) and hormone receptor positive/HER2 positive (34.4%). At a median follow-up of 69.9 months (interquartile range = 32.6-125.9), invasive hormone receptor-positive/HER2-negative disease had the highest recurrence risk among the subtypes (5-year recurrence-free survival = 61.1%, P = .001). Among those who received radiation therapy (n = 79), the 5-year radiation-induced sarcoma rate was 4.8%. CONCLUSION: We observed high rates of ductal carcinoma in situ, hormone receptor-positive, and HER2-positive breast cancers, with a worse outcome in the hormone receptor-positive/HER2-negative luminal tumors, despite appropriate treatment. Confirmation of these findings in further studies could have implications for breast cancer care in those with Li-Fraumeni syndrome.