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Appendix

Figure S1. Sample flow-chart describing the number of biological samples and clinical data obtained through an international multi-institutional effort and the distribution of samples in each microarray

Table S1-S3. S1Choroid plexus tumor chromosomal instability reported in literature S2-Characterization of patient and sample cohort used in analysis S3 Frequency of TP53 mutations in CPTs and characterization of mutation types. Abbreviations: CPC: choroid plexus carcinoma, CPP: choroid plexus papilloma, aCPP: atypical choroid plexus papilloma, SH3: SRC Homology 3 Domain

supplemental figure and table legend

Purpose: To investigate molecular alterations in choroid plexus tumors (CPT) using a genome-wide high-throughput approach to identify diagnostic and prognostic signatures that will refine tumor stratification and guide therapeutic options.Experimental Design: One hundred CPTs were obtained from a multi-institutional tissue and clinical database. Copy-number (CN), DNA methylation, and gene expression signatures were assessed for 74, 36, and 40 samples, respectively. Molecular subgroups were correlated with clinical parameters and outcomes.Results: Unique molecular signatures distinguished choroid plexus carcinomas (CPC) from choroid plexus papillomas (CPP) and atypical choroid plexus papillomas (aCPP); however, no significantly distinct molecular alterations between CPPs and aCPPs were observed. Allele-specific CN analysis of CPCs revealed two novel subgroups according to DNA content: hypodiploid and hyperdiploid CPCs. Hyperdiploid CPCs exhibited recurrent acquired uniparental disomy events. Somatic mutations in TP53 were observed in 60% of CPCs. Investigating the number of mutated copies of p53 per sample revealed a high-risk group of patients with CPC carrying two copies of mutant p53, who exhibited poor 5-year event-free (EFS) and overall survival (OS) compared with patients with CPC carrying one copy of mutant p53 (OS: 14.3%, 95% confidence interval, 0.71%–46.5% vs. 66.7%, 28.2%–87.8%, respectively, P = 0.04; EFS: 0% vs. 44.4%, 13.6%–71.9%, respectively, P = 0.03). CPPs and aCPPs exhibited favorable survival.Discussion: Our data demonstrate that differences in CN, gene expression, and DNA methylation signatures distinguish CPCs from CPPs and aCPPs; however, molecular similarities among the papillomas suggest that these two histologic subgroups are indeed a single molecular entity. A greater number of copies of mutated TP53 were significantly associated to increased tumor aggressiveness and a worse survival outcome in CPCs. Collectively, these findings will facilitate stratified approaches to the clinical management of CPTs. Clin Cancer Res; 21(1); 184–92. ©2014 AACR.

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.

Comprehensive annual screening reduces cancer-related mortality in Li-Fraumeni syndrome (LFS), a cancer-prone disorder caused by pathogenic germline TP53 variants. Blood tests at months 4 and 8 between annual screening are recommended but their effectiveness in early cancer detection has not been established. Interim blood counts and inflammatory biomarkers were evaluated in 132 individuals with LFS (112 adults, 87 female, median age 36 years [range 3–68], median follow-up 37 months [range 2–70]) and test abnormalities were observed in 225 (35%). Thirteen cancers in 12 individuals were diagnosed between annual screenings but only one cancer (colorectal adenocarcinoma) was diagnosed due to an abnormal interim blood test. Fisher’s exact test and generalized estimating equation models found no statistical associations between cancer diagnoses and any test abnormality. Four- and 8-monthly interim screening blood tests may not be of independent benefit for cancer detection in LFS, but annual cancer screening and personalized follow-up remain essential.

Background: Breast Cancer (BC) is one of the most common cancers diagnosed in Li-Fraumeni Syndrome (LFS). Most studies about the frequency of germline pathogenic variant (PV) TP53 p.R337H have been conducted in the South and Southeastern regions of Brazil reaching rates as high as 8% of detection. There is a lack of data on the frequency of this germline PV in other Brazilian regions, especially among patients without access to genetic tests. Objective: This study aims to evaluate the detection rate of TP53 p.R337H in patients (pts) at risk of hereditary breast cancer (HBC) and describe the clinical and demographic profile of the study cohort. Methodology: Hereditary cancer risk assessment based on the National Comprehensive Cancer Network Criteria (NCCN), version 1.2020, was performed in women with BC who were being followed in a public hospital (DF, Brazil) between January 2021 and January 2022. All pts eligible for germline genetic testing according to HBC NCCN criteria were referred for genetic counseling and genetic testing. For those patients who could not afford a comprehensive genetic test, a real time PCR test specifically searching for TP53 p.R337H variant was performed. In case of TP53 p.R337H detection in the proband, genetic counseling and familial variant testing were offered to family members. Results: Among 221 pts eligible for this study, 180 pts performed germline testing, including 100 pts tested only for the TP53 p.R337H variant (real-time PCR) and 80 pts performed out of pocket BC multigene panel testing (including TP53 sequencing). This cohort was mostly represented by pts from Central-West (47%) and Northeast (35%) regions of Brazil. The median age of BC diagnosis was 44 y.o. (18 - 78). Invasive ductal carcinoma represented 92% (n=203) of the tumors, 50% were ER/PR+ HER2-, 25% HER2 +, 25% ER/PR- HER2- (triple negative). Regarding stage at diagnosis, 59% (n=130) were stages IIB-IIIC and 13% IV. The detection rate of TP53 p.R337H was 1.1% (2/180). Among the pts who met the revised Chompret criteria for LFS, this frequency was 5% (2/40). One of them was diagnosed with a stage IIIB IDC ER/PR+HER2- at 28 y.o. and had no relevant family history of cancer. The other pt was diagnosed with a stage IV IDC ER/PR+HER2- at 44 y.o. and the family history revealed four sisters and one niece with BC, and one nephew with brain tumor at 4 y.o. The family members from these two families received genetic counseling and genetic testing. Cascade testing was able to identify 12 additional carriers. All carriers were referred for post-testing follow-up. Conclusion: According to these results, we expect to identify at least one p.R337H carrier in each 90 BC pts treated in the Federal’s District Public Health setting who fulfill HBC NCCN criteria. In a limited resources setting, in Brazil, testing the TP53 p.R337H variant with PCR is a low-cost test that should be considered at least for pts that meet the revised Chompret criteria. The overall detection rate of TP53 p.R337H carriers was lower in comparison to other Brazilian studies from the South/Southeast of the country. Both cases identified in this cohort had advanced local disease or metastatic disease at BC diagnosis, raising the concern about the importance of LFS diagnosis, and high-risk surveillance and risk reduction strategies in this subgroup of pts. Despite the low detection rate of TP53 p.R337H in this cohort, there was a high familial impact through cascade testing. Citation Format: Tatiana S. Correa, Renata L. Sandoval, Eduarda S. Oliveira, Ana Carolina R. Leite, Luiza Nardin Weis, Maria Isabel Achatz, Claudiner P. Oliveira, Paula Fontes Asprino, Romualdo Barroso-Sousa. Frequency of germline TP53 p.R337H variant among women at risk of hereditary breast cancer in a public health system of Central-West of Brazil [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-19.

Background: Breast cancer (BC) is the most common tumor in women with Li-Fraumeni syndrome (LFS), with a cumulative incidence of 85% by the age of 60 years. However, LFS-related BC characteristics are still underexplored since most data derive from small retrospective cohorts. A variable enrichment in HER2-positivity (ranging from 34 to 80%) has been reported, but information regarding the response to anti-HER2 treatments are currently lacking. Moreover, data regarding the new emerging category of HER2-low are missing. Methods: Invasive BCs diagnosed in patients (pts) with TP53 germline pathogenic/likely pathogenic variant between 2002-2022 at Institut Gustave Roussy (France), Dana-Farber Cancer Institute (USA) and Hospital Sírio-Libanês (Brazil) were included. HER2 and hormone receptor (HR) expression were retrospectively retrieved from pathology records and evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. HER2-positive cases were defined by an immunohistochemistry (IHC) score of 3+ and/or HER2 gene amplification by ISH; HER2-negative cases were classified as HER2-low (IHC 1+ or 2+ with negative ISH assay) or HER2-zero (IHC score 0). Pathologic complete response (pCR) was defined as ypT0/is and ypN0. Results: Among 197 invasive BCs identified in a total of 176 pts, 50.3% (n=99) were HER-positive. Among those, median age at BC diagnosis was 33 years (range 21-61) and the most frequent TP53 variants were missense mutations (n=68), affecting the DNA-binding domain in 70.6% of cases and the tetramerization domain in 29.4% of cases. Most BCs were invasive ductal carcinoma (n=90), with histologic grade 3 in 56.6% of cases. At diagnosis, most pts had early stage disease (34.3% stage I; 32.3% stage II; 21.2% stage III), while 6 pts presented de novo stage IV disease. Most tumors were HR-positive (76.8%, n=76), while 23.2% were HR-negative. 38 patients with HER2-positive BCs were treated with neoadjuvant therapy, 32 cases had post-neoadjuvant pathology reports available for pathological response classification. Among those, 26 (81.2%) were HR-positive and 6 (18.8%) HR-negative. Among pts with neoadjuvant treatment data, 87.1% received trastuzumab, which was combined with pertuzumab in 43.3% of cases; chemotherapy regimens included taxanes in all pts, anthracycline in 43.3% and platinum in 16.7%. 71.9% (n=23) of pts reached a pCR (69.2% among HR-positive and 83.3% among HR-negative), while 9 (28.1%) had residual disease; pCR rate was 82.4% among pts treated with an anthracycline-free regimen. At a median follow-up of 36 months, only one patient relapsed. Among HER2-negative BCs with available IHC score and ISH for HER2-low classification (n=85), 28 (32.9%) were HER2-low and 57 (67.1%) HER2-zero. Conclusions: In this first report of treatment results in BC pts with LFS, enrichment of HER2-positive BCs was confirmed and a remarkable pCR rate was observed with neoadjuvant treatment. Our findings require validation in a larger cohort, which is in progress. Collaborative efforts are essential for high quality data about BC treatment in this subgroup of pts. Citation Format: Michele Bottosso, Renata Lazari Sandoval, Benjamin Verret, Natalia Polidorio, Olivier Caron, Alessandra Gennari, Brittany Bychkovsky, Sophie Hyman, Maria Isabel Achatz, Valentina Guarneri, Fabrice Andre, Judy Garbe. HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-18.

PURPOSE The objective of this review was to address the barriers limiting access to genetic cancer risk assessment and genetic testing for individuals with suspected hereditary breast and ovarian cancer (HBOC) through a review of the diagnosis and management steps of HBOC. METHODS A selected panel of Brazilian experts in fields related to HBOC was provided with a series of relevant questions to address before the multiday conference. During this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion, until a consensus was achieved. RESULTS The authors propose specific and realistic recommendations for improving access to early diagnosis, risk management, and cancer care of HBOC specific to Brazil. Moreover, in creating these recommendations, the authors strived to address all the barriers and impediments mentioned in this article. CONCLUSION There is a great need to expand hereditary cancer testing and counseling in Brazil, and changing current policies is essential to accomplishing this goal. Increased knowledge and awareness, together with regulatory actions to increase access to this technology, have the potential to improve patient care and prevention and treatment efforts for patients with cancer across the country.

Endometrial cancer is the only gynecological cancer that is rising in incidence and associated mortality worldwide. Although most cases are diagnosed as early stage disease, with chances of cure after primary surgical treatment, those with advanced or metastatic disease have a poor prognosis because of the quality of treatment options that are currently available. Mismatch repair (MMR)-deficient cancers are susceptible to programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 inhibitors. The US Food and Drug Administration granted accelerated approval to pembrolizumab for MMR-deficient tumors, the first tumor-agnostic approval for a drug. We present a case of stage IV endometrioid endometrial carcinoma with isolated PMS2 protein loss, in which treatment with first-line pembrolizumab therapy achieved a complete clinical and pathological response of tumor.

Li-Fraumeni and Li-Fraumeni-like (LFS/LFL) Syndrome are cancer predisposition syndromes caused by germline pathogenic variants in TP53 and are associated with an increased risk of multiple early-onset cancers. In Southern and Southeastern Brazil, a germline founder variant with partial penetrance located in the oligomerization domain of TP53, c.1010G>A p.(Arg337His, commonly known as R337H), has been detected in 0.3% of the general population. Recently, the functional MIR605 variant rs2043556 (A>G) has been identified as a novel LFS phenotype modifier in families with germline TP53 DNA binding variants. In this study, our goal was to verify MIR605 rs2043556 allele frequencies and further explore its possible effects on the phenotype of 238 Brazilian individuals carrying TP53 p.(Arg337His). The MIR605 rs2043556 G allele was detected in 136 (57.1%) individuals, including 25 homozygotes (10.5%), and although it had been previously associated with an earlier mean age of tumor onset, this effect was not observed in this study (p = 0.8). However, in p.(Arg337His) mutation carriers, the GG genotype was significantly associated with the occurrence of multiple primary tumors (p = 0.005). We provide further evidence of MIR605 rs2043556 G allele's effect as a phenotype modulator in carriers of germline TP53 pathogenic variants.

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. AThe aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and otherWe searched for cases ofAmong 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5%31 years; 66.7% 31-45 years; 21.8%45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20-69 years) compared to 34 years (range 21-63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductalThe expressed phenotype of p.R337H is similar to that of other

PURPOSE Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

Li-Fraumeni syndrome (LFS) is a hereditary genetic condition that predisposes to a wide variety of tumors. Early-onset breast cancer is the most prevalent tumor in female carriers, with a 49% risk by age 60. The risk of developing a second primary breast cancer in LFS remains unknown but it is estimated to be 33%. The Toronto protocol was proposed by Villani et al. (2011) and defined effective strategies for cancer screening in carriers. Risk-reduction mastectomy (RRM) may reduce over 90% breast cancer risk. Due to a founder mutation, TP53 p.R337H, LFS has been observed in a higher-than-expected prevalence in Brazil. This mutation occurs in the oligomerization domain and seems to have a milder lifetime penetrance than regular DNA binding domain mutations. Due to its estimated high frequency in the Brazillian population, this is a public health problem and implementation of effective strategies in breast cancer risk-reduction are needed. In this study, we have evaluated risk-reduction mastectomy in women who carried the founder TP53 p.R337H mutation. A total of 106 women from the Brazilian LFS TP53 p.R337H cohort were included in this study. Imaging surveillance was offered and RRM was discussed. All participants received genetic counseling and signed informed consent. The study was approved by the local ethics committee (HSL-02433418.5.0000.5461). A total of 65.1% (69/106) did not develop breast cancer at the time of this study. Among those, four women opted to perform bilateral prophylactic mastectomy (5.8% - 4/69). Overall, 34.9% (37/106) developed breast cancer prior to enrollment and 12 women were lost to follow-up. A total of 25 women opted to continue surveillance. Eleven (44%) opted to undergo RRM and 14 (66%) chose to continue annual breast magnetic resonance imaging (MRI), according to the Toronto protocol. A total of 32% (8/25) had been diagnosed with a second primary breast cancer prior to the study enrollment. The most common breast cancer histopathological subtype was invasive ductal carcinoma, present in 64% (16/25) in our study population. Only one woman was diagnosed with invasive lobular carcinoma (4%). Twelve percent (3/25) were in situ carcinomas. Estrogen and progesterone receptors stained positive in 76% (19/25). HER-2 was negative in 52% (13/25) of all cases. Our findings show that BPM was not a common procedure in carriers (5.8%). Nevertheless, RRM was performed in 44% of all women who have been previously diagnosed with breast cancer. Ductal invasive carcinoma is the most common cancer in TP53 p.R337H women and most of them have hormone receptor status positive. Unlike other previously published studies on LFS breast can cancer, HER-2 gene was non-amplified in most cases (52%). This is the first study to evaluate the frequency of RRM in a cohort of women with breast cancer carrying the same germline pathogenic variant, TP53 p.R337H. Citation Format: Mariana Cartaxo Alves, Renata Lazari Sandoval, Janina Pontes Pisani, Carla Vanessa Quirino, Elizabeth Santana Santos, Maria Isabel Achatz. Breast cancer in Li-Fraumeni syndrome and risk-reduction mastectomy in TP53 p.R337H carriers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-18.

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.李-佛美尼综合症是一种遗传性的疾病，大概一生中有90%的患癌几率，它要求家庭成员终身接受综合性癌症筛查。本文研究医疗保健对管理李-佛美尼综合症风险和治疗过程中所起的作用，这些风险和治疗均由家长，青少年和成年孩子们来承担着。参与研究的家庭有23个，采用半结构化的访谈。家庭的组成有2-5个家庭成员，每个家庭的较年轻一代人年龄跨度7-40岁。使用草根理论方法，我们针对访谈文稿进行了开放式和集中式解码。家庭成员描述了健康领袖的作用在家庭内如何实现的，还有孩子的成熟，某家庭成员的去世等因素，这些因素都决定了谁承担了什么角色，这些角色在一段时间范围内如何发生变化。他们通常会表达集体性的共同责任，帮助亲戚理解LFS症和实施合适的癌症风险管理。家庭成员通过陪同一起去就医来给与支持以及信息搜集的方式来实现他们的健康作用。健康领袖的作用是代际间的，提供了必要的支持给家庭，特别是在复杂的医疗保健方面的决定。我们的研究结果提供了健康医疗供给方的看法，主要是关于LFS病人和他们的亲戚如何作出特殊的医疗决策和发挥照料者的角色，这些都深受LFS遗传性特性的影响，和这些角色如何随着时间而发生变化。那些可以适应家庭角色动态变化的供给方可以较好地实现亲戚的社会心理和医疗的需要，主要是通过尽力理解承受LFS影响的家庭系统的功能，促进家庭成员们彼此的支持。.

Li–Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome with exceptionally high lifetime cancer risks, caused primarily by germline TP53 variants. Early-onset breast cancer is the most common cancer in women with LFS. Associations between female reproductive factors and breast cancer risk have been widely studied in the general population and BRCA1/2 mutation carriers but not in LFS. We evaluated whether reproductive factors are associated with breast cancer in LFS. Questionnaire data were collected for 152 women with confirmed germline TP53 variants enrolled in the National Cancer Institute's LFS study (NCT01443468); of which, 85 had breast cancer, confirmed by pathology/medical reports. Fisher's exact test and Cox proportional hazards were used to calculate the effect of reproductive factors on breast cancer risk. Lifetime breastfeeding for at least 7 months was associated with lower breast cancer risk (hazard ratio [HR] 0.57, p = 0.05). Parity did not independently change breast cancer risk (HR 1.08, p = 0.8) but suggested an increased risk with older age at first live birth (HR 2.14, p = 0.05). Age at menarche (HR 1.09, p = 0.24) and use of oral contraceptives (HR 0.88; p = 0.7) did not significantly affect breast cancer risk. In this first study of reproductive factors and breast cancer in women with LFS, breastfeeding was observed to be protective against breast cancer risk, especially with at least 7 months of lifetime breastfeeding. Older age at first live birth was suggested to slightly increase breast cancer risk. Larger prospective studies of reproductive factors are warranted in women with LFS before making definitive clinical recommendations.

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.

Comprehensive annual screening reduces cancer-related mortality in Li-Fraumeni syndrome (LFS), a cancer-prone disorder caused by pathogenic germline TP53 variants. Blood tests at months 4 and 8 between annual screening are recommended but their effectiveness in early cancer detection has not been established. Interim blood counts and inflammatory biomarkers were evaluated in 132 individuals with LFS (112 adults, 87 female, median age 36 years [range 3-68], median follow-up 37 months [range 2-70]) and test abnormalities were observed in 225 (35%). Thirteen cancers in 12 individuals were diagnosed between annual screenings but only one cancer (colorectal adenocarcinoma) was diagnosed due to an abnormal interim blood test. Fisher's exact test and generalized estimating equation models found no statistical associations between cancer diagnoses and any test abnormality. Four- and 8-monthly interim screening blood tests may not be of independent benefit for cancer detection in LFS, but annual cancer screening and personalized follow-up remain essential.

Childhood cancer statistics are scarce and incomplete in most emerging and low-income countries (ELIC), in which up to 75% of the cases may arise. In many low-resource contexts, lack of awareness, scarce diagnostic resources, and poor access to care are serious barriers to the recognition of inherited pediatric cancer. Family history is rarely investigated in a systematic way, and genetic testing is usually limited or absent in most ELIC. Therefore, the burden of inherited childhood cancer in low-resource countries is poorly known and is most likely underestimated. Available data reveal important differences in the clinical patterns of inherited childhood cancer between high- and low-income regions. These differences are largely explained by biases in detection, diagnosis, reporting, and management due to constrained socioeconomic resources. Only a small number of national cancer institutions in ELIC have formulated coordinated programs toward inherited childhood cancer. In this chapter, we describe leading initiatives in two intermediate-resource countries representative of large populations in transitions: Malaysia and Brazil. We also discuss the identification in defined population groups of germline mutations due to founder effects, which can lead to large clusters of inherited childhood cancers. Finally, we provide a brief overview of the patterns of retinoblastoma and nephroblastoma in the low-income settings of sub-Saharan Africa, and we discuss the plausible contribution of germline mutations to cancer burden in these areas.

Brazil is the largest country in South America and the most genetically heterogeneous. The aim of the present study was to determine the prevalence of germline pathogenic variants (PVs) in Brazilian patients with breast cancer (BC) who underwent genetic counseling and genetic testing at a tertiary Oncology Center. We performed a retrospective analysis of the medical records of Brazilian patients with BC referred to genetic counseling and genetic testing between August 2017 and August 2019. A total of 224 unrelated patients were included in this study. Premenopausal women represented 68.7% of the cohort. The median age at BC diagnosis was 45 years. Multigene panel testing was performed in 219 patients, five patients performed single gene analysis or family variant testing. Forty-eight germline PVs distributed among 13 genes were detected in 20.5% of the patients (46/224). Eighty-five percent of the patients (91/224) fulfilled NCCN hereditary BC testing criteria. Among these patients, 23.5% harbored PVs (45/191). In the group of patients that did not meet NCCN criteria, PV detection rate was 3% (1/33). A total of 61% of the patients (28/46) harbored a PV in a high-penetrance BC gene: 19 (8.5%) BRCA1/2, 8 (3.5%) TP53, 1 (0.5%) PALB2. Moderate penetrance genes (ATM, CHEK2) represented 15.2% (7/46) of the positive results. PVs detection was statistically associated (pBRCA genes, it represented 43.5% of the positive results and 51.2% of the actionable variants. Considering the observed prevalence of PVs in actionable genes beyond BRCA1/2 (9%, 20/224), multigene panel testing may offer an effective first-tier diagnostic approach in this population.

In Southern and Southeastern Brazil, there is a germline pathogenic variant with incomplete penetrance located in the oligomerization domain of TP53, c.1010G>A (p.Arg337His). Due to a founder effect, the variant is present in 0.3% of the general population of the region. Recently, this variant was identified in 4.4 and 8.9% of two apparently unselected, single center case series of Brazilian lung adenocarcinoma (LUAD) patients from the Southeastern and Central regions of the country, respectively. In the present study, our aim was to examine TP53 c.1010G>A allele and genotype frequencies in LUAD samples obtained from patients diagnosed in Southern Brazil. A total of 586 LUAD samples (tumor DNA) recruited from multiple centers in the region were tested, and the mutant allele was identified using TaqMan® assays in seven cases (7/586, 1.2%) which were submitted to next generation sequencing analyses for confirmation. Somatic EGFR mutations were more frequent in TP53 c.1010G>A carriers than in non-carriers (57.1 vs. 17.6%, respectively). Further studies are needed to confirm if TP53 c.1010G>A is a driver in LUAD carcinogenesis and to verify if there is a combined effect of EGFR and germline TP53 c.1010G>A. Although variant frequency was higher than observed in the general population, it is less than previously reported in LUAD patients from other Brazilian regions. Additional data, producing regional allele frequency information in larger series of patients and including cost-effectiveness analyses, are necessary to determine if TP53 c.1010G>A screening in all Brazilian LUAD patients is justified.

Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected MUS81 c.1292G&gt, A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G&gt, A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G&gt, A induced protein instability and affected DNA damage response. We suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability.

The XAF1-E134* variant increases the cancer risk for carriers of the TP53-R337H allele., Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.

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.

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice-site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one-third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome.