Pierre Hainaut - Academia.edu (original) (raw)

Papers by Pierre Hainaut

Cancer prevention research (Philadelphia, Pa.), Jan 23, 2016

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepat... more We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between pre-diagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested-case control study was conducted within the EPIC cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function and alpha-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95%CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10%...

The Hereditary Basis of Childhood Cancer, 2021

Journal of Clinical Oncology, 2013

e22154 Background: Recent studies in North American and British series have suggested an associat... more e22154 Background: Recent studies in North American and British series have suggested an association between germline TP53 mutations and early onset HER2-positive breast cancer (BC). Mutations in the TP53 gene are estimated to occur in 1:2,000-1:5,000 individuals of the general population. Among women with BC who are unselected for family history they occur in up to 0.25%. In women with early-onset BC (<30 years) they occur in up to 7%. A specific germline TP53 mutation (c.1010G>A; p.R337H) has been encountered in 0.3% of the general population, in 13.3% of Li-Fraumeni-like families and in 0.5-2.4% of BC-affected women in Brazil. In an exploratory approach, the aim of this study was to investigate, in our series, if there is an association between human epidermal growth factor receptor 2 (HER2) amplification and the germline TP53 p.R337H mutation in a series of BC-affected women. Methods: A series of 718 Brazilian BC-affected women was genotyped in our previous study and 64 (8...

Journal of Clinical Oncology, 2012

10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndrome... more 10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a germline TP53 mutation. Recently, a specific germline mutation in exon 10 of the TP53 gene, p.R337H, has been reported at a high prevalence in Southeastern Brazil. Initial studies on this mutation claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma (ADR). However, others recent reports identified p.R377H carriers among LFL families and among a larger spectrum of tumors, such as choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study was to assess the frequency of the p.R337H mutation in children diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central nervous system tumors, leukemia, germline cell tumors and Wilm’s tumor) at the Children’s Cancer Institute of Rio Grande do Sul (Brazil) between 1998 and 2011. Methods: Family history (FH) was recorded in pedigrees...

Journal of Clinical Oncology, 2012

1522 Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni S... more 1522 Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni Syndrome, to the overall burden of cancer is still only partially known. Studies in Southern and Southeastern Brazil have shown that a specific germline mutation at codon 337 (c.1010G>A; p.R337H), has incomplete penetrance and may be present in a significant number of subjects (estimated frequency at the populational level of 1:300 individuals). In an exploratory approach, the aim of the study is to assess the frequency of the p.R337H mutation in women from different Brazilian regions, diagnosed with breast cancer (BC) before 46 and after 55 years of age, and unselected for family history of cancer. Methods: Formalin-fixed paraffin-embedded (FFPE) non-tumoral tissue (lymph nodes or normal breast) of women diagnosed with BC between 2000 and 2010 in 3 pathology laboratories from the Brazilian cities of Porto Alegre, São Paulo and Barretos were obtained retrospectively and analyzed after ...

Current Opinion in Oncology, 2018

Purpose of review Germline pathogenic TP53 mutation may predispose to multiple cancers but penetr... more Purpose of review Germline pathogenic TP53 mutation may predispose to multiple cancers but penetrance and cancer patterns remain incompletely documented. We have analyzed international agency for research on cancer TP53 database to reevaluate age and variant-dependent tumor patterns. Recent findings Genome-wide studies suggest that germline variants are more frequent than estimated prevalence of Li-Fraumeni syndrome (LFS), suggesting that many carriers of potentially pathogenic mutations may not develop the syndrome. Carriers of a germline TP53 mutation who are detected in a clinical context have a penetrance of 80% at age 70. Penetrance varies according to age, sex and mutation type. Temporal tumor patterns show distinct phases, with childhood phase (0-15 years, 22% of all cancers) characterized by adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma and medulloblastoma; early adulthood phase (16-50 years, 51%) including breast cancer, osteosarcoma, soft tissue sarcomas, leukemia, astrocytoma and glioblastoma, colorectal and lung cancer; late adulthood phase (51-80 years, 27%) including pancreatic and prostate cancer. Summary Germline pathogenic variants in TP53 gene have different consequences according to cell, tissue, context and age. The occurrence of frequent variants in patients with no criteria suggestive of LFS calls for attention in predicting individual risk and highlights the need of additional predictors for assigning carriers to appropriate surveillance programs.

Human mutation, Jan 23, 2018

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regardi... more Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 website. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N23...

Human mutation, Dec 1, 2017

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer disorder associated with pathogenic ge... more Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer 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. The aim of this study was to estimate the prevalence of potentially pathogenic TP53 exonic variants in three data sources, totaling 63,983 unrelated individuals from three sequencing databases. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, clinical significance evidences, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131/63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA-binding domain of TP53, with an enrichment for specific variants which were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalenc...

Cancer Genetics, 2016

Rare germline variant (rs78378222) in the TP53 3' UTR: evidence for a new mechanism of cancer pre... more Rare germline variant (rs78378222) in the TP53 3' UTR: evidence for a new mechanism of cancer predisposition in li-fraumeni syndrome.

PloS one, 2015

Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific s... more Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Port...

Epidemiology, 2015

Very few studies have focused on the relationship among dietary carbohydrates, glycemic index (GI... more Very few studies have focused on the relationship among dietary carbohydrates, glycemic index (GI), glycemic load (GL), and breast cancer risk in Latin American women. Our objective was to assess the associations among dietary carbohydrate, GI, GL, and risk of breast cancer, and to further investigate these associations by levels of overweight/obesity and physical activity. We used data from a Mexican population-based case-control study. We recruited a 1,000 women with incident breast cancer and 1,074 matched control women ages 35 to 69 years between 2004 and 2007. We used conditional logistic regression models and energy-adjusted carbohydrates, GI, and GL using the residual method. Total carbohydrate intake was associated with an increased risk of breast cancer among premenopausal women. The odds ratio in the highest versus the lowest quartile was 1.3 (95% confidence interval = 1.0, 1.7; P trend = 0.03). In stratified analyses by body mass index (BMI), the positive association between carbohydrate and risk of premenopausal breast cancer was only observed among overweight women. The odds ratio comparing the top with the bottom quartile was 1.9 (95% confidence interval = 1.2, 3.0; P trend = 0.01) among women with BMI ≥ 25 kg/m. No association was observed among women with BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 25 kg/m. Our findings suggest that high carbohydrate diets are associated with an increased risk of breast cancer among premenopausal Mexican women.

Journal of Cancer Therapy, 2013

Early gastric carcinomas may develop with a molecular profile differing from sporadic carcinomas ... more Early gastric carcinomas may develop with a molecular profile differing from sporadic carcinomas occurring at a later age. In this study, we analyzed a retrospective series of 88 patients with gastric adenocarcinoma diagnosed before the age of 45 years for the presence of TP53 mutations, clinicopathological features and immunohistochemistry to evaluate the expression of markers considered to be important in gastric carcinogenesis (E-cadherin, β-catenin, MUC1, MUC2, MUC5AC, MUC6 and p53). The majority of proportion of tumors were diffuse-type (70%) and advanced stage (56%). Familial history of cancer was positive in 21% of the cases. There was a significant association between altered expression of E-cadherin and β-catenin, and between p53 expression and perineural invasion. TP53 mutations were detected in 14.5% of evaluated cases, including a germline mutation (p.R337H) in a 12-year-old patient. Overall survival analysis showed significant differences in relation with tumor stage and histopathology. The evaluated biomarkers did not present prognostic value in non-exploratory multivariate analyses. The low frequency of TP53 mutations in this series suggests these alterations are not a major molecular event in gastric cancer occurring at early age, although the identification of a case with germline p.R337H mutation is consistent with the hypothesis that a small proportion of early, apparently sporadic gastric cancer, may be associated with widespread Brazilian founder mutations. Further studies are needed to evaluate the prognostic significance of markers for specific groups of patients according to tumor histology and familial history.

Proceedings of the National Academy of Sciences, 2010

A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signalin... more A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signaling pathways that play essential roles during normal development and tumorigenesis. We generated E4F1 conditional knockout mice to address E4F1 functions in vivo in newborn and adult skin. E4F1 inactivation in the entire skin or in the basal compartment of the epidermis induces skin homeostasis defects, as evidenced by transient hyperplasia in the interfollicular epithelium and alteration of keratinocyte differentiation, followed by loss of cellularity in the epidermis and severe skin ulcerations. E4F1 depletion alters clonogenic activity of epidermal stem cells (ESCs) ex vivo and ends in exhaustion of the ESC pool in vivo, indicating that the lesions observed in the E4F1 mutant skin result, at least in part, from cell-autonomous alterations in ESC maintenance. The clonogenic potential of E4F1 KO ESCs is rescued by Bmi1 overexpression or by Ink4a/Arf or p53 depletion. Skin phenotype of E4F...

Proceedings of the National Academy of Sciences, 2014

Significance Germ-line mutation in the tumor suppressor TP53 causes Li–Fraumeni syndrome (LFS), a... more Significance Germ-line mutation in the tumor suppressor TP53 causes Li–Fraumeni syndrome (LFS), a complex predisposition to multiple cancers. Types of cancers and ages at diagnosis vary among subjects and families, with apparent genetic anticipation: i.e., earlier cancer onset with successive generations. It has been proposed that anticipation is caused by accumulation of copy-number variations (CNV) in a context of TP53 haploinsufficiency. Using genome/exome sequencing, we found no evidence of increased rates of CNVs in two successive generations of TP53 mutation carriers and in successive generations of Trp53 -deficient mice. We propose a stochastic model called “genetic regression” to explain apparent anticipation in LFS, caused by segregation of rare SNP and de novo mutations rather than by cumulative DNA damage.

Cancer Research, 2013

Li-Fraumeni syndrome (LFS), an inherited cancer predisposition syndrome, is associated with germl... more Li-Fraumeni syndrome (LFS), an inherited cancer predisposition syndrome, is associated with germline mutations in TP53. It is characterized by high risk of multiple, early cancers. In Brazil, a variant form of LFS is exceedingly frequent due to a widespread founder TP53 mutation, p.R337H, detected in about 0.3% of the general population in Southern Brazil. This mutation occurs in p53 oligomerization domain and its effect on p53 oligomerization is supposed to be dependent upon pH conditions. Recent studies indicate that p53 plays a critical role in regulating differentiation and asymmetric divisions of stem cells. The main objective of this study is to isolate and to characterize Cancer Stem Cells (CSC) in patients with germline mutations in TP53 gene with Li-Fraumeni syndrome and Li-Fraumeni-like Syndrome. We have isolated and characterized CSC from tumors of p.R337H mutation carriers. After informed consent, surgical resection fragments were dissociated and brought in culture. Adhe...

Orphanet Journal of Rare Diseases, 2014

Background: The Li-Fraumeni syndrome (LFS) is an inherited rare cancer predisposition syndrome ch... more Background: The Li-Fraumeni syndrome (LFS) is an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors. Although germline mutations in the tumor suppressor gene TP53 account for over 50% of the families matching LFS criteria, the lack of TP53 mutation in a significant proportion of LFS families, suggests that other types of inherited alterations must contribute to their cancer susceptibility. Recently, increases in copy number variation (CNV) have been reported in LFS individuals, and are also postulated to contribute to LFS phenotypic variability. Methods: Seventy probands from families fulfilling clinical criteria for either Li-Fraumeni or Li-Fraumeni-like (LFS/LFL) syndromes and negative for TP53 mutations were screened for germline CNVs. Results: We found a significantly increased number of rare CNVs, which were smaller in size and presented higher gene density compared to the control group. These data were similar to the findings we reported previously on a cohort of patients with germline TP53 mutations, showing that LFS/LFL patients, regardless of their TP53 status, also share similar CNV profiles. Conclusion: These results, in conjunction with our previous analyses, suggest that both TP53-negative and positive LFS/LFL patients present a broad spectrum of germline genetic alterations affecting multiple loci, and that the genetic basis of LFS/LFL predisposition or penetrance in many cases might reside in germline transmission of CNVs.

The Lancet Oncology, 2009

The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early... more The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early cancer has led to mass newborn testing for this mutation in the State of Paraná, southern Brazil. Newborn screening for inherited cancer risk is complex and controversial. In this paper, we discuss the justifications for this screening by considering the medical and scientific evidence for this mutation. R337H has been identified in Brazilian families with Li-Fraumeni or related syndromes predisposing to cancers in childhood (ie, brain, renal, and adrenocortical carcinomas), adolescence (ie, soft tissue and bone sarcomas), and young adulthood (ie, breast cancer). R337H has also been detected in children with adrenocortical carcinoma without a documented family history of cancer. The mutation is estimated to occur in about 0.3% of the population in southern Brazil and is associated with increased cancer risk throughout life. Cancer patterns in families positive for R337H suggest strong genetic modifying effects, making it difficult to predict individual risk. Because protocols for cancer-risk management in Li-Fraumeni or related syndromes are debatable, extreme care should prevail in predictive testing of children for R337H. A detailed assessment of the risks, benefits, and costs is needed to ensure that medical, social, and ethical justifications for newborn screening are met.

Cancer prevention research (Philadelphia, Pa.), Jan 23, 2016

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepat... more We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between pre-diagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested-case control study was conducted within the EPIC cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function and alpha-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95%CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10%...

The Hereditary Basis of Childhood Cancer, 2021

Journal of Clinical Oncology, 2013

e22154 Background: Recent studies in North American and British series have suggested an associat... more e22154 Background: Recent studies in North American and British series have suggested an association between germline TP53 mutations and early onset HER2-positive breast cancer (BC). Mutations in the TP53 gene are estimated to occur in 1:2,000-1:5,000 individuals of the general population. Among women with BC who are unselected for family history they occur in up to 0.25%. In women with early-onset BC (<30 years) they occur in up to 7%. A specific germline TP53 mutation (c.1010G>A; p.R337H) has been encountered in 0.3% of the general population, in 13.3% of Li-Fraumeni-like families and in 0.5-2.4% of BC-affected women in Brazil. In an exploratory approach, the aim of this study was to investigate, in our series, if there is an association between human epidermal growth factor receptor 2 (HER2) amplification and the germline TP53 p.R337H mutation in a series of BC-affected women. Methods: A series of 718 Brazilian BC-affected women was genotyped in our previous study and 64 (8...

Journal of Clinical Oncology, 2012

10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndrome... more 10593 Background: Childhood cancers are a common feature in Li-Fraumeni/Li Fraumeni-Like Syndromes (LFS/LFL), associated with the inheritance of a germline TP53 mutation. Recently, a specific germline mutation in exon 10 of the TP53 gene, p.R337H, has been reported at a high prevalence in Southeastern Brazil. Initial studies on this mutation claimed that the main, if not exclusive, cancer risk in carriers is childhood adrenocortical carcinoma (ADR). However, others recent reports identified p.R377H carriers among LFL families and among a larger spectrum of tumors, such as choroid plexus carcinoma (CPC) and osteosarcoma. The aim of this study was to assess the frequency of the p.R337H mutation in children diagnosed with tumors of the LFS/LFL spectrum: ADR, sarcoma, central nervous system tumors, leukemia, germline cell tumors and Wilm’s tumor) at the Children’s Cancer Institute of Rio Grande do Sul (Brazil) between 1998 and 2011. Methods: Family history (FH) was recorded in pedigrees...

Journal of Clinical Oncology, 2012

1522 Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni S... more 1522 Background: The exact contribution of TP53 germline mutations, associated with Li Fraumeni Syndrome, to the overall burden of cancer is still only partially known. Studies in Southern and Southeastern Brazil have shown that a specific germline mutation at codon 337 (c.1010G>A; p.R337H), has incomplete penetrance and may be present in a significant number of subjects (estimated frequency at the populational level of 1:300 individuals). In an exploratory approach, the aim of the study is to assess the frequency of the p.R337H mutation in women from different Brazilian regions, diagnosed with breast cancer (BC) before 46 and after 55 years of age, and unselected for family history of cancer. Methods: Formalin-fixed paraffin-embedded (FFPE) non-tumoral tissue (lymph nodes or normal breast) of women diagnosed with BC between 2000 and 2010 in 3 pathology laboratories from the Brazilian cities of Porto Alegre, São Paulo and Barretos were obtained retrospectively and analyzed after ...

Current Opinion in Oncology, 2018

Purpose of review Germline pathogenic TP53 mutation may predispose to multiple cancers but penetr... more Purpose of review Germline pathogenic TP53 mutation may predispose to multiple cancers but penetrance and cancer patterns remain incompletely documented. We have analyzed international agency for research on cancer TP53 database to reevaluate age and variant-dependent tumor patterns. Recent findings Genome-wide studies suggest that germline variants are more frequent than estimated prevalence of Li-Fraumeni syndrome (LFS), suggesting that many carriers of potentially pathogenic mutations may not develop the syndrome. Carriers of a germline TP53 mutation who are detected in a clinical context have a penetrance of 80% at age 70. Penetrance varies according to age, sex and mutation type. Temporal tumor patterns show distinct phases, with childhood phase (0-15 years, 22% of all cancers) characterized by adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma and medulloblastoma; early adulthood phase (16-50 years, 51%) including breast cancer, osteosarcoma, soft tissue sarcomas, leukemia, astrocytoma and glioblastoma, colorectal and lung cancer; late adulthood phase (51-80 years, 27%) including pancreatic and prostate cancer. Summary Germline pathogenic variants in TP53 gene have different consequences according to cell, tissue, context and age. The occurrence of frequent variants in patients with no criteria suggestive of LFS calls for attention in predicting individual risk and highlights the need of additional predictors for assigning carriers to appropriate surveillance programs.

Human mutation, Jan 23, 2018

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regardi... more Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 website. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N23...

Human mutation, Dec 1, 2017

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer disorder associated with pathogenic ge... more Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer 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. The aim of this study was to estimate the prevalence of potentially pathogenic TP53 exonic variants in three data sources, totaling 63,983 unrelated individuals from three sequencing databases. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, clinical significance evidences, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131/63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA-binding domain of TP53, with an enrichment for specific variants which were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalenc...

Cancer Genetics, 2016

Rare germline variant (rs78378222) in the TP53 3' UTR: evidence for a new mechanism of cancer pre... more Rare germline variant (rs78378222) in the TP53 3' UTR: evidence for a new mechanism of cancer predisposition in li-fraumeni syndrome.

PloS one, 2015

Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific s... more Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Port...

Epidemiology, 2015

Very few studies have focused on the relationship among dietary carbohydrates, glycemic index (GI... more Very few studies have focused on the relationship among dietary carbohydrates, glycemic index (GI), glycemic load (GL), and breast cancer risk in Latin American women. Our objective was to assess the associations among dietary carbohydrate, GI, GL, and risk of breast cancer, and to further investigate these associations by levels of overweight/obesity and physical activity. We used data from a Mexican population-based case-control study. We recruited a 1,000 women with incident breast cancer and 1,074 matched control women ages 35 to 69 years between 2004 and 2007. We used conditional logistic regression models and energy-adjusted carbohydrates, GI, and GL using the residual method. Total carbohydrate intake was associated with an increased risk of breast cancer among premenopausal women. The odds ratio in the highest versus the lowest quartile was 1.3 (95% confidence interval = 1.0, 1.7; P trend = 0.03). In stratified analyses by body mass index (BMI), the positive association between carbohydrate and risk of premenopausal breast cancer was only observed among overweight women. The odds ratio comparing the top with the bottom quartile was 1.9 (95% confidence interval = 1.2, 3.0; P trend = 0.01) among women with BMI ≥ 25 kg/m. No association was observed among women with BMI &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 25 kg/m. Our findings suggest that high carbohydrate diets are associated with an increased risk of breast cancer among premenopausal Mexican women.

Journal of Cancer Therapy, 2013

Early gastric carcinomas may develop with a molecular profile differing from sporadic carcinomas ... more Early gastric carcinomas may develop with a molecular profile differing from sporadic carcinomas occurring at a later age. In this study, we analyzed a retrospective series of 88 patients with gastric adenocarcinoma diagnosed before the age of 45 years for the presence of TP53 mutations, clinicopathological features and immunohistochemistry to evaluate the expression of markers considered to be important in gastric carcinogenesis (E-cadherin, β-catenin, MUC1, MUC2, MUC5AC, MUC6 and p53). The majority of proportion of tumors were diffuse-type (70%) and advanced stage (56%). Familial history of cancer was positive in 21% of the cases. There was a significant association between altered expression of E-cadherin and β-catenin, and between p53 expression and perineural invasion. TP53 mutations were detected in 14.5% of evaluated cases, including a germline mutation (p.R337H) in a 12-year-old patient. Overall survival analysis showed significant differences in relation with tumor stage and histopathology. The evaluated biomarkers did not present prognostic value in non-exploratory multivariate analyses. The low frequency of TP53 mutations in this series suggests these alterations are not a major molecular event in gastric cancer occurring at early age, although the identification of a case with germline p.R337H mutation is consistent with the hypothesis that a small proportion of early, apparently sporadic gastric cancer, may be associated with widespread Brazilian founder mutations. Further studies are needed to evaluate the prognostic significance of markers for specific groups of patients according to tumor histology and familial history.

Proceedings of the National Academy of Sciences, 2010

A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signalin... more A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signaling pathways that play essential roles during normal development and tumorigenesis. We generated E4F1 conditional knockout mice to address E4F1 functions in vivo in newborn and adult skin. E4F1 inactivation in the entire skin or in the basal compartment of the epidermis induces skin homeostasis defects, as evidenced by transient hyperplasia in the interfollicular epithelium and alteration of keratinocyte differentiation, followed by loss of cellularity in the epidermis and severe skin ulcerations. E4F1 depletion alters clonogenic activity of epidermal stem cells (ESCs) ex vivo and ends in exhaustion of the ESC pool in vivo, indicating that the lesions observed in the E4F1 mutant skin result, at least in part, from cell-autonomous alterations in ESC maintenance. The clonogenic potential of E4F1 KO ESCs is rescued by Bmi1 overexpression or by Ink4a/Arf or p53 depletion. Skin phenotype of E4F...

Proceedings of the National Academy of Sciences, 2014

Significance Germ-line mutation in the tumor suppressor TP53 causes Li–Fraumeni syndrome (LFS), a... more Significance Germ-line mutation in the tumor suppressor TP53 causes Li–Fraumeni syndrome (LFS), a complex predisposition to multiple cancers. Types of cancers and ages at diagnosis vary among subjects and families, with apparent genetic anticipation: i.e., earlier cancer onset with successive generations. It has been proposed that anticipation is caused by accumulation of copy-number variations (CNV) in a context of TP53 haploinsufficiency. Using genome/exome sequencing, we found no evidence of increased rates of CNVs in two successive generations of TP53 mutation carriers and in successive generations of Trp53 -deficient mice. We propose a stochastic model called “genetic regression” to explain apparent anticipation in LFS, caused by segregation of rare SNP and de novo mutations rather than by cumulative DNA damage.

Cancer Research, 2013

Li-Fraumeni syndrome (LFS), an inherited cancer predisposition syndrome, is associated with germl... more Li-Fraumeni syndrome (LFS), an inherited cancer predisposition syndrome, is associated with germline mutations in TP53. It is characterized by high risk of multiple, early cancers. In Brazil, a variant form of LFS is exceedingly frequent due to a widespread founder TP53 mutation, p.R337H, detected in about 0.3% of the general population in Southern Brazil. This mutation occurs in p53 oligomerization domain and its effect on p53 oligomerization is supposed to be dependent upon pH conditions. Recent studies indicate that p53 plays a critical role in regulating differentiation and asymmetric divisions of stem cells. The main objective of this study is to isolate and to characterize Cancer Stem Cells (CSC) in patients with germline mutations in TP53 gene with Li-Fraumeni syndrome and Li-Fraumeni-like Syndrome. We have isolated and characterized CSC from tumors of p.R337H mutation carriers. After informed consent, surgical resection fragments were dissociated and brought in culture. Adhe...

Orphanet Journal of Rare Diseases, 2014

Background: The Li-Fraumeni syndrome (LFS) is an inherited rare cancer predisposition syndrome ch... more Background: The Li-Fraumeni syndrome (LFS) is an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors. Although germline mutations in the tumor suppressor gene TP53 account for over 50% of the families matching LFS criteria, the lack of TP53 mutation in a significant proportion of LFS families, suggests that other types of inherited alterations must contribute to their cancer susceptibility. Recently, increases in copy number variation (CNV) have been reported in LFS individuals, and are also postulated to contribute to LFS phenotypic variability. Methods: Seventy probands from families fulfilling clinical criteria for either Li-Fraumeni or Li-Fraumeni-like (LFS/LFL) syndromes and negative for TP53 mutations were screened for germline CNVs. Results: We found a significantly increased number of rare CNVs, which were smaller in size and presented higher gene density compared to the control group. These data were similar to the findings we reported previously on a cohort of patients with germline TP53 mutations, showing that LFS/LFL patients, regardless of their TP53 status, also share similar CNV profiles. Conclusion: These results, in conjunction with our previous analyses, suggest that both TP53-negative and positive LFS/LFL patients present a broad spectrum of germline genetic alterations affecting multiple loci, and that the genetic basis of LFS/LFL predisposition or penetrance in many cases might reside in germline transmission of CNVs.

The Lancet Oncology, 2009

The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early... more The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early cancer has led to mass newborn testing for this mutation in the State of Paraná, southern Brazil. Newborn screening for inherited cancer risk is complex and controversial. In this paper, we discuss the justifications for this screening by considering the medical and scientific evidence for this mutation. R337H has been identified in Brazilian families with Li-Fraumeni or related syndromes predisposing to cancers in childhood (ie, brain, renal, and adrenocortical carcinomas), adolescence (ie, soft tissue and bone sarcomas), and young adulthood (ie, breast cancer). R337H has also been detected in children with adrenocortical carcinoma without a documented family history of cancer. The mutation is estimated to occur in about 0.3% of the population in southern Brazil and is associated with increased cancer risk throughout life. Cancer patterns in families positive for R337H suggest strong genetic modifying effects, making it difficult to predict individual risk. Because protocols for cancer-risk management in Li-Fraumeni or related syndromes are debatable, extreme care should prevail in predictive testing of children for R337H. A detailed assessment of the risks, benefits, and costs is needed to ensure that medical, social, and ethical justifications for newborn screening are met.