Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.

BACKGROUND: Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. OBJECTIVE AND DESIGN: This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. RESULTS: 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. CONCLUSION: Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Evaluation of MLH1 I219V polymorphism in unrelated South American individuals suspected of having Lynch syndrome.

BACKGROUND: Some single-nucleotide polymorphisms are associated with higher risk of colorectal cancer development and are suggested to explain part of the genetic contribution to Lynch syndrome. AIM: To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features. MATERIALS AND METHODS: DNA was obtained from peripheral blood and polymerase chain reaction (PCR) was performed, followed by direct sequencing. RESULTS: The Val allelic of the I219V polymorphism was found in 51.61% (64/124) of the individuals, with an allelic frequency of 0.3. MLH1 or MHS2 pathogenic mutations were found in 32.81% (21/64) and in 23.33% (14/60) of Val-carriers and non-carriers, respectively. CONCLUSION: The Val-carrying genotype was frequent in the studied population; however, it does not appear to exert any modifier effect on MLH1 or MSH2 pathogenic mutations and the development of colorectal cancer.

Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries.

BACKGROUND: Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. METHODS: Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. RESULTS: Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson). CONCLUSIONS: The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.

Molecular insights on basal-like breast cancer.

Molecular classification of breast cancer (BC) identified diverse subgroups that encompass distinct biological behavior and clinical implications, in particular in relation to prognosis, spread, and incidence of recurrence. Basal-like breast cancers (BLBC) compose up to 15% of BC and are characterized by lack of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification with expression of basal cytokeratins 5/6, 14, 17, epidermal growth factor receptor (EGFR), and/or c-KIT. There is an overlap in definition between triple-negative BC and BLBC due to the triple-negative profile of BLBC. Also, most BRCA1-associated BCs are BLBC, triple negative, and express basal cytokeratins (5/6, 14, 17) and EGFR. There is a link between sporadic BLBC (occurring in women without germline BRCA1 mutations) with dysfunction of the BRCA1 pathway. Despite the molecular and clinical similarities, these subtypes respond differently to neoadjuvant therapy. BLBCs are associated with an aggressive phenotype, high histological grade, poor clinical behavior, and high rates of recurrences and/or metastasis. Their molecular features render these tumors especially refractory to anti-hormonal-based therapies and the overall prognosis of this subset remains poor. In this article, the molecular profile, genomic, and epigenetic characteristics as well as BRCA1 pathway dysfunction, clinicopathological behavior, and therapeutic options in BLBC are presented, with emphasis on the discordant findings in current literature.

Advances and applications of oral cancer basic research.

Cancer of the oral cavity accounts for almost 3% of cancer cases in the world. The incidence varies widely reflecting geographic differences in exposure to risk factors. The recent rise in younger age groups and females seen in many countries is of particular concern. Treatment and management of complications, locoregional recurrence and further primary tumors result in high morbidity and mortality especially when the disease is advanced stage at initial diagnosis. Progress in cancer research has provided abundant new knowledge about cellular processes and molecular biology underlying oral carcinogenesis and tumor progression. The present review attempts to summarize the current most widely-used research approaches and their application in the prevention, diagnosis, effective treatment, and improved outcome of oral cancer.

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals.

Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.

Frequency of extracolonic tumors in Brazilian families with Lynch syndrome: analysis of a hereditary colorectal cancer institutional registry.

Lynch syndrome (LS) is caused by inherited germline mutations in mismatch repair (MMR) genes. It is one of the commonest forms of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is characterized by early age of onset, with a tendency for multiplicity and an increased risk for extra-colonic tumors at particular sites. In this study we have evaluated the frequency of extra-colonic tumors in 60 unrelated LS families fulfilling the Amsterdam criteria (ACI. ACII) from the Oncotree database of the Hereditary Colorectal Cancer Registry of the AC Camargo Hospital. All families' pedigree was extensively analyzed, varying from 2 to 6 generations with a total of 2,095 individuals evaluated. As expected, colorectal cancer was the most frequent tumor in the families (334 cases). We found 200 extracolonic tumors among all individuals with a higher ratio in women (123 cases) than men (77 cases). By far, breast cancer (32 cases) was the most frequent extracolonic manifestation in women followed by endometrial (20 cases) and uterine cervix cancer (20 cases). For man, prostate (16 cases) and stomach (12 cases) cancer were the most frequent extracolonic tumors. It is well know that establishing the diagnosis is challenging and requires knowledge and surveillance. Thus, recognition of individuals and families with hereditary predisposition to cancer according to clinical and molecular features, combined with intensive surveillance and management programs, can contribute substantially to improve results related to the diagnosis and characterization of LS.

Frequency of polymorphisms and protein expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) in central nervous system tumors / Frequência dos polimorfismos e da expressão protéica do inibidor de quinase dependente de ciclina 1A (CDKN1A) em tumores do sistema nervoso central

Context and objective: Genetic investigation of central nervous system (CNS) tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR) and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene in patients with and without CNS tumors. Design and setting: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clínicas de Ribeirão Preto. Methods: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. Results: The frequencies of the heterozygote (Ser/Arg) and polymorphic homozygote (Arg/Arg) genotypes of codon 31 in the control subjects were 28.0 percent and 1.2 percent, respectively. However, the 3'UTR site presented frequencies of 24.2 percent (C/T) and 0.6 percent (T/T). These frequencies were not statistically different (P > 0.05) from those seen in the patients with CNS tumors (19.4 percent and 0.0 percent, codon 31; 15.8 percent and 2.6 percent, 3'UTR site). Regarding the protein expression in ependymomas, 66.67 percent did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14 percent and 61.54 percent, respectively). Conclusion: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects.

Contexto e objetivo: A investigação genética dos tumores do sistema nervoso central (SNC) provê valiosa informação sobre os genes que regulam a proliferação, diferenciação, angiogênese, migração e apoptose. O objetivo deste estudo é determinar a prevalência entre os polimorfismos genéticos (códon 31 e da região 3' não traduzida, 3'UTR) e a expressão protéica do gene inibidor de quinase dependente de ciclina 1A (CDKN1A) em pacientes com e sem tumor do SNC. Tipo de estudo e local: Estudo transversal analítico com grupo controle, desenvolvido no Laboratório de Biologia Molecular do Departamento de Oncologia Pediátrica do Hospital das Clínicas de Ribeirão Preto. Métodos: 41 pacientes com tumor do SNC e um grupo controle de 161 indivíduos sem câncer pareados por idade, sexo e etnia foram genotipados mediante uma reação de polimorfismo no comprimento de fragmentos de restrição (RFLP). A análise das proteínas foi realizada em 36 pacientes com tumor de SNC mediante Western Blotting. Resultados: A frequência do genótipo heterozigoto (Ser/Arg) e do homozigoto polimórfico (Arg/Arg) do códon 31 nos controles foi 28,0 por cento e 1,2 por cento, respectivamente. Entretanto, o sítio 3'UTR apresentou uma frequência de 24,2 por cento (C/T) e 0,6 por cento (T/T). Estas frequências não são significativamente diferentes (P > 0,05) daquelas observadas no grupo dos pacientes com tumor de SNC (19,4 por cento e 0,0 por cento, códon 31; 15,8 por cento e 2,6 por cento, sítio 3'UTR). Com respeito à expressão protéica, nos ependimomas, 66,67 por cento não expressaram a proteína CDKN1A. Estes resultados foram similares entre os meduloblastomas e os astrocitomas, os quais não expressaram a proteína com 57,14 por cento e 61,54 por cento, respectivamente. Conclusão: Não foram encontradas diferenças significativas entre o padrão de expressão protéica, polimorfismos de CDKN1A e os três tipos de tumores de SNC em indivíduos brasileiros.

Mismatch repair genes in Lynch syndrome: a review.

Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50%) and MSH2 (40%), while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

Mismatch repair genes in Lynch syndrome: a review: [review] / Genes de reparo de DNA na síndrome de Lynch: uma revisão: [revisão]

Lynch syndrome represents 1-7 percent of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50 percent) and MSH2 (40 percent), while others account for 10 percent. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

A síndrome de Lynch representa de 1-7 por cento de todos os casos de câncer colorretal. É uma síndrome de herança autossômica dominante que predispõe ao câncer e é causada por mutações nos genes de reparo de ácido desoxirribonucléico (DNA). Desde a descoberta dos principais genes com função de reparo de DNA, mutações nos genes MSH2, MLH1, MSH6, PMS2 e PMS1 estão relacionadas com a susceptibilidade à síndrome de Lynch. Outro gene, MLH3, tem sido proposto como tendo papel na predisposição à síndrome de Lynch, porém mutações de significância clínica nesse gene não são claras. De acordo com o banco de dados InSiGHT (International Society for Gastrointestinal Hereditary Tumors), aproximadamente 500 diferentes mutações associadas à síndrome de Lynch são conhecidas, envolvendo primeiramente MLH1 (50 por cento), MSH2 (40 por cento) e outros (10 por cento). Grandes progressos têm ocorrido para nosso entendimento das bases moleculares da síndrome de Lynch. A caracterização molecular será a forma mais precisa para definirmos a síndrome de Lynch e irá fornecer informações preditivas mais precisas sobre o risco de câncer colorretal e extra-colônico, além de permitir regimes otimizados de manejo.

Frequency of polymorphisms and protein expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) in central nervous system tumors.

CONTEXT AND OBJECTIVE: Genetic investigation of central nervous system (CNS) tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR) and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene in patients with and without CNS tumors. DESIGN AND SETTING: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clínicas de Ribeirão Preto. METHODS: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. RESULTS: The frequencies of the heterozygote (Ser/Arg) and polymorphic homozygote (Arg/Arg) genotypes of codon 31 in the control subjects were 28.0% and 1.2%, respectively. However, the 3'UTR site presented frequencies of 24.2% (C/T) and 0.6% (T/T). These frequencies were not statistically different (P > 0.05) from those seen in the patients with CNS tumors (19.4% and 0.0%, codon 31; 15.8% and 2.6%, 3'UTR site). Regarding the protein expression in ependymomas, 66.67% did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14% and 61.54%, respectively). CONCLUSION: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects.

Recurrence Factors In Stage II Colon Cancer

Objective and Methods: For evaluating recurrence factors in Stage II colon adenocarcinoma a clinical, non-experimental, longitudinal and retrospective study was done in the Department of Abdomen of INEN from January 1, 1990 to December 31,2000. Results: In 200 eligible patients 20 (10%) recurrence cases were observed that appeared in an average 2.3 years after surgery. The main site of recurrence was local-regional (5.5%), pulmonary (2.5%), hepatic (1%), and peritoneal (1%). The following factors were considered: age, sex, CEA level, type of operation (elective or emergency), site of the primary injury,invasion (T3 or T4), lymphatic vessel invasion, histologic differentiation, and synchronous carcinoma. We found that patients more than 70 years old (p=0.0305) have a lesser disease-free time. Be more than 70 years old was the only recurrencerelated factor; this group has 2.56 times more risk of recurrence. No other studied variable was related to recurrence.