Search

The Prospective Lynch Syndrome Database (PLSD) has been developed as an international, multicentre, prospective, observational study that aims to provide age and organ-specific cancer risks according to gene and gender, estimates of survival after cancer and information on the effects of interventions. Recent reports from PLSD provided improved estimates of cancer risks and survival and showed that different time intervals between surveillance colonoscopies did not affect the incidence, stage or prognosis of colorectal cancer. The PLSD reports suggest that current management guidelines for Lynch syndrome should be revised in light of the different gene and gender-specific cancer risks and the good prognosis for the most commonly associated cancers. In this review, we describe the discrepancies between the current management guidelines for Lynch Syndrome and the most recent prospective observational studies, indicating the areas of further research. Keywords Lynch syndrome · Hereditary non-polyposis colorectal cancer · Colorectal cancer · Colonoscopy · Surveillance · Prevention · Precision medicine · PLSD · Cancer incidence

Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families from Argentina, Brazil and Chile. Herein, we collected clinical information on these families and performed segregation analysis and RNA splicing studies to assess the implication of these VUS in LS etiology. Pedigrees showed a clear pattern of variant co-segregation with colorectal cancer and/or other LS-associated malignancies. Tumors presented deficient expression of MLH1-PMS2 proteins in 7/7 of the LS families, and MSI-high status in 3/3 cases. Moreover, RNA analyses revealed that c.588+5G>C and c.588+5G>T induce skipping of exon 7 whereas c.677+5G>A causes skipping of exon 8. In sum, we report that the combined clinical findings in the families and the molecular studies provided the evidences needed to demonstrate that the three MLH1 variants are causative of LS and to classify c.588+5G>C and c.677+5G>A as class 5 (pathogenic), and c.588+5G>T as class 4 (likely-pathogenic). Our findings underline the importance of performing clinical and family analyses, as well as RNA splicing assays in order to determine the clinical significance of intronic variants, and contribute to the genetic counseling and clinical management of patients and their relatives.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Resumen Los avances en la investigación clínica, genética y molecular del cáncer colorrectal (CCR) realizados durante los últimos años han permitido su detección temprana, así como su tratamiento oportuno. Sin embargo, uno de los mayores desafíos de esta enfermedad es su naturaleza heterogénea y la participación de diversas vías moleculares en su carcinogénesis. La implementación de las tecnologías ómicas -como la genómica, la proteómica, la transcriptómica y la epigenómica- en la investigación biomédica de pacientes con CCR hereditario ha permitido identificar nuevos genes o polimorfismos de nucléotido único (SNP, por su sigla en inglés) que afectan la expresividad del cáncer. Por otra parte, las herramientas bioinformáticas han contribuido a generar nuevas hipótesis sobre el CCR, orientando el abordaje de estos pacientes hacia una medicina personalizada. Este avance científico y tecnológico tiene un impacto en la salud, tanto a nivel individual como colectivo, por lo que es importante reflexionar sobre la viabilidad de desarrollar estrategias de salud pública para la implementación de un programa integral y genético de prevención y manejo del cáncer en Perú, en especial del CCR hereditario. Abstract Progress in clinical, genetic and molecular research of colorectal cancer (CRC) in recent years has allowed its early detection and timely and targeted treatment. However, one of the greatest challenges is the heterogeneous nature of CRC and the involvement of various molecular pathways in its carcinogenesis. The implementation of technologies known as omics -such as genomics, proteomics, transcriptomics and epigenomics- in biomedical research on patients with hereditary CRC has allowed the identification of new genes or single nucleotide polymorphisms (SNPs) that affect the expressivity of cancer. Bioinformatics tools have also contributed to generate new hypotheses about CRC, guiding the approach to these patients towards personalized medicine. This scientific and technological progress has an impact on health, both at the individual and the collective level, so it is important to reflect on the feasibility of developing public health strategies for the implementation of a comprehensive and genetic program for the prevention and treatment of cancer in Peru, especially hereditary CRC.

Hearing and balance disorders are related to the inner ear and are among the major cause of falls in older adults. Hearing loss that commonly occurs with aging (aka presbyacusis) can result from noise exposure, smoking, ototoxic drugs and genetic factors such as mutations in nuclear and mitochondrial genes. Mutations in mitochondrial DNA (mtDNA) have been reported to play an important role in cell function by providing energy, as well as, cell death (apoptosis). This study aims to systematically review mitochondrial mutations associated with presbyacusis and suggests preventive measurements to improve the quality of life in older adults.

Microsatellite instability (MSI) is a hallmark tool for Lynch syndrome (LS) screening and a prognostic marker for sporadic colorectal cancer (CRC). In regions with limited resources and scarce CRC molecular characterization as South America, the implementation of universal MSI screening is under debate for both its purposes. We sought to estimate the frequency of BAT26 in colorectal adenocarcinomas and to determine associated clinical and histological features. Consecutive patients from a CRC registry were included. BAT26 determination was performed in all cases; if instability was found, immunohistochemistry (IHC) and BRAF mutation analyses were done, as appropriate. Differences were assessed by chi-squared or Fisher’s exact test, or by T test or Mann–Whitney. Multiple logistic regression was used to identify factors independently associated with BAT26-unstable tumors. We included 155 patients; mean age was 65.6 (SD 14.4) and 56.1% were male. The frequency of BAT26-unstable tumors was 22% (95% CI 15.7–29.3). Factors independently associated with BAT26-unstable tumors were right colon localization (OR 3.4, 95% CI 1.3–8.7), histological MSI features (OR 5.1, 95% CI 1.9–13.6) and Amsterdam criteria (OR 23.2, 95% CI 1.9–286.7). IHC was altered in 85.3% BAT26-unstable tumors and 70.6% lacked MLH1 expression; 47.8% of these harbored BRAF V600E mutation. We provide evidence to link the frequency of BAT26 to an increased diagnostic yield (up to 1.4-folds) of suspected LS cases in comparison to the revised Bethesda guidelines alone. In regions with limited resources, clinical and histological features associated with BAT26-unstable status could be useful to direct MSI screening in sporadic CRCs and may help guide clinical care and future research. Fil: González, María Laura. Hospital Italiano; Argentina Fil: Causada Calo, Natalia. Hospital Italiano; Argentina. McMaster University; Canadá Fil: Santino, Juan Pablo. Hospital Italiano; Argentina Fil: Dominguez Valentin, Mev. The Norwegian Radium Hospital; Noruega Fil: Ferro, Fabiana Alejandra. Hospital Italiano; Argentina Fil: Sammartino, Inés. Hospital Italiano; Argentina Fil: Kalfayan, Pablo Germán. Hospital Italiano; Argentina Fil: Verzura, Maria Alicia. Hospital Italiano; Argentina Fil: Piñero, Tamara Lejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; Argentina Fil: Cajal, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; Argentina Fil: Pavicic, Walter Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; Argentina Fil: Vaccaro, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; Argentina

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.

Background In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family’s pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families’ path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families’ pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2). Methods Women with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay. Results We identified 48 women who were tested negative for their family’s path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X). Conclusion All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries., Radium Hospital Foundation (Oslo, Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, Helse Sør-Øst (Norway) in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, the French Association Recherche contre le Cancer (ARC) in the analysis, and interpretation of data, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (Gefluc) in the analysis, and interpretation of data, the Association Nationale de la Recherche et de la Technologie (ANRT, CIFRE PhD fellowship to H.T.) in the analysis, and interpretation of data and by the OpenHealth Institute in the analysis, and interpretation of data. Barretos Cancer Hospital received financial support by FINEP-CT-INFRA (02/2010), info:eu-repo/semantics/publishedVersion

Background The genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines. Methods The Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays. Results We identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing. Conclusions Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.

To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS (BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families.

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. [...]

Heredity is a major risk factor for colorectal cancer (CRC). Identification of individuals and families at increased risk allows for targeted surveillance, which has been shown to reduce morbidity and mortality from CRC (1, 2). Lynch syndrome is a multi-tumor syndrome with particularly high risks for colorectal, endometrial, and ovarian cancer (3–6). The syndrome is caused by germline DNA-mismatch repair (MMR) gene mutations with major contributions from MLH1 (MIM#120436) (42%), MSH2 (MIM#609309) (33%), MSH6 (MIM#600678) (18%), and PMS2 (MIM#600259) (8%). Only about one-third of the Lynch syndrome families fulfill the Amsterdam criteria (AC) (7–9). The cumulative incidence of any cancer at 70 years of age is 72% for MLH1 and MSH2 mutation carriers but lower in MSH6 (52%) and PMS2 (18%) mutation carriers. MSH6 and PMS2 carriers developed no cancers before 40 years of age (10). Mutation screening in a relatively large proportion of South American families with suspected Lynch syndrome has recently identified 99 disease-predisposing mutations in MLH1 and MSH2, which mutation spectrum is predominated by MLH1 (60%) and MSH2 (40%). Among the reported mutations, genetic hot-spot regions, new and potential founder mutations have been described in the South American population (11, 12). Several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in at least 15 independent loci associated with CRC risk (odds ratio ranging from 1.10 to 1.26 per risk allele) (13–15). Although there is no evidence that these SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall and therefore any evidence of proven clinical utility in Lynch syndrome (16). The MLH1 Ile219Val (rs1799977) is a common germline alteration, located in exon 8 at the nucleotide 655. This polymorphism has been described in a high frequency of the South American Lynch syndrome population, but no modifier effect of CRC risk and MMR disease-predisposing mutation carriers was observed (17). However, it has been reported to confer a twofold-increased risk of CRC development in sporadic Mexican patients (18). Other conditions that have been associated with this polymorphism include childhood acute lymphoblastic leukemia, breast cancer, radiation-induced rectal or bladder toxicity, and ulcerative colitis (19–23). It is unknown whether the MLH1 Ile219Val polymorphism has an effect on cancer risk and in the MMR capacity in Argentinean families with suspected Lynch syndrome. Thus, we aim to determine its frequency, its correlation with disease-predisposing MMR gene mutations, and to delineate the clinical characteristics from these families.

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.

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer (HNPCC), represents 2% - 4% of all cases of colorectal cancer. LS 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 LS: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). The diagnostic features of LS have accumulated and been refined over time. Today, LS is defined by a set of clinical, pathological, and molecular features that encompass: a family history of colorectal cancer, a particular spectrum of extracolonic neoplasms, multiple colorectal tumors, early onset of cancer, particular histological features among colorectal cancers, presence of DNA microsatellite instability, loss of expression of DNA mismatch repair proteins, and germline mutation in a DNA mismatch repair gene. This review provides an overview of the diagnosis and management of LS patients, including some recently reported patents.

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10⁻30%), compared to 35% (95% confidence interval 22⁻48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32⁻39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.

ObjectiveTranscriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.MethodsGlobal gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset.Results5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged.ConclusionsThese data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.

Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics. Electronic supplementary material The online version of this article (doi:10.1007/s10689-014-9728-1) contains supplementary material, which is available to authorized users.

In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers.

Introduction Heredity is estimated to cause at least 20% of colorectal cancer. The hereditary nonpolyposis colorectal cancer subset is divided into Lynch syndrome and familial colorectal cancer type X (FCCTX) based on presence of mismatch repair (MMR) gene defects. Purpose We addressed the gene expression signatures in colorectal cancer linked to Lynch syndrome and FCCTX with the aim to identify candidate genes and to map signaling pathways relevant in hereditary colorectal carcinogenesis. Experimental design The 18 k whole-genome c-DNA-mediated annealing, selection, extension, and ligation (WG-DASL) assay was applied to 123 colorectal cancers, including 39 Lynch syndrome tumors and 37 FCCTX tumors. Target genes were technically validated using real-time quantitative RT-PCR (qRT-PCR) and the expression signature was validated in independent datasets. Results Colorectal cancers linked to Lynch syndrome and FCCTX showed distinct gene expression profiles, which by significance analysis of microarrays (SAM) differed by 2188 genes. Functional pathways involved were related to G-protein coupled receptor signaling, oxidative phosphorylation, and cell cycle function and mitosis. qRT-PCR verified altered expression of the selected genes NDUFA9, AXIN2, MYC, DNA2 and H2AFZ. Application of the 2188-gene signature to independent datasets showed strong correlation to MMR status. Conclusion Distinct genetic profiles and deregulation of different canonical pathways apply to Lynch syndrome and FCCTX and key targets herein may be relevant to pursue for refined diagnostic and therapeutic strategies in hereditary colorectal cancer.

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.

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.

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.