SEOM clinical guideline for treatment of kidney cancer (2017)

The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge

Mammographic density and breast cancer in women from high risk families

Introduction: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. Methods: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. Results: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. Conclusions: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization

Simple Summary Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancer (RCC), with no data on its prevalence worldwide. No genotype-phenotype associations have been described. The aim of our study was to describe the genotypic and phenotypic features of the largest series of patients with HLRCC from Spain reported to date. Of 27 FH germline pathogenic variants, 12 were not previously reported in databases. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants. The frequency of RCCs (10.9%) was lower than those reported in the previously published series. Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys

Estudio de la prevalencia de mutaciones de los genes BRCAL y BRCAZ en mujeres con cáncer de mama menores de 41 años. Relación con los antecedentes oncológicos familiares y características clínico-patológicas.

RESUMEN El cáncer de mama es la neoplasia más frecuente en la mujer. Existen factores de riesgo conocidos como la edad avanzada y la historia familiar de cáncer de mama. La mayor parte del cáncer de mama es esporádico, sólo del 5 al 10% son atribuibles a mutaciones de la línea germinal en genes de susceptibilidad. Del 15 al 20% se producen en agregaciones familiares, que se deben a interacciones de múltiples genes y factores ambientales, o a genes de baja penetrancia. Existen modelos que estiman la probabilidad de ser portadora de mutación en BRCA1/2, como: el modelo de Couch, Myriad II y BRCAPRO. Objetivos. 1. Determinar la prevalencia de mutaciones BRCA1/2. 2. Estimar la frecuencia de mutaciones BRCA1 y en función de sus antecedentes familiares de cáncer de mama u ovario. 3. Estudiar si existen otros tumores más frecuentes en los familiares en relación con los casos de cáncer de mama esporádicos. 4. Estudiar las características clínico-patológicas comparando casos esporádicos y los debidos a mutaciones en los genes BRCA1/2. 5. Conocer la utilidad en nuestra población de los modelos capaces de predecir la probabilidad de mutación BRCA1/2. Material y métodos. Se seleccionaron 124 mujeres diagnosticadas de cáncer de mama antes de los 41 años, no seleccionadas por su historia familiar. Entre los años 1989-1999. La estrategia utilizada para el análisis de BRCA1/2, fue inicialmente un cribado mediante TT-SSCP, cuando se localizaba un patrón anómalo, se caracterizaba la alteración mediante secuenciación directa. Resultados. Hemos localizado 6 mutaciones patogénicas y 13 mutaciones de significado incierto. La prevalencia de mutaciones en los genes BRCA en nuestra población es de 5.6%. BRCA1 0.8% y BRCA2 4.8%. El grupo de alto riesgo constituido por mujeres con cáncer de mama antes de los 41 años y un familiar de 1° grado con cáncer de mama/ovario, o familiar varón con cáncer de mama, tienen un RR 4.92, con p=0.037. En el grupo con antecedentes de cáncer de ovario en la familia, el RR es 10.74, y p=0.005. Respecto a las características clínico-patológicas, sólo hemos detectado diferencias en el estadio. No se han encontrado diferencias respecto a la supervivencia. Entre los métodos de predicción de probabilidad de mutación BRCA, el modelo de Frank y BRCAPRO son los de mayor sensibilidad y especificidad. Conclusiones. La frecuencia de mutaciones en los genes BRCA1 y BRCA2 es 5.6%. La mayor parte de las mutaciones definitivas encontradas (6 de 7) se localizaron en el gen BRCA2 (85.7%). La mayor parte de las mutaciones caracterizadas en BRCA2 (66.7%) se encuentran localizadas en el interior del exón 23. Las pacientes con familiares de primer grado con cáncer de mama u ovario, o con un varón afecto de cáncer de mama en su familia, forman un grupo, clasificado de alto riesgo, donde se encuentran mutaciones BRCA en un porcentaje (15.4%) significativamente mayor (p=0.037) al resto de las pacientes (3.1%). Los antecedentes familiares de cáncer de ovario son significativamente mayores (p=0.005) entre las portadoras de mutaciones en BRCA (37.5%) que entre las no portadoras (3.5%). Las mujeres portadoras de mutación BRCA se diagnostican en estadíos más avanzados que las mujeres no portadoras. Los métodos predictivos de mutación en BRCA1/2, Myriad II y BRCAPRO, son útiles para seleccionar pacientes en nuestra muestra . Considerando la baja frecuencia de mutaciones BRCA1/2, otros factores genéticos actualmente desconocidos deben jugar un papel importante. Estos resultados no hacen aconsejable un estudio molecular de BRCA en mujeres con cáncer de mama por el único hecho de haberlo desarrollado a una edad temprana. ____________________________________________________________________________________________________Breast cancer is the most frequent tumour in women and hereditary predisposition may contribute to it in a small subset of patients. Up 5 to 10% can be attributed to mutations in BRCA1/2. Between 1989 -1999, we selected 124 breast cancer women, diagnosed before 41 years, not selected by their family history. In this group, mutations in BRCA1/2 genes were studied. The strategy used for the analysis of BRCA1/2, was initially amplified by PCR, mutation screening through SSCP, and abnormal bands were directly sequenced. Seven patients (5.6%) were found to have pathogenic mutations: one in BRCA1 (0.8%) and six in BRCA2 (4.8%). Most pathogenic mutations (6 of 7) were located in BRCA2 (85.7%). Most mutations characterized in BRCA2 (66.7%) are located in exon 23. The patients with first degree relatives suffering from breast or ovarian cancer, or having a male relative with breast cancer were classified as "high risk". In this high risk group 4 of 26 women (15.4%) were BRCA mutation carriers, compared with 3 of 96 women (3.1%) without those previously defined familial characteristics (p=0.037). The familial history of ovarian cancer is also different between BRCA mutation carriers (37.5%) and those not harbouring any mutation (3.5%) (p=0.005). BRCA mutation carriers were diagnosed in more advanced stages of breast cancer. Several models may estimate the probability of presenting a mutation in BRCA1/2,. In our sample Myriad II and BRCAPRO, are useful to predict the presence of mutations. Considering the low frequency BRCA1/2 mutations, other currently unknown genetics factors should play an important role. These results do not make advisable a molecular study of BRCA1/2 mutations in women developing breast cancer at an early age. Familial history should be considered as the most relevant factor

Hereditary Cancer In Women

[spa] La mayoría de los casos de cáncer son esporádicos, entre un 20-30% presentan agregación familiar, mientras que solo el 5 -10% son de carácter hereditario. Las familias e individuos en los que se sospecha que padecen cáncer hereditario deben someterse a un proceso de asesoramiento genético, que es de gran importancia para la prevención y detección temprana de tumores malignos. Los síndromes más frecuentes de cáncer hereditario son el síndrome de mama-ovario hereditario, la poliposis adenomatosa familiar y el síndrome de Lynch. El diagnóstico genético facilita realizar una estimación de los riesgos de desarrollar diferentes cánceres, permitiendo tomar decisiones de vigilancia y preventivas que reducen estos riesgos. El objetivo final es reducir la mortalidad por cáncer mediante el diagnóstico precoz y la prevención.[eng] Most cases of cancer are sporadic, whereas 5-10% are hereditary and about 20-30% of cancers tend to cluster in families. Families and individuals who are suspected of suffering from hereditary cancer need to undergo a process known as genetic counseling, which is of considerable importance in the prevention and early detection of malignant tumours. The most common hereditary cancer syndromes are: hereditary breast-ovarian cancer syndrome, familial adenomatous polyposis and Lynch syndrome. Genetic diagnosis allows clinicians to estimate the risks of developing different cancers in order to make decisions over surveillance and prophylactic surgery to reduce these risks. The ultimate goal is to reduce cancer mortality through early diagnosis and prevention

Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families of Eastern Spain

5 páginas, 1 tabla.-- et al.It is well established that mutations in BRCA1 and BRCA2 genes significantly increase the risk of breast and ovarian cancer. We here report 23 novel genetic variants of the BRCA1 and BRCA2 genes found in 349 cancer-prone unrelated families from Eastern Spain detected during the first 2 years of performance of the Program of Genetic Counseling of Valencia Community. Mutational screening was performed by pre-screening the heteroduplex formed in the PCR products obtained amplifying BRCA1 and BRCA2 genes by conformation sensitive electrophoresis. We detected 10 deletereous mutations, four in BRCA1 (three frame-shift (FS) and one nonsense mutation (NS)) and six in BRCA2 (four FS and one NS mutation). Moreover, we detected 13 unclassified variants, four in BRCA1 (one missense (MS), two synonymous (SYN) and one intronic (I) variant) and nine in BRCA2 (six MS, one SYN and two I). The relevance of the novel mutations is discussed. Our contribution broadens the BRCA1/2 world mutational spectra.Peer reviewe