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Genetic diagnosis of hereditary cancer syndromes offers the opportunity to establish more effective predictive and preventive measures for the patient and their families. The ultimate objective is to decrease cancer morbidity and mortality in high genetic risk families. Next Generation Sequencing (NGS) offers an important improvement in the efficiency of genetic diagnosis, allowing an increase in diagnostic yield with a substantial reduction in response times and economic costs. Consequently, the implementation of this new technology is a great opportunity for improvement in the clinical management of affected families. The aim of these guidelines is to establish a framework of useful recommendations for planned and controlled implementation of NGS in the context of hereditary cancer. These will help to consolidate the strengths and opportunities offered by this technology, and minimise the weaknesses and threats which may derive from its use. The recommendations of international societies have been adapted to our environment, taking the Spanish context into account at organisational and juridical levels. Forty-one statements are grouped under six headings: clinical and diagnostic utility, informed consent and genetic counselling pre-test and post-test, validation of analytical procedures, results report, management of information and distinction between research and clinical context. This guide has been developed by the Spanish Association of Human Genetics (AEGH), the Spanish Society of Laboratory Medicine (SEQC-ML) and the Spanish Society of Medical Oncology (SEOM)., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Five percent of all cases of breast cancer (BC) show a hereditary component related to gene mutations with an autosomic dominant transmission. To date, few genes are known to be responsible of hereditary BC. The germline mutations of BRCA1 or BRCA2 genes account for less than 50% of families with breast/ovarian cancer predisposition. The large percentage of families with multiple cases of female BC and no BRCA1 and BRCA2 mutations detected could be attributed to the existence of other high or low susceptibility genes acting together with lifestyle risk factors. The predisposition to BC in carriers of ATM mutations has been documented previously. Due to the frequency of ATM heterozygotes in the general population, the mutations in this gene could be associated with up to 5% of BC cases. The mutation 1100delC of the CHEK2 gene seems to be a low penetrance allele of BC susceptibility. The objective of the present manuscript is to review some of the susceptibility genes identified to date.

Background and Objective: It is estimated that 5-10% of all breast cancers are hereditary, mainly are due to germline mutations in the BRCA1 and BRCA2 genes., Patients and Method: A BRCA2 screening was carried out in familial breast/ovarian cancer at two centres in Spain and Chile. The 6857delAA mutation was identified in 3 Spanish families and one Chilean, all of them with Spanish ancestors. The BRCA2 haplotype of the 6857delAA carriers was analyzed using five microsatellite markers flanking the BRCA2 gene, spanning a region of 6 cM: cen-D13S260, D13S1698, (BRCA2), D13S171, D13S310 and D13S267-tel., Results: Two families shared the allelic variants of the 5 microsatellites studied. Markers D13S260 and D13S267 differed in one allele in two families, respectively. The defined haplotype was absent in non-carriers from these families, and was not detected in 100 control chromosomes without the mutation., Conclusions: Our results suggest the existence of a common ancestry with the mutation originating in the Northeast of Spain. Given the migratory movements from Spain to Latin America, the screening of recurrent Spanish mutations can be useful in establishing a more rational and cost-effective analysis in such populations.

Background: Li-Fraumeni syndrome is a dominantly inherited disorder characterized by early-onset breast cancer, soft-tissue sarcomas and osteosarcomas, acute leukemia, adrenocortical neoplasms and central nervous system tumors. Germline mutations in gene TP53 are identified in a percentage of affected families., Patients and Method: Eight families with aggregation of childhood sarcomas, brain tumors, breast cancers in pre-menopausal women, and renal tumors were screened for TP53 germ-line mutations. SSCP and posterior direct sequencing were performed for genetic analysis. We also report a previously undescribed family with the Li-Fraumeni syndrome carrying a germline mutation., Results: Seven families fulfilled so-called Li-Fraumeni like criteria and one fulfilled classical criteria. A new germ-line mutation in codon 238 at exon 7 of the gene TP53 was identified in the family fulfilling classical criteria. This mutation has not been previously reported., Conclusions: The clinical heterogeneity as well as the molecular complexity and consequences of mutation analysis and genetic counseling make it necessary to develop protocols in this area. A multidisciplinary approach is needed; this approach should be coordinated by a Familial Cancer Genetic Counseling Unit.

Background: Clinico-pathological differences between BRCA1 or BRCA2 mutation-associated breast cancer (BC) and sporadic BC are little known., Patient and Methods: We analysed the clinico-pathological characteristics and clinical follow-up of 30 patients with BC. BRCA1 and BRCA2 mutations were detected by SSCP and PTT., Results: There were no differences in age, size or nodal status at the time of diagnosis. Mammography features were more heterogeneous in BRCA2 than in BRCA1 BC. All BRCA1 mutation-associated BC corresponded to infiltrating ductal carcinomas (20% medullary carcinomas) with a more aggressive pathological behavior. The frequency of local recurrences was 14% in BRCA1 and 20% in BRCA2. Contralateral BC and ovarian cancer (OC) were observed in 27% and 20% of BRCA1 cases, respectively, and 6% and 6% of BRCA2 cases. The median follow-up in BRCA1 and BRCA2 BC was 131 and 54 months, respectively., Conclusions: There were no differences in age at diagnosis and stage between BRCA1 and BRCA2 breast cancer. The mammographic pattern in BRCA2 was more heterogeneous. BRCA1 mutations were associated with more aggressive histopathologic findings and a higher risk of a second BC and OC.