Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals.

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.

Uptake of predictive testing among relatives of BRCA1 and BRCA2 families: a multicenter study in northeastern Spain.

Identifying a BRCA mutation among families with hereditary breast and ovarian cancer enables distinguishing those who may benefit from a specific medical management. This study aimed to evaluate the uptake of predictive testing among close relatives of a proband in Spanish families with a BRCA1 or BRCA2 mutation, and to determine the associated demographic and clinical predictors. A retrospective cohort of families undergoing clinical genetic testing at four university hospitals in northeastern Spain was considered. From 108 unrelated BRCA1/2 families, 765 close relatives of probands were analyzed. Sixty percent of the first-degree and 28% of the second-degree relatives underwent predictive testing within a median time of 2 and 6 months, respectively, since the mutation disclosure to the proband. Relatives undergoing genetic testing were more likely to be female, first-degree, and belong to a family with a proband who had a high educational level. Relatives were also more likely to have offspring, a previous cancer diagnosis, and to be aged between 30 and 64 years. Among second-degree relatives, having a first-degree relative with cancer was highly correlated with uptake. In conclusion, uptake of BRCA1/2 predictive testing among close relatives was notably high and within a short period of time after disclosure of the mutation to the proband. Being female, a high educational level of the proband, and having a close relative with cancer were associated with uptake among relatives. Further studies are warranted to determine whether information is disseminated properly by probands and to learn about the reasons for those not undergoing testing.

Opinion about reproductive decision making among individuals undergoing BRCA1/2 genetic testing in a multicentre Spanish cohort.

BACKGROUND: Mutations in breast cancer BRCA1/2 genes increase breast and ovarian cancer risk and are transmitted with an autosomal dominant pattern. Opinion about reproductive decisions among individuals undergoing BRCA1/2 testing in our institutions is unknown. MATERIALS AND METHODS: Individuals (n = 77) undergoing BRCA1/2 testing were included in a prospective multicentre study to assess the clinical impact of genetic testing. Demographic and clinical information, psychological status and opinion about reproductive decisions were collected in two questionnaires administered prior to testing. Opinion regarding the use of assisted reproduction techniques for hereditary cancer susceptibility among health care professionals was also collected. RESULTS: Twenty-eight individuals (36%) reported that they would decide to have children, regardless of their result. In case of a mutation, 9 (12%) believed that they would decide not to have children, 42 (55%) would consider prenatal diagnosis (PND), 37 (48%) would consider preimplantation genetic diagnosis (PGD) and 23 (30%) would consider adoption. Fifty-seven (74%) and 47 (61%) reported that they considered it ethical to offer PND or PGD, respectively, to BRCA+ patients. Individuals older than 40 years were more likely to consider PND or PGD than younger subjects (P = 0.02 and 0.05, respectively). Individuals with cancer compared with those without a diagnosis of malignancy were more likely to consider PGD (61 versus 30%, P = 0.02) and to consider that it was ethical to offer it (74 versus 44%, P = 0.02). Most health care professionals were in favour of PND and PGD for individuals with hereditary cancer susceptibility (58 and 61%, respectively). CONCLUSIONS: BRCA1/2 genetic results could influence an individual's decisions regarding reproduction. Health care professionals who serve individuals undergoing BRCA testing should incorporate patient education regarding the potential impact of such testing on family planning.