Judit Sanz

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

BACKGROUNDnMutations 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.nnnMATERIALS AND METHODSnIndividuals (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.nnnRESULTSnTwenty-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).nnnCONCLUSIONSnBRCA1/2 genetic results could influence an individuals 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.

BRCA1 mutation analysis in 83 Spanish breast and breast/ovarian cancer families.

A group of 83 Spanish BC/OC families were analysed for BRCA1 germ‐line mutations. Analysis of the entire coding sequence was carried out by SSCP and PTT. We identified 5 frameshift mutations: 185delAG (2 times), 189insTGTC, 1241delAC, and 5537delA and 3 missense mutations in BRCA1: 330A > G, 1240C > T, and 5263G > A. The 185delAG mutation was identified in 2 families. One of them was the only Gypsy family participating in our study. All carriers shared the known founder haplotype, although they did not have any Jewish ancestry. Three frameshift mutations were found among the 14 families with 3 or more BC cases and 1 or more OC, which results in a higher percentage (21.4%) of BRCA1 mutations in this group of high risk families. Two missense mutations were found in families with 2 or 3 BC and no OC, indicating a low proportion (4.8%) of mutations in these families. There was no association between bilateral BC and a mutation carrier status. The frequency of BRCA1 involvement is lower than that of any other country hitherto reviewed. Our results highlight the influence of geographical and ethnic origin of the population studied. Int. J. Cancer 83:465–469, 1999.

Genetic counseling program in familial breast cancer: Analysis of its effectiveness, cost and cost-effectiveness ratio

Women with a family history of breast cancer are at increased risk for developing this neoplasm. Starting surveillance more frequently at a younger age than the general population and the possibility of undergoing genetic testing are options for their medical management. We analyzed the benefits and costs of our clinical program in familial breast cancer (FBC) and carried out a cost‐effectiveness analysis of such procedure. The benefits and costs of performing genetic counseling and a screening program in FBC based on 143 high‐risk families registered in our database between June 1995 and December 2001 were analyzed. A decision tree was constructed to estimate the survival benefit and cost‐effectiveness of the clinical genetic counseling program compared with the strategy of not performing any screening protocol. We estimated that the prevalence of a BRCA mutation in an unaffected relative of our high‐risk cohort was 10% and that 53% of the mutations are found in the BRCA1 gene. We assigned a 58.5% lifetime risk of breast cancer for a 30‐year‐old mutation carrier according to the SEER data. The effectiveness of the screening was obtained from our experience and data for estimating survival were derived from other studies with longer follow‐up. We used our local payment data to calculate the costs of the program. A mutation in the BRCA1 or BRCA2 genes was identified in 20% of the probands. Seventy primary breast cancer cases were recorded since the onset of the program. Thirty percent of the tumors were diagnosed through the screening program and 71% of them were lymph node‐negative compared to 49% of the tumors diagnosed outside the program (p = 0.1). The cost‐effectiveness ratio of our FBC genetic counseling and screening program was 4,294 euros per life‐year gained. The model was sensitive to the prevalence of mutation carriers, the lifetime risk of breast cancer and the effectiveness of the screening. In our setting and according to our model, this analysis suggests that a program of genetic testing and screening for breast cancer in a high‐risk population may be cost‐effective. These results need to be confirmed as more effective interventions for cancer prevention and screening are being implemented.

Identification of the 185delAG BRCA1 mutation in a Spanish Gypsy population

Abstract The 185delAG BRCA1 deletion occurs with a high frequency in Ashkenazi Jews. We detected this mutation in two Spanish Gypsy women (the only Gypsy participants) in an extensive study of 90 high-risk families and 160 women with early-onset breast cancer. One of these Gypsy women belonged to a high-risk family and the other had had early-onset breast cancer. The mutation was also detected in 1 out of 25 Gypsy samples unrelated to breast cancer. All the samples with the mutation shared the marker alleles present in Jewish samples with 185delAG. This is the first report of this mutation in a non-Jewish well-defined ethnic population. According to these findings the carrier frequency of this mutation in Gypsy individuals could be several times higher than that of the general population, and this should be taken into consideration in genetic screening for cancer in Gypsy populations.

MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome.

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 6xa0months, 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 64xa0years. 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.

Sex Ratio Distortion in Offspring of Families with BRCA1 or BRCA2 Mutant Alleles: An Ascertainment Bias Phenomenon?

SummaryBackground. There has been controversy regarding whether BRCA1 germline mutations favor female births or whether the sex imbalances observed are attributable to ascertainment bias. Our aims were to compare the sex ratios among offspring of BRCA1-positive, BRCA2-positive, and BRCA-negative families undergoing genetic testing in clinical programs, and to determine whether ascertainment bias is responsible for the observed preponderance of female offspring.Patients and methods. A total of 145 breast and/or ovarian cancer families with mutations in BRCA1 (nxa0=xa083) or BRCA2 (nxa0=xa062), and 90 families without identifiable mutation were collected for the study from familial cancer clinics in Barcelona, Spain, and Boston, US. Sex ratio was analyzed among all births in the families and offspring of all (tested and obligate) carriers. In order to minimize the effect of family history of cancer, the analysis was also performed among offspring of the most recent generation of mutation-positive carriers who did not have affected children and compared with a control group comprised of the offspring of the most recent adult generation of non-carriers from families with a known mutation.Results. There was a statistically higher proportion of female births in all groups (BRCA1 59% (95% CIxa0=xa057–61%), BRCA2 58% (56–61%), and BRCA-negative 59% (56–61%), respectively). The female preponderance persisted in analyses limited to offspring of BRCA1 and BRCA2 carriers (61% (57–65%), and 62% (58–66%), respectively), with no differences between the two mutation groups. In contrast, the excess of female offspring disappeared when ascertainment or recall biases were minimized, 44% (37–52%), and 39% (26–53%) for BRCA1; 51% (44–58%), and 46% (33–60%) for BRCA2.Conclusions. Our findings suggest that there is no asymmetry in birth outcomes among BRCA1 or BRCA2 mutations carriers. Rather ascertainment bias in families participating in genetic testing, or in the family history information they provide is likely to account for excess of female offspring previously reported.

Análisis del haplotipo en portadores de la mutación 6857delAA en el gen BRCA2 en 4 familias con cáncer de mama u ovario hereditario

Fundamento y objetivo: Entre un 5 y un 10% de los canceres de mama son de caracter hereditario y se conocen en la actualidad 2 genes principalmente responsables: BRCA1 y BRCA2. Pacientes y metodo: En el estudio genetico de pacientes con antecedentes familiares de cancer de mama/ovario hereditario realizado en 2 centros, en Espana y Chile, se identifico la mutacion 6857delAA en el gen BRCA2 de 3 familias espanolas y de una chilena. Se realizo el analisis del haplotipo en los portadores mediante 5 microsatelites que rodean el gen y abarcan una region de 6 cM: cen-D13S260, D13S1698 (BRCA2), D13S171, D13S310 y D13S267-tel. Resultados: Dos familias comparten la variante alelica de los 5 microsatelites estudiados. Los marcadores D13S260 y D13S267 difieren cada uno en una familia. No se identifico el haplotipo comun en los no portadores de la mutacion y su frecuencia fue menor del 10% en los cromosomas control. Conclusiones: Los resultados apuntan a la existencia de un ancestro comun con la mutacion, originada en el area de Cataluna. Teniendo en cuenta los movimientos migratorios desde Espana a Latinoamerica, la busqueda en estos paises de mutaciones aparecidas recurrentemente en Espana puede favorecer un analisis mas racional, efectivo y de menor coste en dichos genes.

Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole‐exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal‐dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE‐deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch‐repair function (POLE‐exo*/MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations.