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Abstract: Introduction: Bilateral salpingo-oophorectomy (BSO) is a common procedure for preventing breast and ovarian cancer in high-risk women. The goal of this study was to determine the incidence of subsequent breast cancer (BC) in a high-risk population and to identify clinical and epidemiological predictors of BC following BSO. Materials and methods: One hundred and thirty-three consecutive high-risk women, tested for BRCA1 and BRCA2 mutations due to family history, underwent preventive or therapeutic BSO at one of the study hospitals. One hundred and three patients had breast tissue at risk and were considered evaluable for the event-free survival analysis. Twenty-five women harbored a deleterious mutation in BRCA1 and 25 in BRCA2 genes. Results: Fifteen cases of invasive BC were diagnosed with a median interval of 49 months after BSO. Multivariate analysis showed that a prior BC after 50 years of age (p =0.004), age over 50 years at the time of BSO (p =0.005), and prior replacement or contraceptive hormonal treatment (p =0.007) were significantly associated with a shorter event-free survival. Conclusion: In conclusion, age at prior diagnosis of cancer, age at BSO and prior hormonal treatment may be predictors of breast cancer after BSO. [Copyright &y& Elsevier]

Background: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. Results: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61–0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12–26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. Conclusions: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing. [ABSTRACT FROM AUTHOR]

Objectives: Decisional regret is an indicator of satisfaction with the treatment decision and can help to identify those patients who need more support and evaluate the efficacy of decision support interventions. The objectives of this study are, 1) to evaluate the psychometric properties of the Decision Regret Scale and 2) to analyze the moderating effect of psychological distress on functional status and regret in patients with cancer following adjuvancy.Methods: A prospective, multicenter cohort of 403 patients who completed the Decision Regret Scale (DRS), Health-Related Quality of Life (EORTC QLQ-C30), and Brief Symptom Inventory (BSI). The evaluation was conducted six months after receiving adjuvant treatment in patients with resected cancer.Results: After treatment, most participants (51.9%) experienced no decision regret; 33.7% felt mild regret, and 14.4% exhibited high levels of regret. The Spanish version of the DRS demonstrated satisfactory properties: it had a strong, clear unidimensional factorial structure with substantial loadings. Decisional regret was related with lower scores on functional, symptom, and quality of life scales, and higher levels of psychological distress (all P = 0.001). Psychological distress was found to have a moderating effect on the relationship between functional state and decision regret.Conclusions: The Spanish version of the DRS is a reliable, valid tool to evaluate regret and post-decisional quality in clinical practice and further highlights the potential clinical implications of psychological distress for the relation between physical status and regret. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]