BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) patients have a high hereditary risk of cancer, especially breast (BC), endometrial (EC), and thyroid cancer (TC). However, the prognosis of PHTS-related cancers is unknown. METHODS: This European cohort study included adult PHTS patients with data from medical files, registries, and/or questionnaires. Overall survival (OS) was assessed using Kaplan-Meier analyses and were compared with sporadic cancer and the general population using standardized mortality (SMR) and relative survival rates (RSR). Survival bias was addressed using left-truncation. RESULTS: Overall, 147 BC patients were included. The 10y-OS was 77% (95%CI = 66-90), decreasing with increasing stage from 90% (95%CI = 73-100) for stage 0 to 0% (95%CI = 0-0) for stage IV. BC relative survival was comparable to sporadic BC in the first two years (2y-RSR = 1.1; 95%CI = 1.1-1.1) and increasing thereafter (5y-RSR = 1.7; 95%CI = 1.6-1.7). For TC (N = 56) and EC (N = 35), 10y-OS was 87% (95%CI = 74-100) and 64% (95%CI = 38-100), respectively. Overall and cancer-specific mortality in female PHTS patients exceeded general population rates (SMR = 3.7; 95%CI = 2.6-5.0 and SMR = 2.7; 95%CI = 1.6-4.4). CONCLUSIONS: The prognosis of PHTS-related cancers was comparable to the general population. The higher overall mortality in PHTS patients is presumably related to their higher cancer incidence. These findings, and the high survival observed in early-stage cancer, emphasise the importance of recognising PHTS early to facilitate cancer surveillance.

• Publication type
• Journal Article MeSH

INTRODUCTION: Carriers of genetic mutations with a high risk of developing breast cancer have a lifetime risk of this cancer of up to 70%. To reduce the risk, patients have the option of a risk-reducing mastectomy. There is limited data with only short follow-ups on its safety. The aim of the study was to determine the long-term incidence of breast cancer in healthy patients with no previous surgery, who underwent bilateral risk-reducing mastectomies (BRRMs). METHODS: We retrospectively reviewed 274 patients from our facility with no previous breast surgery, who underwent BRRM from 1981 to 2022, due to genetic mutations, a strong family history, or having very dense mammary glands. We approached these patients during their checkups, by phone call or email, and we asked them if they had developed breast cancer after their procedures. We recorded the patients' demographic factors, their genetic mutation types, and the mastectomy methods carried out. RESULTS: A total of 274 patients had BRRMs with a mean follow-up after 76 months; 208 patients had undergone nipple-sparing mastectomies, 39 patients had undergone skin-sparing mastectomies, and 27 patients had skin-reducing mastectomies. One BRCA1+ patient developed breast cancer 21 months after undergoing the risk-reducing skin-sparing mastectomy procedure. None of the patients died of breast cancer. CONCLUSIONS: The incidence of breast cancer in the monitored patients is comparable to the results of the other related studies. The study result confirms that risk-reducing mastectomies reduce the risk of breast cancer in high-risk populations, regardless of the type of mastectomy performed.

• Publication type
• Journal Article MeSH

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been attributed to homologous recombination (HR) defects, other roles of HR factors have also been linked to response to PARPi, including replication fork protection. In this study, we investigated PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models in relation to HR proficiency and replication fork protection. Analysis of BRCA1/2 status showed that in our cohort of 31 ovarian cancer PDX models 22.6% harbored a BRCA1/2 alteration (7/31), and 48.3% (15/31) were genomically unstable as measured by copy number alteration analysis. In vivo, PARPi olaparib response was measured in 15 selected PDX models. Functional assessment of HR using ex vivo irradiation-induced RAD51 foci formation identified all olaparib-sensitive PDX models, including four models without BRCA1/2 alterations. In contrast, replication fork protection or replication speed in ex vivo tumor tissue did not correlate with olaparib response. Targeted panel sequencing in olaparib-sensitive models lacking BRCA1/2 alterations revealed a MUS81 variant as a possible mechanism underlying PARPi sensitivity. Combined, we show that ex vivo RAD51 analysis effectively predicts in vivo olaparib response and revealed a subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models, lacking a BRCA1/2 alteration.

• Publication type
• Journal Article MeSH

BACKGROUND: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). METHODS: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. RESULTS: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). CONCLUSIONS: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

• Publication type
• Journal Article MeSH
• Preprint MeSH

In women at high risk of developing breast cancer, bilateral prophylactic mastectomy (BPM) 1 significantly reduces the risk; simultaneously, breast reconstruction preserves body integrity. Given the complex and personal nature of such surgical procedures, patient assessment of satisfaction and health-related quality of life (HRQoL) 2 is essential in evaluation of surgical outcomes. With this review, we aim to organize the current knowledge on patient-reported outcomes (PROs) 3 in bilateral prophylactic surgery. Literature search was conducted using the databases Google Scholar, PubMed, and Web of Science to address the following questions, which can help clinicians and women undergoing the procedures navigate their healthcare decision-making process: How does BPM with reconstruction influence cancer-related distress? How does the surgery impact patient satisfaction and HRQoL? How do preoperative PROs differ from postoperative outcomes? Does the type of BPM and the type of reconstruction impact patient satisfaction and HRQoL? Furthermore, we summarize available patient-reported outcome measures (PROMs) 4 that can be administered to women undergoing BPM with reconstruction. In addition, we discuss possible future directions for PRO research in prophylactic breast surgery.

• Keywords
• Bilateral prophylactic mastectomy, Breast reconstruction, Health-related quality of life, Hereditary breast cancer, Patient-reported outcomes, Satisfaction,
• MeSH
• Patient Reported Outcome Measures MeSH
• Quality of Life MeSH
• Humans MeSH
• Mammaplasty * methods   MeSH
• Mastectomy methods   MeSH
• Breast Neoplasms * prevention & control   surgery   MeSH
• Prophylactic Mastectomy * methods   MeSH
• Patient Satisfaction MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes.

• Keywords
• early-onset, genetic predisposition, germline pathogenic variant, ovarian cancer,
• MeSH
• Adult MeSH
• Carcinoma, Ovarian Epithelial genetics   MeSH
• Genetic Predisposition to Disease * MeSH
• Genes, BRCA2 MeSH
• Humans MeSH
• Ovarian Neoplasms * pathology   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Risk Factors MeSH
• Germ-Line Mutation MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• BRCA1 Protein MeSH
• BRCA2 Protein MeSH

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

• MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Genes, BRCA2 * MeSH
• Heterozygote MeSH
• Weight Gain genetics   MeSH
• Body Mass Index MeSH
• Humans MeSH
• Breast Neoplasms * epidemiology   genetics   pathology   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Retrospective Studies MeSH
• Risk MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• BRCA1 protein, human MeSH Browser
• BRCA2 protein, human MeSH Browser
• BRCA1 Protein MeSH
• BRCA2 Protein MeSH

PURPOSE: Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL. METHODS: We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion. RESULTS: Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays. CONCLUSION: Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.

• MeSH
• Ataxia Telangiectasia Mutated Proteins * genetics   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * drug therapy   MeSH
• Humans MeSH
• Mutation MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Protein Serine-Threonine Kinases genetics   therapeutic use   MeSH
• Cell Cycle Proteins genetics   MeSH
• Ataxia Telangiectasia MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• ATM protein, human MeSH Browser
• Ataxia Telangiectasia Mutated Proteins * MeSH
• Tumor Suppressor Proteins MeSH
• Protein Serine-Threonine Kinases MeSH
• Cell Cycle Proteins MeSH

Unnafected female carriers of BRCA1 and BRCA2 pathogenic/likely pathogenic variants (P/LPVs) are at higher risk of breast cancer (BC) and ovarian cancer (OC). In the retrospective single-institution study in the Czech Republic, we analyzed the rate, longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) on the incidence of BC and OC in BRCA1/2 carriers diagnosed between years (y) 2000 to 2020. The study included 496 healthy female BRCA1/2 carriers. The median follow-up was 6.0 years. RRM was performed in 156 (31.5%, mean age 39.3 y, range 22-61 y) and RRSO in 234 (47.2%, mean age 43.2 y, range 28-64 y) BRCA1/2 carriers. A statistically significant increase of RRM (from 12% to 29%) and RRSO (from 31% to 42%) was observed when comparing periods 2005-2012 and 2013-2020 (p < 0.001). BC developed in 15.9% of BRCA1/2 carriers without RRM vs. 0.6% of BRCA1/2 carriers after RRM (HR 20.18, 95% CI 2.78- 146.02; p < 0.001). OC was diagnosed in 4.3% vs. 0% of BRCA1/2 carriers without vs. after RRSO (HR not defined due to 0% occurrence in the RRSO group, p < 0.001). Study results demonstrate a significant increase in the rate of prophylactic surgeries in BRCA1/2 healthy carriers after 2013 and the effectiveness of RRM and RRSO on the incidence of BC and OC in these populations.

• Keywords
• Angelina Jolie effect, BRCA1, BRCA2, breast cancer, cancer prevention, ovarian cancer, risk-reducing mastectomy, risk-reducing salpingo-oophorectomy,
• Publication type
• Journal Article MeSH

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

• MeSH
• Bayes Theorem MeSH
• Carcinoma, Ovarian Epithelial genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Breast Neoplasms * MeSH
• Ovarian Neoplasms * epidemiology   genetics   MeSH
• Prospective Studies MeSH
• Risk Factors MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH