Population attributable faction (PAF) shows the proportion of the disease that could be prevented if the cause could be removed. PAFs for most types of familial cancer have not been determined. We used the Swedish Family-Cancer Database on 10.2 million individuals and 688,537 parental and 116,741 offspring cancers to calculate familial risks, proportions of affected individuals, and familial PAFs for 28 neoplasms among 0-66-year-old offspring. The data were calculated by an exact proband status in the nuclear families. The familial risks for offspring cancer were increased at 23 of 28 sites from the same cancer in only the parent, at 17 sites from a sibling proband and at 12 sites from a parent and sibling proband. The highest PAFs by parent were for prostate (9.01%), breast (3.67%), and colorectal (5.15%) cancer. However, considering that in gender-specific cancers, the familial effect may originate from grandparents, the PAFs for prostate and breast cancer could be multiplied by 2. The PAFs for the sibling history of prostate, breast, and colorectal cancers were 1.55, 2.85, and 1.23% and for the parent and sibling history 0.99, 0.42, and 0.48%, respectively. Because of mutually exclusive proband definition, the PAFs were additive, giving a total PAF of 20.55% for prostate, 10.61% for breast, and 6.87% for colorectal cancer. The present PAF values give an estimate of the heritable single locus or additive effects for cancer in nuclear families. The data show that the familial PAF of prostate cancer was 20.55%, and breast cancer 10.61%, but for most other sites, it was between 1 and 3%.
Increased knowledge about inherited susceptibility for cancer and the identification of genes associated with cancer risk has increased the need for individuals with training in genetics to work closely with oncology professionals in the familial cancer arena. Genetic counselors can provide a variety of useful services: They may function as clinical coordinators of a family cancer risk counseling (FCRC) program and serve as study coordinatiors on research teams. In the oncology practice setting, genetic counselors who are trained to do cancer risk counseling can help ascertain and evaluate familial clusters of cancers. In the context of FCRC, the genetic counselor can educate family members about risk factors for cancer and the significance of a positive family history, assess psychosocial functioning and provide psychosocial support and referrals. Genetic susceptibility testing should be offered only with appropriate genetic counseling.
Background Germline pathogenic variants (gPVs) in BRCA1, BRCA2, and CHEK2 are well‑established cancer predisposition factors of prostate cancer. However, their contribution across the full spectrum of urological cancers remains insufficiently characterized. The primary objective was to describe the spectrum and outcomes of urological cancers in BRCA1/2 and CHEK2 gPV carriers, while secondary objectives were to assess overall survival (OS) and compare age at diagnosis, stage, and survival outcome by gene affected. Methods This is a retrospective descriptive study including patients diagnosed with urological cancers and testing positive for gPVs in BRCA1, BRCA2, or CHEK2, identified at the Hereditary Cancer Risk Clinic of the Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). Familial and individual files were systematically reviewed to identify individuals with urological malignancies carrying gPVs. Descriptive statistics were used to summarize clinicopathologic characteristics. Survival outcomes were estimated using the Kaplan-Meier method and log-rank test for comparisons between groups, with p<0.05 considered statistically significant. Results A total of 968 BRCA1/2 or CHEK2 families were identified, of which 47 included 50 patients with urological cancer and a gPV in the genes of interest. Among BRCA1/2 carriers, BRCA2 was the most frequently affected gene (37 patients), with the BRCA2 Portuguese founder variant (c.156_157insAlu) identified in 23.1% of cases. Among prostate cancer patients carrying BRCA1/2 gPVs, all individuals with high-grade or metastatic disease carried BRCA2 gPVs. These patients were diagnosed at a younger age than either what is expected from the general population or patients with BRCA1-associated prostate cancer in this study. Also, BRCA2 prostate cancer patients were more frequently diagnosed with other cancers, with male breast cancer being the most frequent (32%). Regarding family history, breast cancer was the most common malignancy observed (71% in BRCA1 and 74% in BRCA2 families), followed by other cases of prostate cancer (42% in BRCA1 vs. 34% in BRCA2). The median OS among prostate cancer patients with advanced disease was 38 months (95% CI: 5.6-70.3), with no statistically significant difference between BRCA1 and BRCA2 carriers (p=0.408). All renal cancer patients with BRCA gPVs were female, had a personal history of breast cancer, and presented clear cell histology. Among urothelial cancer patients, one carried a BRCA1 gPV, and six carried BRCA2 gPVs. Most presented with non-muscle‑invasive bladder cancer (71.4%), except for two BRCA2 carriers who had advanced disease. CHEK2‑associated urological cancers included renal cancer (n=1) and prostate cancer (n=5), all of which showed favorable outcomes. No testicular cancers were identified. Conclusion This study highlights the heterogeneous spectrum of urological cancers associated with BRCA1, BRCA2, and CHEK2 gPVs in a Portuguese cohort, including the role of the Portuguese founder variant. While prostate cancer is the most frequent urological cancer in these families, increasing access to and awareness of genetic testing may better inform future studies about these cancer phenotypes. We reinforce that the systematic assessment of personal and family cancer history in these patients may assist in identifying individuals who could benefit from genetic evaluation and tailored surveillance strategies for carriers and their families.
Development of pouch cancer is a great challenge to both surgeons and patients with familial adenomatous polyposis (FAP) after restorative proctocolectomy (RPC). We aimed to present our experience with pouch cancer diagnosis and review literature data regarding incidence and associated risk factors. This retrospective study enrolled FAP patients undergoing RPC between 1981 and 2023 in our academic institution. It included only J-pouch stapled patients with at least three years of follow-up. Patients' demographics and disease features were retrieved. After excluding seven patients, we selected 87 RPC, and three cases (3.4%) of pouch cancer were identified. They were diagnosed in three men aged 23-40 years at RPC and 41-62 years at cancer diagnosis. Interval from RPC to pouch cancer diagnosis varied from 11.6 to 20 years (average 14.6 years). All patients had colorectal cancers (CRC) detected in the specimen from the index surgery, two of them with multicenter lesions. A brief review of the literature series showed that pouch cancer has been detected in incidences ranging from 0.8 to 3.4%. Male sex, CRC in the RPC specimen, pouch phenotype during follow-up and an association with duodenal adenomas are considered risk factors. Pouch cancer is a rare event associated with specific risk factors. After RPC, all patients should undergo endoscopic surveillance, with special attention to those who develop an aggressive phenotype during the first decade of follow-up. Familial adenomatous polyposis (FAP) is an autosomal dominant disease associated with mutations in the APC gene. As a dominantly inherited cancer-predisposing syndrome, the main challenge of FAP management is the significant risk of CRC that requires prophylactic colectomy in a timely manner aiming to reduce colorectal cancer (CRC) risk while maintaining quality of life. Cancer prevention is most usually accomplished through restorative procedures such as total colectomy with ileorectal anastomosis (IRA) or a restorative proctocolectomy with ileoanal anastomosis (RPC). The development of ileoanal pouch cancer is not so common in patients with FAP, even in specialized centers. Pouch cancer is a rare disease diagnosed in incidences varying from 0.8 to 3.4% in worldwide FAP series. Male patients, presence of CRC in the RPC specimen, colorectal phenotype, and association with duodenal adenomas are considered the main risk factors. Pouch adenomas develop after both hand-sewn or stapled anastomosis. Pouch polypectomy might prevent the development of adenocarcinomas, as patients under surveillance are diagnosed with more localized diseases. O desenvolvimento de câncer na bolsa ileal constitui um grande desafio para o cirurgião e pacientes com Polipose Adenomatosa Familiar (PAF) após a proctocolectomia (RPC). Apresentar nossa experiência com o diagnóstico de câncer na bolsa ileal e rever a literatura relacionada à incidência e fatores de risco associados. O presente estudo retrospectivo envolveu pacientes PAF submetidos a RPC entre 1981 e 2023 em nossa instituição acadêmica. Incluíram-se apenas doentes com 3 anos de seguimento, Dados demográficos e características da doença foram extraídos dos prontuários. Após excluir 7 doentes, foram selecionados 87 RPC e 3 casos (3.4%) de câncer na bolsa ileal foram identificados. Os tumores foram diagnosticados em 3 homens com 23-40 anos na RPC e 41-62 anos no diagnóstico de câncer. O intervalo entre RPC e câncer na bolsa variou de 11.6 a 20 anos (média 14.6 anos). Todos os doentes tiveram câncer colorretal (CRC) detectados néco espime da cirurgia primária, dois deles com lesões multicêntrica. Uma breve revisão das séris da literatura demonstrou que o câncer de bolsa ileal tem sido detectado em incidências variando de 0.8 a 3.4%. Sexo masculino, CRC no espécime da RPC, fenótipo da bolsa durante o seguimento e associação com adenomas duodenais são considerados fatores de risco. Câncer na bolsa ileal é um evento raro associado com fatores de risco específicos. Após proctocolectomia, todos os doentes devem fazer vigilância endoscópica, com especial atenção para aqueles que desenvolvem fenótipo agressivo na bolsa durante os primeiros dez anos de seguimento.
BACKGROUND The incidence of breast cancer is high among women, with a significant proportion of cases being familial. However, the driver genes for breast cancer can differ across families. CASE REPORT Our patient was a 37-year-old woman diagnosed with triple-negative breast cancer (TNBC) by pathology, revealing invasive ductal carcinoma of the outer upper quadrant of the breast, WHO grade 3. The maximum diameter of the microscopic invasive cancer was approximately 0.5 cm. No definite vascular tumor thrombus or nerve invasion was observed. Some (30-90%) of the tumor cells disappeared, and the remaining tumor cells showed degeneration, interstitial sclerosis, scattered lymphocyte infiltration, and hemosiderin deposition. No cancer was found in the nipple and base resection margins, or in the other quadrants. The chemotherapy response was classified as grade III according to the MP (Miller and Payen classification) scoring system. Blood samples were collected from affected family members. Whole-exome sequencing (WES) and bioinformatics analyses were used to identify potential driver genes, followed by Sanger sequencing for validation, which ultimately confirmed the pathogenic gene and the underlying mechanism in this family. CONCLUSIONS A series of analyses suggested that the co-occurrence of heterozygous deletions in BRCA1 and OBSCN was the main cause of breast cancer in this family. The simultaneous association of 2 genes with the occurrence of breast cancer was discovered for the first time in this family, which could help guide disease prevention for family.
Background: Familial prostate cancer (PCa) accounts for nearly 20% of all PCa cases and is associated with increased genetic susceptibility and earlier disease onset. However, early detection and risk stratification in genetically predisposed individuals remain challenging. Circulating cell-free DNA (cfDNA) provides a minimally invasive source of tumor-derived genomic and epigenomic information. Integrating multi-omic cfDNA analyses may enhance the discovery of biomarkers relevant to familial PCa biology. Methods: We conducted a pilot feasibility study employing whole-genome, strand-specific sequencing of cfDNA from eight patients with familial PCa. A unified analytical pipeline was used to jointly profile genomic alterations and epigenomic features. Variant calling, methylation mapping, and allele-specific methylation (ASM) analysis were performed to identify somatic mutations, characterize epigenetic dysregulation, and explore potential interactions between genetic and epigenetic mechanisms. Results: Sequencing revealed 18,878 genetic variants, including 2276 potentially pathogenic alterations. We identified 26 recurrent high-impact mutations, such as stop-gain and start-loss variants, in genes including MUC4, MCM9, and SKA3. Epigenomic profiling demonstrated widespread gene-specific hypermethylation, consistent with transcriptional repression in these loci. ASM events were detected in TTC22, TEX51, WDR89, LAIR2, and SKA3, suggesting coordinated interactions between somatic variation and epigenetic regulation in familial PCa. Conclusions: This proof-of-concept study highlights the feasibility and potential of integrating whole-genome and epigenome profiling of cfDNA to decode the molecular architecture of familial prostate cancer. By jointly capturing genomic alterations and epigenetic signatures, including allele-specific methylation, this multi-omic liquid biopsy approach supports a high-resolution exploration of biologically relevant molecular features. Moreover, this integrated profiling strategy provides a minimally invasive and clinically scalable tool that may substantially improve risk assessment. These findings offer a promising foundation for future validation studies in larger cohorts, with the aim of advancing multi-omic cfDNA analysis as a next-generation technology in the field of precision oncologic epigenetics.
Hereditary cancers represent 5%-10% of all cancers, typically characterized by familial aggregation, early onset, and/or multiple primary tumors. Isolated cases with extreme early-onset or multiple unrelated cancers are rare and frequently underdiagnosed. This study aimed to improve genetic diagnostic yield in unresolved patients with strong clinical suspicion of hereditary cancer. Inclusion criteria were (1) ≥4 primary tumors in different organs (or ≥3 if two are rare), (2) adult-type cancers at ≤25 years, or (3) profuse gastrointestinal adenomatous polyposis before age 50 years or profuse polyposis of unknown type before age 30 years. Germline DNA from 98 patients selected through ERN-GENTURIS underwent short-read whole-genome sequencing (WGS). Ninety had received negative results from standard genetic testing, whereas eight had not been tested. Variant analysis was performed using the RD-Connect GPAP and Solve-RD frameworks. Pathogenic or likely pathogenic variants in phenotype-related high-penetrance genes were found in 6% of patients, including APC and TP53 mosaicisms and germline variants in TP53, BAP1, BARD1, and MBD4 (homozygous). Three patients carried pathogenic variants in hereditary cancer genes unrelated to their phenotype, and a heterozygous ERCC3 pathogenic variant was detected in a young patient with breast cancer. Suggestive variants of uncertain significance were identified, including a chromosome 3 inversion affecting VHL and MLH1 in a patient with renal and gastric cancers. Potentially regulatory noncoding variants in phenotype-associated genes were observed in 15% of patients (22 variants). Comprehensive resequencing of patients suspected of hereditary cancer increased the diagnostic yield by 6%. Detected pathogenic variants involved phenotype-related genes not previously analyzed or missed because of mosaicism. WGS further enables identification of novel gene associations and structural, deep intronic, or regulatory variants.
The Adenomatous Polyposis Coli gene (APC) is a key tumor suppressor in colorectal cancer (CRC). While germline mutations in its Mutation Cluster Region (MCR) are implicated in familial CRC, the prognostic impact of specific mutation types within distinct populations remains poorly characterized. This study sequenced the APC-MCR in 96 Iranian familial CRC patients, 6 disease controls (gastritis/celiac), and 10 healthy controls. Variants were classified per ACMG guidelines. Patients were stratified into four genetic categories: Wild-Type (WT), Variant of Uncertain Significance (VUS) only, Truncating pathogenic/likely pathogenic (P/LP), and Missense P/LP. Associations with clinicopathological features were assessed using Chi-square, Fisher's exact tests, and independent t-tests. OR with 95% CI were calculated. Pathogenic mutations were identified in 39.6% (38/96) of patients and 0% of controls (P < 0.0001). A significant association existed between the mutation type and the tumor stage (P = 0.001). Advanced-stage (III/IV) disease was present in 22.2% of WT, 31.8% of VUS only, 61.3% of Truncating P/LP, and 71.4% of Missense P/LP patients. Truncating P/LP mutations conferred significantly higher odds of advanced-stage disease (OR = 5.54, 95% CI: 1.98-15.51, P = 0.001) versus WT. No significant association was found with age, sex, grade, or tumor location. The type of APC mutation, specifically truncating variants, is a powerful biomarker for advanced tumor stage in Iranian familial CRC, underscoring the critical need for genotype-driven risk stratification.
This study aimed to compare clinicopathological features of familial non-medullary thyroid cancer (FNMTC) and sporadic non-medullary thyroid cancer (sNMTC) and assess whether age at onset contributes to the different behavior of these 2 entities. A retrospective study including 31 patients with FNMTC, and 31 age- and sex-matched patients with sNMTC. Histological variant, multifocality, tumor infiltration, angioinvasion, TNM stage, lymph node metastasis, BRAF and p53 expression, ATA risk stratification, and the presence of chronic lymphocytic thyroiditis (CLT) were compared between groups. Then, we identified a cutoff age to stratify patients by age of onset (≤35 vs >35 years). FNMTC presented at a more advanced stage at diagnosis compared to sNMTC, with a higher proportion of medium-high TNM stages. Among FNMTC, early-onset (≤35 years) cases showed higher BRAF expression, more frequent lymph node metastases, a higher proportion of medium-high TNM stages, and intermediate-to-high ATA risk compared to late-onset cases (>35 years). Medium-high TNM stage, BRAF expression, and lymph node metastases were observed more frequently in early onset FNMTC than in age-matched sNMTC. Late-onset FNMTC patients exhibited a higher prevalence of CLT than early-onset FNMTC and late-onset sNMTC patients. These findings underscore the relevance of age at disease onset in shaping the clinical phenotypes of FNMTC. The distinct pathological features of early-onset vs late-onset FNMTC suggest different pathophysiological mechanisms, with the former likely driven by direct genetic/oncogenic alterations, and the latter influenced by autoimmune thyroiditis-related carcinogenesis, a hypothesis that warrants further investigation in larger prospective studies.
Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germline E-cadherin/CDH1 mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germline E-cadherin/CDH1 mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.
Breast cancer is known to have an inherited component, consistent in some families with autosomal dominant inheritance; in such families the disease often occurs in association with ovarian cancer. Previous genetic linkage studies have established that in some such families disease occurrence is linked to markers on chromosome 17q. This paper reports the results of a collaborative linkage study involving 214 breast cancer families, including 57 breast-ovarian cancer families; this represents almost all the known families with 17q linkage data. Six markers on 17q, spanning approximately 30 cM, were typed in the families. The aims of the study were to define more precisely the localization of the disease gene, the extent of genetic heterogeneity and the characteristics of linked families and to estimate the penetrance of the 17q gene. Under the assumption of no genetic heterogeneity, the strongest linkage evidence was obtained with D17S588 (maximum LOD score [Zmax] = 21.68 at female recombination fraction [theta f] = .13) and D17S579 (Zmax = 13.02 at theta f = .16). Multipoint linkage analysis allowing for genetic heterogeneity provided evidence that the predisposing gene lies between the markers D17S588 and D17S250, an interval whose genetic length is estimated to be 8.3 cM in males and 18.0 cM in females. This position was supported over other intervals by odds of 66:1. The location of the gene with respect to D17S579 could not be determined unequivocally. Under the genetic model used in the analysis, the best estimate of the proportion of linked breast-ovarian cancer families was 1.0 (lower LOD-1 limit 0.79). In contrast, there was significant evidence of genetic heterogeneity among the families without ovarian cancer, with an estimated 45% being linked. These results suggest that a gene(s) on chromosome 17q accounts for the majority of families in which both early-onset breast cancer and ovarian cancer occur but that other genes predisposing to breast cancer exist. By examining the fit of the linkage data to different penetrance functions, the cumulative risk associated with the 17q gene was estimated to be 59% by age 50 years and 82% by age 70 years. The corresponding estimates for the breast-ovary families were 67% and 76%, and those for the families without ovarian cancer were 49% and 90%; these penetrance functions did not differ significantly from one another.
The term synchronous refers to 2 or more primary independent malignancies, when the second (or subsequent) arises within 6 months after diagnosis of the first malignancy. Synchronous endometrial and ovarian cancers are found in 10% of patients with ovarian cancer and 5% of patients with endometrial cancer. Using a variety of criteria, pathologists can distinguish synchronous primary tumors from metastatic disease. Primary surgical staging remains the gold standard for treating patients with synchronous endometrial and ovarian cancers. Adjuvant therapy is still controversial in the early stages of the disease. Genetic evaluation of patients with a positive family history may be crucial for quicker diagnosis and to identify those with familial cancer syndrome. We present the case of a 47-year-old premenopausal woman with abdominal pain who qualified for surgery due to suspicion of an ovarian tumor during a physical examination and imaging studies. After the final histopathologic examination, the patient was diagnosed with synchronous endometrial cancer, FIGO IA, and ovarian cancer, FIGO IIIC stage .
Early onset colorectal cancer (EoCRC), commonly defined as colorectal cancer diagnosed in people under 50 years of age, is increasing in incidence in Australia and New Zealand. The underlying cause of this remains unclear, despite its growing public health importance. The objective of this scoping review was to comprehensively map and synthesise the literature for EoCRC across Australia and New Zealand, focusing on themes and data sources. A scoping review was performed according to the PRISMA guidance. English language, humans, publications 01/01/2000-31/05/2025, Australian and/or New Zealand patients, studies addressing EoCRC (adenocarcinoma). A systematic literature review was performed: 698 titles and abstracts were screened, 72 full texts were reviewed, with 59 studies included for final analysis. Studies were mostly derived from national and state-based cancer registries and thus presented results achievable by analysis of these databases: incidence, patient demographics, familial cancer syndromes and genetics, tumour characteristics, treatment, short term outcomes and survival. Direct comparison between studies was difficult due to the heterogeneity of patient groups and outcome measures. Gaps identified in the literature included lack of longitudinal risk factor analysis and detailed clinicopathological data. Australia and New Zealand benefit from the mandatory reporting of colon cancer into central registries. To further progress our understanding of EoCRC, prospectively collected and detailed clinicopathological data are required. Despite relatively small populations, the incidence of colorectal cancer in Australia and New Zealand remains among the highest in the world; insights obtained locally have potential global impact.
The Brazilian Genome Map Oncology Subproject (BGMO) integrates paired germline and tumour WGS with lifestyle assessment across Brazil. We aimed to describe clinical, lifestyle, and genomic characteristics of probands with breast, prostate, and colorectal cancers and cascade-testing results in relatives. We conducted a cross-sectional analysis of 275 unrelated adults with breast (BC), prostate (PC), or colorectal cancer (CRC) across nine centres. Paired blood-tumour WGS was performed, and pathogenic/likely pathogenic (P/LP) germline variants were assessed using a 106-gene virtual panel. Somatic oncogenic/likely oncogenic variants were classified by tier. Lifestyle exposures before diagnosis were recorded with a questionnaire. First- and second-degree relatives of probands with P/LP variants in cancer-susceptibility genes were invited for targeted testing. The cohort included 140 BC (50.9%), 65 PC (23.6%), and 70 CRC (25.5%). Overall, 174 (63.3%) participants were women; mean age at diagnosis was 58.4 years (range 29-87). Most self-identified as brown (58.9%), followed by white (29.8%) and black (9.5%). Thirty-three probands (12.0%) carried P/LP germline variants, including 26 (9.5%) in cancer-susceptibility genes. Fifty relatives from 26 families underwent targeted testing; 19 (38.0%) carried the familial variant. Somatic WGS was successful in 269 probands; 88 tumours harboured 91 Tier 1 variants. This multicentre hospital-based WGS study provides an early snapshot of germline, somatic, lifestyle, and familial genetic findings in three high-burden cancers in Brazil and supports expansion to larger, longitudinal BGMO phases. Brazilian Ministry of Health (PROADI-SUS programme).
This study investigates how a polygenic risk score (PRS) influences colorectal cancer (CRC) risk across clinically and molecularly defined risk groups. 1,839 European-descendant individuals were stratified according to low (<20%), intermediate (20 to 80%), or high (>80%) PRS, based on 93 CRC-associated SNPs, for four high risk groups: (i) Lynch syndrome [LS; with CRC: n = 679, CRC-free carriers: n = 422]; (ii) early-onset sporadic CRC [EOS-CRC; n = 518], (iii) positive family history for CRC [F-CRC; n = 220]; and, in EOS-CRC and F-CRC patients (iv) MSI/dMMR CRC [n = 144] vs MSS/pMMR CRC [n = 485]. CRC risk was compared to population-based controls [n = 3,119] and late-onset sporadic CRC patients from UK Biobank [LOS-CRC; n = 781] using multivariable logistic regression and Cox models. PRS was significantly increased in all risk groups compared to population controls. Being in the high PRS category doubled CRC risk in EOS-CRC and F-CRC corresponding to cumulative incidences before 50 and 75 years of 24% and 13%, respectively. PRS was significantly higher in EOS-CRC than LOS-CRC. In LS, PRS in non-CRC carriers lay between CRC-LS and population controls. Non-LS individuals with MSI/dMMR tumors showed significantly lower PRS than those with pMMR/MSS tumors, but no difference compared to LS CRC individuals. PRS most strongly influences CRC risk in unexplained EOS- and F-CRC. The effect in LS individuals strongly depends on the penetrance of the altered gene and study design. Non-significant trends can partly be explained by the sample size of subgroups. Larger collaborative, prospective studies are needed to validate PRS for personalized CRC risk stratification.
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Cancer vaccines offer a promising strategy for cancer prevention, particularly in hereditary cancer syndromes such as Lynch syndrome (LS). LS is characterized by a high lifetime risk of developing various malignancies due to defects in DNA mismatch repair, leading to an accumulation of mutations, particularly frameshift insertion/deletions (indels) within microsatellite loci. These indels create shared tumour-specific neoantigens, which are unique to LS and can be recognized by the immune system and trigger cancer cell killing. Importantly, these neoantigens are also present in precancerous lesions, making LS an ideal target for immune-interception strategies aimed at prevention. Over the years, a variety of vaccine designs targeting different antigens along with a range of delivery platforms have been explored for different types of tumours, each with its own advantages and limitations. In this review, we provide an overview of the key antigens and delivery platforms used in cancer preventive vaccine development for LS, evaluate their limited clinical outcomes to date, and explore the future directions of preventive vaccine immunotherapy. A particular focus is placed on the promising potential of dendritic cell vaccination therapy as a future approach in this field.
Genetic and familial susceptibility accounts for 10% of pancreatic ductal adenocarcinoma (PDAC) cases and represents a small but relevant subgroup in which early detection may meaningfully affect outcomes. Pathogenic germline variants (PGVs) in susceptibility genes, such as BRCA2/ATM/CDKN2A/STK11/PALB2/TP53, as well as mismatch repair genes, confer a substantially higher lifetime risk, while families fulfilling the criteria for familial pancreatic cancer (FPC) exhibit disease clustering in the absence of an identifiable PGV. Over the past two decades, surveillance strategies for high-risk individuals (HRIs) have evolved from exploratory registries to structured clinical programs, generating expanding evidence with tangible clinical implications. Data from the international CAPS (Cancer of the Pancreas Screening) consortium, the Dutch nationwide surveillance program, and the IRFARPC (Italian Registry of Families at Risk for Pancreatic Cancer) consistently demonstrate a stage shift toward earlier, resectable disease and improved survival among cancers detected under surveillance. However, uncertainties remain regarding the magnitude of benefit, eligibility criteria, surveillance start age, cost-effectiveness, and the risk of overdiagnosis. This review critically appraises current evidence, focusing on the Italian and European experience, evaluates the pros and cons of HRIs surveillance, and proposes updated criteria and considerations for a structured, registry-based national program aligned with new evidence.
Tubo-ovarian cancer represents the most lethal gynecologic malignancy, and its burden is compounded by the absence of effective screening and the substantial lifetime risk carried by women with germline BRCA1 or BRCA2 pathogenic variants. While risk-reducing salpingo-oophorectomy remains the standard for prevention, conferring reduction in tubo-ovarian cancer risk and improved overall survival, it also induces premature menopause with significant effects on quality of life and bone, cardiovascular, and sexual health. These consequences have driven the exploration of alternative preventive strategies, and a paradigm shift toward individualized risk assessment. Emerging data highlight that tubo-ovarian cancer risk among BRCA pathogenic variant carriers is not uniform but influenced by gene type, variant position, family history, and modifiable factors such as parity, breastfeeding, and oral contraceptive use. Modern risk models integrate genetic, familial, and lifestyle data to refine personalized estimates and guide the timing of intervention. Concurrently, the understanding that many high-grade serous carcinomas originate in the fallopian tube has prompted evaluation of risk-reducing salpingectomy with delayed oophorectomy as a staged surgical strategy that may balance oncologic safety with preservation of hormonal function. Ultimately, management of BRCA pathogenic variant carriers must combine genomic precision, reproductive planning, and patient-centered counseling to align cancer prevention with quality of life, supporting truly individualized care in hereditary tubo-ovarian cancer risk reduction. Despite several reviews on hereditary tubo-ovarian cancer prevention, a clinically relevant gap remains in translating contemporary evidence into a practical counseling framework for women with BRCA1/2 pathogenic variants. This narrative review aims to synthesize current evidence on tubo-ovarian cancer risk assessment and risk-reducing strategies in this population, with a focus on individualized counseling and shared decision-making.
Breast cancer risk among transgender and gender-diverse individuals undergoing gender-affirming chest masculinization ("top") surgery remains poorly defined. This study aimed to characterize breast cancer risk and management in this population. We conducted retrospective chart review of patients undergoing top surgery within an academic plastic surgery practice. Variables included family and reproductive history, genetic testing, International Breast Intervention Study (IBIS) scores, and final pathology. The primary outcome was elevated breast cancer risk, defined as IBIS ≥ 20% (high risk) or 15%-19% (intermediate). Significance was set at p < 0.05. From April 2019 to December 2024, 284 individuals underwent top surgery. One-third reported a family history of breast cancer, and two of fifteen genetically tested patients carried pathogenic variants. IBIS scores were calculable in 79 patients, with 43% demonstrating intermediate or high risk (IBIS ≥ 15%). Seven patients were referred to breast surgical oncology and fifteen to genetics; four high-risk individuals elected risk-reducing mastectomy. One case of ductal carcinoma in situ was identified during risk-reducing mastectomy. A subset of top surgery patients exhibit elevated familial, genetic, or IBIS-based breast cancer risk. Although incidental malignancy was rare, structured risk assessment and selective referral may improve screening and management in this population.