Hereditary Cancer in Clinical Practice最新文献

Background: Triple-negative breast cancer is a heterogeneous molecular subtype of BC. Pathological complete response (pCR) is an important surrogate marker for recurrence-free and overall survival.

Aim of study: The aim of this study was to evaluate clinical and pathological factors that are associated with complete pathological response status in triple-negative breast cancer patients receiving neoadjuvant chemotherapy.

Materials and methods: Eighty triple-negative breast cancer patients who underwent neoadjuvant chemotherapy followed by surgery at Pauls Stradins Clinical University Hospital between January 2018 and January 2020 were retrospectively analysed. Twenty-six patients (32.5%) were BRCA1/2 pathogenic variant carriers.

Results: A total of 32.5% (n = 26) of patients in all study groups and 57.7% (n = 15) of patients with BRCA1/2 pathogenic variants achieved pCR. Forty-seven patients received platinum-based neoadjuvant chemotherapy, and 19 patients (40.4%) achieved complete pathological response. Patients in the pCR group presented with significantly higher Ki-67 scores (p = 0.007), BRCA1/2 pathogenic variants (p = 0.001) and younger age (p = 0.02) than those in the non-pCR group. pCR did not significantly impact recurrence-free survival (RFS) or overall survival (OS). Multivariate analysis revealed that pretreatment N stage (clinical nodal status) was an independent prognostic factor for RFS and OS.

Conclusions: BRCA1 pathogenic variants, high Ki67 score and young age were predictors of pathological complete response, while clinical nodal status predicted survival outcomes in triple-negative breast cancer.

Large amounts of germline sequencing data have recently become available and we sought to compare these results with population-based family history data. Family studies are able to describe aggregation of any defined cancers in families. The Swedish Family-Cancer Database is the largest of its kind in the world, covering the Swedish families through nearly a century with all cancers in family members since the start of national cancer registration in 1958. The database allows estimation of familial risks, ages of cancer onset and the proportion of familial cancer in different family constellations. Here, we review the proportion of familial cancer for all common cancers and specify them based on the number of affected individuals. With the exception of a few cancers, age of onset of familial cancer is not different from all cancers combined. The highest proportions of familial cancer were found for prostate (26.4%), breast (17.5%) and colorectal (15.7%) cancers, but the proportions of high-risk families with multiple affected individuals were only 2.8%, 1% and 0.9%, respectively. A large sequencing study on female breast cancer found that BRCA1 and BRCA2 mutations could account for 2% of the cases (subtracting the proportions in healthy individuals) and that all germline mutations accounted for 5.6% of the cases. Early age of onset was a distinct feature of only BRCA mutations. In heritable colorectal cancer, Lynch syndrome genes dominate. Large studies on penetrance in Lynch syndrome have shown an approximately linear increase in risk from 40-50 years up to age 80 years. Interesting novel data revealed a strong modification of familial risk by unknown factors. High-risk germline genetics of prostate cancer is characterized by BRCA and other DNA repair genes. HOXB13 encodes a transcription factor which contributes to germline risk of prostate cancer. A strong interaction was shown with a polymorphism in the CIP2A gene. The emerging germline landscape of common cancers can be reasonably accommodated by family data on these cancers as to high-risk proportions and age of onset.

The current understanding of the inherited risk of colorectal cancer (CRC) started with an observational clinical era in the late 19^th century, which was followed by a genetic era starting in the late 20^th century. Genome-wide linkage analysis allowed mapping several high-risk genes, which marked the beginning of the genetic era. The current high-throughput genomic phase includes genome-wide association study (GWAS) and genome-wide sequencing approaches which have revolutionized the conception of the inherited risk of CRC. On the one hand, GWAS has allowed the identification of multiple low risk loci correlated with CRC. On the other, genome-wide sequencing has led to the discovery of a second batch of high-to-moderate-risk genes that correlate to atypical familial CRC and polyposis syndromes. In contrast to other common cancers, which are usually dominated by a polygenic background, CRC risk is believed to be equally explained by monogenic and polygenic architectures, which jointly contribute to a quarter of familial clustering. Despite the fact that genome-wide approaches have allowed the identification of a continuum of responsible high-to-moderate-to-low-risk variants, much of the predisposition and familial clustering of CRC has not yet been explained. Other genetic, epigenetic and environmental factors might be playing important roles as well. In this review we aim to provide insights on the complementary roles played by different genomic approaches in allowing the current understanding of the genetic architecture of inherited CRC.

Background: Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear.

Case presentation: We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8-11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease.

Conclusions: To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health.

Background: Women carrying BRCA1/2 pathogenic variants are exposed to elevated risks of developing breast cancer (BC) and are faced by a complex decision-making process on preventative measures, i.e., risk-reducing mastectomy (RRM), and intensified breast surveillance (IBS). In this prospective cohort study we investigated the effect of anxiety, personality factors and coping styles on the decision-making process on risk management options in women with pathogenic variants in BRCA1/2.

Methods: Breast cancer unaffected and affected women with a pathogenic variant in the BRCA1 or BRCA2 gene were psychologically evaluated immediately before (T0), 6 to 8 weeks (T1) and 6 to 8 months (T2) after the disclosure of their genetic test results. Uptake of RRM and IBS was assessed at T2. Psychological data were gathered using questionnaires on risk perception, personality factors, coping styles, decisional conflict, depression and anxiety, including the Hospital Anxiety and Depression Scale (HADS). We performed tests on statistical significance and fitted a logistic regression based on significance level.

Results: A total of 98 women were included in the analysis. Baseline anxiety levels in women opting for RRM were high but decreased over time, while they increased in women opting for intensified breast surveillance (IBS). Elevated levels of anxiety after genetic test result disclosure (T1) were associated with the decision to undergo RRM (p < 0.01; OR = 1.2, 95% CI = 1.05-1.42), while personal BC history and personality factors seemed to be less relevant.

Conclusions: Considering psychosocial factors influencing the decision-making process of women with pathogenic variants in BRCA1/2 may help improving their genetic and psychological counselling. When opting for IBS they may profit from additional medical and psychological counselling.

Trial registration: Retrospectively registered at the German Clinical Trials Register under DRKS00027566 on January 13, 2022.

A brief description of why and for which purposes the Prospective Lynch Syndrome Database was established, the principles and design, and the main classes of results are given. Data input is assumption-free input enabling validation of paradigms used to explain the results. The design is considering cancer/age as discrete events to occur or not in a time dimension in a closed room compliant with population genetic paradigms and last centuries developing paradigms of interpreting discrete events reflecting conditional and/or co-occurring stochastic probabilities. Which may be in contrast to the paradigm that any observed event has a cause. The results may indicate that some current paradigms on carcinogenesis should be reconsidered. The complete analytic code in MySQL© syntax together with a flowchart illustrating how the different pieces of codes interrelate are included as supplementary files, enabling third parties to use or modify the code to examine prospectively observed events in their own activities when referring to this report as the source.

Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants.

Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands.

Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups.

Conclusions: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Lynch Syndrome (LS) is a highly variable entity with some patients presenting at very young ages with malignancy whereas others may never develop a malignancy yet carry an unequivocal genetic predisposition to disease. The most frequent LS malignancy remains colorectal cancer, a disease that is thought to involve genetic as well as environmental factors in its aetiology. Environmental insults are undeniably associated with cancer risk, especially those imparted by such activities as smoking and excessive alcohol consumption. Notwithstanding, in an inherited predisposition the expected exposures to an environmental insult are considered to be complex and require knowledge about the respective exposure and how it might interact with a genetic predisposition. Typically, smoking is one of the major confounders when considering environmental factors that can influence disease expression on a background of significant genetic risk. In addition to environmental triggers, the risk of developing a malignancy for people carrying an inherited predisposition to disease can be influenced by additional genetic factors that do not necessarily segregate with a disease predisposition allele. The purpose of this review is to examine the current state of modifier gene detection in people with a genetic predisposition to develop LS and present some data that supports the notion that modifier genes are gene specific thus explaining why some modifier gene studies have failed to identify associations when this is not taken into account.

Background: There is a growing need for genetic testing of women with epithelial ovarian cancer. Mainstream genetic testing provides an alternative care pathway in which non-genetic healthcare professionals offer pre-test counseling themselves. We aimed to explore the impact of mainstream genetic testing on patients' experiences, turnaround times and adherence of non-genetic healthcare professionals to the mainstream genetic testing protocol.

Methods: Patients receiving pre-test counseling at the gynecology departments between April 2018 and April 2020 were eligible to participate in our intervention group. Patients receiving pre-test counseling at the genetics department between January 2017 and April 2020 were eligible to participate in our control group. We evaluated patients' experiences with questionnaires, consisting of questions regarding knowledge, satisfaction and psychosocial outcomes. Patients in the intervention group were sent two questionnaires: one after pre-test counseling and one after receiving their DNA test result. Patients in our control group were sent one questionnaire after receiving their test result. In addition, we collected data regarding turnaround times and adherence of non-genetic healthcare professionals to the mainstream genetic testing protocol.

Results: Participation was 79% in our intervention group (105 out of 133 patients) and 60% in our control group (91 out of 152 patients). Knowledge regarding genetics, decisional conflict, depression, anxiety, and distress were comparable in the two groups. In the intervention group, the risk of breast cancer in patients carrying a pathogenic germline variant was discussed less often (49% versus 74% in control group, p ≤ 0.05), and the mean score of regret about the decision to have genetic testing was higher than in the control group (mean 12.9 in the intervention group versus 9.7 in the control group, p ≤ 0.05), although below the clinically relevant threshold of 25. A consent form for the DNA test and a checklist to assess family history were present for ≥ 95% of patients in the intervention group.

Conclusion: Mainstream genetic testing is an acceptable approach to meet the increase in genetic testing among women with epithelial ovarian cancer.

Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in ~ 52% of reads in DNA extracted from tumour, ~ 10% of reads in DNA extracted from peripheral blood leukocytes and ~ 10% of reads in DNA extracted from buccal mucosa. The second BRCA1 c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in ~ 59% of reads in DNA extracted from tumour, ~ 14% of reads in DNA extracted from peripheral blood leukocytes and similarly in ~ 14% of reads in both DNA extracted from buccal mucosa and urine sample. Sanger sequencing confirmed the presence of these variants at a corresponding low level consistent with mosaicism that may not have been detected by this method alone. This report demonstrates the clinical benefit for two women of BRCA1/BRCA2 germline NGS testing at a depth that can detect low-level mosaicism. As well as informing appropriate treatments, tumour sequencing results may facilitate the detection and interpretation of low-level mosaic variants in the germline. Both results have implications for other cancer risks and for relatives when providing a family cancer risk assessment and reproductive risk. The implications for laboratory practice, clinical genetics management and genetic counselling for constitutional mosaicism of BRCA1/BRCA2 are discussed.