Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy ...with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS‐associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS‐associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.
The value of high‐throughput germline genetic testing is increasingly recognized in clinical cancer care. Disease‐associated germline variants in cancer patients are important for risk management and ...surveillance, surgical decisions and can also have major implications for treatment strategies since many are in DNA repair genes. With the increasing availability of high‐throughput DNA sequencing in cancer clinics and research, there is thus a need to provide clinically oriented sequencing reports for germline variants and their potential therapeutic relevance on a per‐patient basis. To meet this need, we have developed the Cancer Predisposition Sequencing Reporter (CPSR), an open‐source computational workflow that generates a structured report of germline variants identified in known cancer predisposition genes, highlighting markers of therapeutic, prognostic and diagnostic relevance. A fully automated variant classification procedure based on more than 30 refined American College of Medical Genetics and Genomics (ACMG) criteria represents an integral part of the workflow. Importantly, the set of cancer predisposition genes profiled in the report can be flexibly chosen from more than 40 virtual gene panels established by scientific experts, enabling customization of the report for different screening purposes and clinical contexts. The report can be configured to also list actionable secondary variant findings, as recommended by ACMG. CPSR demonstrates comparable sensitivity and specificity for the detection of pathogenic variants when compared to other algorithms in the field. Technically, the tool is implemented in Python/R, and is freely available through Docker technology. Source code, documentation, example reports and installation instructions are accessible via the project GitHub page: https://github.com/sigven/cpsr.
What's new?
The Cancer Predisposition Sequencing Reporter is a unique bioinformatics tool for identifying genetic variants that may be therapeutically relevant. Many cancers arise from rare germline mutations in cancer predisposition genes. Knowing what variants a patient is carrying can help clinicians make decisions about risk‐reduction interventions and surveillance, but interpretation of the variant profile can be challenging. This tool generates a report of variants in known cancer predisposition genes, highlighting those with therapeutic, prognostic, and diagnostic relevance.
Opportunities to directly study the founding of a human population and its subsequent evolutionary history are rare. Using genome sequence data from 27 ancient Icelanders, we demonstrate that they ...are a combination of Norse, Gaelic, and admixed individuals. We further show that these ancient Icelanders are markedly more similar to their source populations in Scandinavia and the British-Irish Isles than to contemporary Icelanders, who have been shaped by 1100 years of extensive genetic drift. Finally, we report evidence of unequal contributions from the ancient founders to the contemporary Icelandic gene pool. These results provide detailed insights into the making of a human population that has proven extraordinarily useful for the discovery of genotype-phenotype associations.
The Prospective Lynch Syndrome Database (PLSD) has been developed as an international, multicentre, prospective, observational study that aims to provide age and organ-specific cancer risks according ...to gene and gender, estimates of survival after cancer and information on the effects of interventions. Recent reports from PLSD provided improved estimates of cancer risks and survival and showed that different time intervals between surveillance colonoscopies did not affect the incidence, stage or prognosis of colorectal cancer. The PLSD reports suggest that current management guidelines for Lynch syndrome should be revised in light of the different gene and gender-specific cancer risks and the good prognosis for the most commonly associated cancers.
In this review, we describe the discrepancies between the current management guidelines for Lynch Syndrome and the most recent prospective observational studies, indicating the areas of further research.
Background & Aims:
Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing ...cancer in a large series of
MSH6 mutation carriers.
Methods:
Mutation analysis was performed in 20 families with a germline mutation in
MSH6. We compared the cancer risks between
MSH6 and
MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors.
Results:
A total of 146
MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in
MSH6 than in
MLH1 or
MSH2 mutation carriers (
P = 0.002). In female
MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (
P = 0.0049) and the risk for endometrial cancer significantly higher (
P = 0.02) than in
MLH1 and
MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in
MSH6 mutation carriers, but the difference was not significant (
P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in
MSH6.
Conclusions:
We recommend starting colonoscopic surveillance in female
MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for
MSH6 mutation analysis.
Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1 are responsible for the majority of cases involving hereditary breast and ovarian cancer. Whereas all truncating ...mutations are considered as functionally deleterious, most of the missense variants identified to date cannot be readily distinguished as either disease-associated mutations or benign polymorphisms. The C-terminal domain of BRCA1 displays an intrinsic transactivation activity, and mutations linked to disease predisposition have been shown to confer loss of such activity in yeast and mammalian cells. In an attempt to clarify the functional importance of the BRCA1 C-terminus as a transcription activator in cancer predisposition, we have characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Missense variants A1669S, C1697R, R1699W, R1699Q, A1708E, S1715R and G1738E and a truncating mutation, W1837X, were characterized using yeast- and mammalian-based transcription assays. In addition, four additional missense variants (V1665M, D1692N, S1715N and D1733G) and one in-frame deletion (V1688del) were included in the study. Our findings demonstrate that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. We also report a discrepancy between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. We show that transcription-based assays can aid in the characterization of deleterious mutations in the C-terminal part of BRCA1 and may form the basis of a functional assay.
Epidemiology is the study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to the control of health problems ....
To examine psychological distress in women at risk of familial breast-ovarian cancer (FBOC) or hereditary non-polyposis colorectal cancer (HNPCC) with absence of demonstrated mutations in the family ...(unknown mutation).
Two-hundred and fifty three consecutive women at risk of FBOC and 77 at risk of HNPCC and with no present or past history of cancer. They were aware of their risk and had received genetic counseling. Comparisons were made between these two groups, normal controls, and women who were identified to be BRCA1 mutation carriers. The questionnaires Beck Hopelessness Scale (BHS), General Health Questionnaire (GHQ-28), Hospital Anxiety and Depression Scale (HADS) and Impact of Event Scale (IES) were employed to assess psychological distress.
No significant differences concerning psychological distress were observed between women with FBOC and women with HNPCC. Compared to mutation carriers for BRCA1, the level of anxiety and depression was significantly higher in the FBOC group with absence of demonstrated mutation. Compared to normal controls, the level of anxiety was higher, while the level of depression was lower in the groups with unknown mutation.
Women in the absence of demonstrated mutations have higher anxiety and depression levels than women with known mutation-carrier status. Access to genetic testing may be of psychologically benefit to women at risk for FBOC or HNPCC.
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