There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological ...cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.
Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.
Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.
This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.
Response to Tolva et al Sampson, Julian R; Dominguez-Valentin, Mev; Seppälä, Toni T ...
Genetics in medicine,
04/2020, Letnik:
22, Številka:
4
Journal Article
The authors wish to make the following corrections to this paper 1: The authors would like to replace Table 3 in 1. The corrections are correcting typographical errors when translating our database ...in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. ....
Abstract Background BRCA2 c.68-7T>A has been demonstrated to cause aberrant splicing and is possibly pathogenic. The population prevalence of the variant is 0.2%, which higher than usual for ...pathogenic BRCA2 variants. The pathogenicity of the variant is discussed. Methods The outpatient genetic clinic at The Norwegian Radium Hospital, part of Oslo University Hospital, has invited breast cancer kindreds for genetic examinations and prospective follow-up of high risk patients since 1988. We have complete files of all activities and results, and we examined the files for association between BRCA2 c.68-7T>A and breast cancer. Results Seventeen out of 714 (2.4%) breast cancer kindreds sequenced for BRCA2 carried the variant BRCA2 c.68-7T>A (p < 0.0001 compared to population controls). Segregation analysis was inconclusive (likelihood ratio 0.36) for pathogenicity. Two breast cancers were prospectively observed during 134 observation years (annual incidence rate 1.5% (95% CI 0.15% to 5.4%) and one additional breast cancer was diagnosed at first (prevalence) round. Conclusion BRCA2 c.68-7T>A is associated with breast cancer. In the families selected due to aggregation of breast cancer, carriers of the BRCA2 c.68-7T>A variant have increased risk for breast cancer. It is, however, possible that the variant has lower penetrance than the average pathogenic BRCA2 variants, and that in the families selected for having known aggregation of breast cancer other (modifying) factors contributed to the observed results.
Weight gain and other anthropometric measures on the risk of ovarian cancer for women with
mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body ...mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among
and
mutation carriers.
In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer.
This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54;
= 0.02). Current BMI of 26.5 kg/m
or greater was associated with an increased risk of ovarian cancer in
mutation carriers, compared with those with a BMI less than 20.8 kg/m
(Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36;
= 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer.
Adult weight gain is a risk factor for ovarian cancer in women with a
or
mutation.
These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.
The aims of the Prospective Lynch Syndrome Database (PLSD) are to provide empirical prospectively observed data on the incidences of cancer in different organs, survival following cancer and the ...effects of interventions in carriers of pathogenic variants of the mismatch repair genes (
) categorized by age, gene and gender. Although PLSD is assumption-free, as with any study the ascertainment procedures used to identify the study cohort will introduce selection biases which have to be declared and considered in detail in order to provide robust and valid results. This paper provides a commentary on the methods used and considers how results from the PLSD reports should be interpreted. A number of the results from PLSD were novel and some in conflict with previous assumptions. Notably, colonoscopic surveillance did not prevent colo-rectal cancer, survival after colo-rectal, endometrial and ovarian cancer was good, no survival gain was observed with more frequent colonoscopy, new causes of cancer-related death were observed in survivors of first cancers due to later cancers in other organs, variants in the different
genes caused distinct multi-cancer syndromes characterized by different penetrance and phenotypes. The www.PLSD.eu website together with the InSiGHT database website (https://www.insight-group.org/variants/databases/) now facilitate evidence-based personalized precision health care for individual carriers at increased risk of cancer. The arguments are summarized in a final discussion on how to conceptualize current knowledge for the different practical purposes of treating cancers, genetic counselling and prevention, and for understanding /research on carcinogenetic mechanisms.
To evaluate the rate of prophylactic contralateral mastectomy in an international cohort of women with hereditary breast cancer and to evaluate the predictors of uptake of preventive surgery.
Women ...with a BRCA1 or BRCA2 mutation who had been diagnosed with unilateral breast cancer were followed prospectively for a minimum of 1.5 years. Information was collected on prophylactic surgery, tamoxifen use, and the occurrence of contralateral breast cancer.
Nine hundred twenty-seven women were included in the study; of these, 253 women (27.3%) underwent a contralateral prophylactic mastectomy after the initial diagnosis of breast cancer. There were large differences in uptake of contralateral prophylactic mastectomy by country, ranging from 0% in Norway to 49.3% in the United States. Among women from North America, those who had a prophylactic contralateral mastectomy were significantly younger at breast cancer diagnosis (mean age, 39 years) than were those without preventive surgery (mean age, 43 years). Women who initially underwent breast-conserving surgery were less likely to undergo contralateral prophylactic mastectomy than were women who underwent a mastectomy (12% v 40%; P < 10(-4)). Women who had elected for a prophylactic bilateral oophorectomy were more likely to have had their contralateral breast removed than those with intact ovaries (33% v 18%; P < 10(-4)).
Age, type of initial breast cancer surgery, and prophylactic oophorectomy are all predictive of prophylactic contralateral mastectomy in women with breast cancer and a BRCA mutation. The acceptance of contralateral preventive mastectomy was much higher in North America than in Europe.
Genetic predisposition to prostate cancer includes multiple common variants with a low penetrance (single nucleotide polymorphisms)
and rare variants with higher penetrance. The mismatch repair (MMR) ...genes MLH1, MSH2, MSH6 , and PMS2 are associated with Lynch syndrome where colon and endometrial cancers are the predominant phenotypes. The purpose of our
study was to investigate whether germ-line mutations in these genes may be associated with prostate cancer. One hundred and
six male carriers or obligate carriers of MMR mutations were identified. Nine had contracted prostate cancer. Immunohistochemical
analysis was done on tumor tissue from eight of the nine tumors. Observed incidence, cumulative risk at 60 and 70 years of
age, age of onset, and Gleason score were compared with expected as assessed from population-based series. Absence of gene
product from the mutated MMR gene was found in seven of eight tumors. Expected number of prostate cancers was 1.52 compared
with 9 observed ( P < 0.01). Mean age of onset of prostate cancer was 60.4 years compared with 66.6 expected ( P = 0.006); the number of men with a Gleason score between 8 and 10 was significantly higher than expected ( P < 0.00001). Kaplan-Meier analysis suggested that cumulative risk by 70 years in MMR mutation carriers may be 30% (SE, 0.088)
compared with 8.0% in the general population. This is similar to the high risk associated with BRCA2 mutations. To our knowledge, this study is the first to indicate that the MMR genes may be among the rare genetic variants
that confer a high risk of prostate cancer when mutated. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2460–7)
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