Syndrome Mutation Carriers Research Articles

Information needs of Lynch syndrome and BRCA 1/2 mutation carriers considering risk-reducing gynecological surgery: a qualitative study of the decision-making process

BackgroundRisk-reducing gynecological surgery (RRGS) is a prophylactic procedure that may be offered to BRCA1, BRCA2, and Lynch syndrome (LS) mutation carriers to reduce the risk of developing gynecological cancer. This study was conducted to better understand patients’ information needs and evaluate how patients weigh different sources of information in their decision-making process surrounding RRGS.MethodsThis study used a qualitative approach to understanding women’s perspectives towards RRGS. Semi-structured interviews were conducted virtually with 8 women. Women offered RRGS between 35 and 70 years of age who are English-speaking and have an identifiable BRCA or LS mutation were included. Data from interviews was coded with constant comparative analysis to develop themes.ResultsOf the eight women, six had selected to undergo either prophylactic hysterectomy or oophorectomy: 5 decided yes to RRGS; 1 decided no; 2 were undecided. Thematic analysis found that the key factors affecting women’s decisions around prophylactic surgery were cancer risk, surgical menopause, and psychological readiness. To make an informed decision, women relied most heavily on information provided by healthcare professionals (e.g. doctors, genetic counselors) and family members with prior cancer experience. However, some women reported that they did not feel adequately informed enough to make a decision and identified COVID-19 as a significant barrier affecting access to information.ConclusionThis qualitative study revealed the key sources of information influencing attitudes regarding RRGS and how women consulted different sources of information to reach a decision. Results underscore the need for greater attention to women’s information needs in the context of psychological readiness, particularly amidst the pandemic. Research involving a larger sample size may help to better inform how support can be provided to individuals with BRCA and LS mutations considering RRGS.

Associations between pathological features and risk of metachronous colorectal cancer.

Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.

Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated. 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p<0·0001) and in people with Down syndrome (n=32; r=-0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Exploring mutation specific beta blocker pharmacology of the pathogenic late sodium channel current from patient-specific pluripotent stem cell myocytes derived from long QT syndrome mutation carriers

ABSTRACT The congenital long QT syndrome (LQTS), one of the most common cardiac channelopathies, is characterized by delayed ventricular repolarization underlying prolongation of the QT interval of the surface electrocardiogram. LQTS is caused by mutations in genes coding for cardiac ion channels or ion channel-associated proteins. The major therapeutic approach to LQTS management is beta blocker therapy which has been shown to be effective in treatment of LQTS variants caused by mutations in K+ channels. However, this approach has been questioned in the treatment of patients identified as LQTS variant 3(LQT3) patients who carry mutations in SCN5A, the gene coding for the principal cardiac Na+ channel. LQT3 mutations are gain of function mutations that disrupt spontaneous Na+ channel inactivation and promote persistent or late Na+ channel current (INaL) that delays repolarization and underlies QT prolongation. Clinical investigation of patients with the two most common LQT3 mutations, the ΔKPQ and the E1784K mutations, found beta blocker treatment a useful therapeutic approach for managing arrhythmias in this patient population. However, there is little experimental data that reveals the mechanisms underlying these antiarrhythmic actions. Here, we have investigated the effects of the beta blocker propranolol on INaL expressed by ΔKPQ and E1784K channels in induced pluripotent stem cells derived from patients carrying these mutations. Our results indicate that propranolol preferentially inhibits INaL expressed by these channels suggesting that the protective effects of propranolol in treating LQT3 patients is due in part to modulation of INaL.

Exercise induced worsening of mechanical heterogeneity and diastolic impairment in Long QT syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Background Left ventricular (LV) mechanical dispersion and prolonged myocardial contraction are associated with symptoms in long QT syndrome (LQTS) mutation carriers. Sub-clinical LV diastolic impairment has also been reported in this group. Purpose To investigate at rest and during exercise the combined effect of prolonged myocardial contraction and increased mechanical dispersion on myocardial diastolic function and symptoms in LQTS subjects. Methods 47 LQTS patients (36 LQT1, 11 LQT2) underwent a bicycle exercise test in semi-supine position. ECG and echo parameters were recorded at rest, peak exercise (p.e) and were compared with 35 healthy individuals. Results No difference was seen between LQTS and control subjects for age (45 ± 15 vs 47 ± 13 years, p = 0.2), gender (53 vs 54% females, p = 0.3) or LV Ejection Fraction (65 ± 6 vs 67 ± 7%, p = 0.3). LQTS subjects, compared to controls, had not only prolonged QTc interval, but also longer contraction duration (tGLS), total isovolumic time (t-IVT), delayed early relaxation phase (tESR) and markedly decreased filling time (FT) at rest and p.e. Unlike controls, these electromechanical disturbances deteriorated further with exercise, during which additional decrease of the LV systolic (GLS) and diastolic myocardial function (ESR) and attenuated LV stroke volume response (Δ SV: +2 ± 0.5 vs +4 ± 1 vs +32 ± 4%, p&amp;lt; 0.0001) were noted. Such abnormal response to exercise was of greater degree in symptomatic patients and in the LQT1 subgroup and appeared to be amplified by b-blocker therapy (p &amp;lt; 0.05). Worsening myocardial contraction dispersion (SD-tGLS) at p.e was the strongest discriminator for previous clinical events (AUC 0.960, 95% CI 0.020 - 0.995, p &amp;lt; 0.0001) and its discriminating power excelled further by adding early relaxation delay. Conclusions Our findings suggest that in LQTS subjects prolonged and dyssynchronous mechanical contraction during exercise may be associated with inadequate cardiac output increase and symptoms. Table 1. REST PEAK LQT CONTROL p- LQT CONTROL p- QTc (ms) 453 ± 42 413 ± 17 &amp;lt; 0.0001 455 ± 44 390 ± 19 &amp;lt; 0.0001 GLS (%) 17.3 ± 4.3 18.7 ± 1.3 0.05 19.1 ± 32.6 23.5 ± 11.6 0.0001 tGLS (%) 47 ± 7.2 42 ± 6.3 0.0001 58.7 ± 10 40.1 ± 5.8 &amp;lt; 0.0001 ESR (%) 1 ± 0.3 2 ± 0.3 &amp;lt; 0.0001 1.1 ± 0.4 2.8 ± 0.4 &amp;lt; 0.0001 tESR (%) 61.4 ± 6.8 58.7 ± 4.1 0.03 69.7 ± 5.9 56.1 ± 2.9 &amp;lt; 0.0001 SD TGLS (ms) 58 ± 8 31 ± 8 &amp;lt; 0.0001 61 ± 8 24 ± 10 &amp;lt; 0.0001 Exercise response in long QT syndrome patients and controls

Quantitative T-wave morphology assessment from surface ECG is linked with cardiac events risk in genotype-positive KCNH2 mutation carriers with normal QTc values.

Long QT syndrome (LQTS) mutation carriers have elevated the risk of cardiac events even in the absence of QTc prolongation; however, mutation penetrance in patients with normal QTc may be reflected in abnormal T-wave shape, particularly in KCNH2 mutation carriers. We aimed to assess whether the magnitude of a three-dimensional T-wave vector (TwVM) will identify KCNH2-mutation carriers with normal QTc at risk for cardiac events. Adult LQT2 patients with QTc < 460 ms in men and <470 ms in women (n = 113, age 42 ± 16 years, 43% male) were compared with genotype-negative family members (n = 1007). The TwVM was calculated using T-wave amplitudes in leads V6, II, and V2 as the square root of (TV62 + TII2 + (0.5*TV2)2 ). Cox regression analysis adjusted for gender and time-dependent beta-blocker use was performed to assess cardiac event (CE) risk, defined as syncope, aborted cardiac arrest, implantable cardioverter-defibrillator therapy, or sudden death. Dichotomized by median of 0.30 mV, lower TwVM was associated with elevated CE risk compared to those with high TwVM (HR = 2.95, 95% CI, 1.25-6.98, P = .014) and also remained significant after including sex and time-dependent beta-blocker usage in the Cox regression analysis (HR = 2.64, 95% CI, 1.64-4.24, P < .001). However, these associations were found only in women but not in men who had low event rates. T-wave morphology quantified as repolarization vector magnitude using T-wave amplitudes retrieved from standard 12-lead electrocardiogram predicts cardiac events risk in LQT2 women and appears useful for risk stratification of KCNH2-mutation carriers without QTc prolongation.

CN115 - Communication of genetic information to family members in hereditary cancers and healthcare providers’ role

BackgroundIn hereditary cancers, disclosure of genetic testing and communication of genetic information to family members is crucial to manage their potential cancer risk. In Switzerland, according to privacy law, genetic information can be passed on to at-risk relatives only through the individual identified with the pathogenic mutation but 20-40% of at-risk family members remain unaware of relevant genetic information and less than 50% refer to genetic services. Healthcare providers have a relevant and challenging role in supporting family communication on genetics but this is still limited and not clear. The aim of the study is to explore how mutation carriers’ communicate about genetics within family members and how this is concretely supported in clinical practice. MethodsOngoing qualitative study. Data are collected with distinct focus groups with a purposeful sample of about 30 hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) mutation carriers and 30 relatives from three linguistic areas of Switzerland. The sample is diversified in terms of gender, clinical history and attitude towards family communication. Interviews with 15 healthcare providers routinely involved in genetic counselling are performed, too. Data collection and data analysis continue iteratively until data saturation according to constant comparative method. ResultsQualitative data from focus groups and interviews show that family communication of genetic information is complex, affected by a wide variety of factors and closely interconnected with the disease condition. Communication to family members takes place according to different patterns and changes along the trajectory of life and illness. Healthcare providers play an important role. ConclusionsSupporting communication of genetic information within family members is a challenging aspect of genetic healthcare and risk communication. Research about communication on genetics is timely and essential to implement interventions that can enhance cascade testing and genetic information for cancer prevention and control in clinical practice and for multilevel public health initiatives. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Mutation spectrum of germline cancer susceptibility genes among unselected Chinese colorectal cancer patients.

Background: Genetic factors play an important role in colorectal cancer (CRC) risk, yet the prevalence and spectrum of germline cancer susceptibility gene mutations among unselected Chinese CRC patients is largely undetermined.Methods: We performed next-generation sequencing with a 73-genes panel and analyzed the prevalence and spectrum of germline mutations in 618 unselected Chinese CRC patients. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations. Clinical characteristics were assessed by age and mutation status. Protein expressions and interactions of MLH1 missense variants were evaluated by western blot and co- immunoprecipitation.Results: Overall, 112 (18.1%) of 618 unselected Chinese CRC patients were found to carry at least one pathogenic or likely pathogenic variant (totaling 97 variants), including 70 (11.3%) Lynch syndrome (LS) mutation carriers and 42 (6.8%) non-LS mutation carriers. LS mutation carriers were significantly younger at CRC diagnosis and were more likely to have right-sided, poorly differentiated, early stage, high-frequency microsatellite instability (MSI-H) or dMMR CRC and a family history of cancer compared with noncarriers. Non-LS mutation carriers were more likely to be proficient mismatch repair (pMMR) than noncarriers (p=0.039). We found four clinical variables (gender, tumor histological stage, cancer stage and mutation status) that showed significant differences between patients younger and older than 50 years old. Higher mutation rates were found in patients under 50 years old (p=0.017). Thirty-three novel variants were discovered and evaluated as pathogenic mutations by our study.Conclusion: Given the high frequency and wide spectrum of mutations, genetic testing with a multigene panel should be considered for all Chinese CRC patients under 50 years old and is also needed to determine whether a gene is associated with CRC susceptibility and to promote clinical translation.

Reducing the Risk of Gynecologic Cancer in Hereditary Breast Ovarian Cancer Syndrome Mutation Carriers: Moral Dilemmas and the Principle of Double Effect.

Hereditary breast ovarian cancer (HBOC) syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in 90 percent of affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives (COCs). Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification of prophylactic surgery and the use of COC to reduce the risk of gynecologic cancer in HBOC syndrome mutation carriers. Summary: Hereditary breast ovarian cancer syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in most affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives. Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification for those unfavorable effects.

Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome.

Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer in Lynch Syndrome mutation carriers

BackgroundThis study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers. MethodsSixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery. ResultsOne of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery. ConclusionRisk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers.

Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types

Background:In Lynch syndrome, inherited mismatch repair (MMR) defects predispose to colorectal cancer and to a wide spectrum of extra-colorectal tumours. Utilising a cohort study design, we aimed to determine the risk of extra-colorectal cancer and to identify yet unrecognised tumour types.Methods:Data from 1624 Lynch syndrome mutation carriers in the Danish hereditary non-polyposis colorectal cancer register were used to estimate the sex- and age-specific incidence rate ratios (IRRs) for 30 extra-colorectal malignancies with comparison to the general population.Results:Significantly increased IRRs were identified for 13 cancer types with differences related to gender, age and disease-predisposing gene. The different cancer types showed variable peak age incidence rates (IRs) with the highest IRs for ovarian cancer at age 30–49 years, for endometrial cancer, breast cancer, renal cell cancer and brain tumours at age 50–69 years, and for urothelial cancer, small bowel cancer, gastric cancer, pancreatic cancer and skin tumours after age 70.Conclusions:The broad spectrum of tumour types that develop at an increased incidence defines Lynch syndrome as a multi-tumour syndrome. The variable incidences in relation to age, gender and gene suggest a need for individualised surveillance.

Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers: Randomized controlled trial.

Lynch syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund-the Netherlands (WCRF-NL) health promotion materials on awareness and knowledge of and adherence to these recommendations. In this randomized controlled trial (n = 226), the intervention group (n = 114) received WCRF-NL health promotion materials. All LS mutation carriers were asked to fill out questionnaires at 2 weeks before (baseline, T0) and at 2 weeks (T1) and 6 months (T2) after the intervention. Linear mixed models were performed on awareness (0-7) and knowledge (0-7) of the recommendations, and on the secondary outcomes, that is adherence, distress, cancer worry, and risk perception. Compared with the control group, the intervention group became significantly more aware (overall mean difference = 1.24; 95%CI = 0.82-1.67) and obtained significantly improved knowledge of the recommendations (overall mean difference = 1.65; 95%CI = 1.27-2.03). Differences were significantly larger for T1 (Pinteraction = .003 and ≤.001, respectively) but remained significant for T2. No effect on secondary outcomes was found. In conclusion, provision of WCRF-NL health promotion materials increases awareness and knowledge of lifestyle recommendations for cancer prevention among LS mutation carriers without causing additional distress, but does not affect adherence.

Quality of life following prophylactic gynecological surgery: experiences of female Lynch mutation carriers.

Lynch syndrome (LS) is a genetic condition conferring an elevated risk of gastrointestinal, gynecologic and other malignancies, often before the age of 50. Current guidelines recommend prophylactic gynecologic surgery to manage inherited cancers for female mutation carriers. Data is lacking on women's quality of life following surgery. In this pilot study, we explored how women described their quality of life post-prophylactic gynecologic surgery and the factors that affected post-surgery experiences. A qualitative interview study was the chosen design. Ten female Lynch syndrome mutation carriers were interviewed by phone. Interviews were transcribed and analysed for themes relating to quality of life post-surgery using content analysis and constant comparison. Women largely reported doing well since their surgeries, though all described deleterious impacts on quality of life. Positive impacts of surgery included a reduction in cancer worry and an increase in healthy lifestyle behaviors, while negative impacts due to the sudden onset of menopause and impact on sexual function were common. Pre-surgical knowledge, drug and topical therapies, and post-surgical support all contributed to a positive quality of life. This small pilot study revealed increased endocrine symptoms and a negative impact on sexual health following prophylactic gynecological surgery. Women who were informed of potential symptoms pre-surgery coped better with surgical outcomes, as did women using some form of HRT. All women experienced reduced cancer worry post-surgery. Findings highlight areas for discussion in pre-operative settings (e.g., sexual health), as well as the need for better follow-up support post-surgery.

1056PD - Preventive dendritic cell vaccination in healthy Lynch syndrome mutation carriers

1056PD - Preventive dendritic cell vaccination in healthy Lynch syndrome mutation carriers

Abstract 5216: Broadening tumor spectrum in Lynch syndrome: increased incidence for 15 distinct cancer types

Abstract Introduction: Lynch syndrome is a multi-tumor syndrome predominantly associated with an increased risk of colorectal cancer, but is indeed linked to a yet uncertain number of extra-colonic tumor types. Methods: In order to determine the risk for extra-colonic tumors in Lynch syndrome, we determined the incidence rates for 21 distinct malignancies in the national Danish Lynch syndrome cohort compared to an age-and sex matched control cohort from the Danish population. Results: Based on data from 1494 Lynch syndrome mutation carriers, significantly increased risks were demonstrated for 15 cancer types. These included Lynch syndrome-related malignancies, such as cancer of the endometrium, the ovary, the small bowel, the urinary tract and brain tumors as well as tumor types with an undefined role in Lynch syndrome, such as breast cancer, gastric cancer, pancreatic cancer, skin cancer, prostate cancer, lung cancer, kidney cancer, and testicular cancer. Distinctive peak ages were defined with the highest incidence rate ratio at age 30-49 years for ovarian cancer and 50-69 years for endometrial cancer, breast cancer, and brain tumors to continuously increasing incidence rate ratios with increasing age for e.g. urothelial cancer, gastric cancer, pancreatic cancer and skin cancer. Conclusion: The broad tumor spectrum in Lynch syndrome is of relevance to consider during genetic counseling, whereas the variable peak incidence ages provide a basis for precision surveillance programs that consider the different risks throughout life. Citation Format: Christina Therkildsen, Steen Ladelund, Lars Joachim Lindberg, Lars Smith-Hansen, Mef Nilbert. Broadening tumor spectrum in Lynch syndrome: increased incidence for 15 distinct cancer types. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5216.

Equivalent Helicobacter pylori infection rates in Lynch syndrome mutation carriers with and without a first-degree relative with gastric cancer.

Patients with Lynch syndrome (LS) are at an increased risk of developing gastric cancer. In 2010, a guideline that recommended to screen all patients for Helicobacter pylori was implemented in the Netherlands. H. pylori is an important risk factor in the development of gastric cancer in the general population, and eradication of the bacterium reduces this risk. We aimed to assess the proportion of LS patients being tested and the yield and also addressed the question whether H. pylori infection is more prevalent in LS families with known cases of gastric cancer. Proven mutation carriers from five different Dutch hospitals were included. The implementation of H. pylori screening and its outcome was examined. The observation period was 2008-2013. The presence of first-degree family members with gastric cancer was noted, and it was observed if H. pylori infection was more prevalent in Lynch families with known cases of gastric cancer. Obtainable endoscopy reports were reviewed. Four hundred forty-three (male, 184) proven mutation carriers were included. The proportion of patients screened increased after 2010, from 37 to 68%. Twenty percent of the patients were infected. The 25 patients who had a first-degree family member with gastric cancer did not have a higher infection rate. In 30% of cases, an endoscopy was performed; in four patients, intestinal metaplasia and in eight patients, gastric cancer was found. The recommendation to screen for H. pylori is increasingly followed. The prevalence of infection in this patient group does not differ from the general population. Patients who had a first-degree family member with gastric cancer did not have a higher infection rate.

Abstract IA44: Cancer prevention: Dendritic cell enhanced immune responses towards neoantigens in patients with Lynch syndrome

Abstract To date, dendritic cell (DC)-based immunotherapy is explored worldwide in clinical vaccination trials with cancer patients. Although during the past 15 years the concept of DC vaccination has been clearly proven and found safe, the number of patients that have long-term benefit is still limited. Therefore the development of bioassays that predict clinical outcome are essential to optimize cellular anticancer immunotherapy. We have developed a robust and simple skin test to evaluate the capacity of tumor-specific T cells to migrate, recognize their targets and exert effector functions. This bioassay detects skin infiltrating T lymphocytes (SKILs) with an elevated antineoplastic potential and hence identifies patients responding to immunotherapy once started. The identification of a biomarker already available before start of treatment would facilitate decision-making regarding (prophylactic) immunotherapy. We recently identified that the ratio between peri/intratumoral T cells in the primary tumor, is an excellent predictor of survival after DC-based immunotherapy in metastatic melanoma patients. Patients with a high density of T cells in primary tumors, hence putative candidates for DC vaccination, are Lynch syndrome patients. They have an up to 80% lifetime risk of colorectal cancer (CRC) due to a germline DNA mismatch-repair gene mutation (Lynch syndrome). MMR deficiency in tumor DNA causes shifts in the translational reading frame resulting in the expression of neoantigens. We exploited these neoantigens for vaccination of Lynch syndrome-associated CRC using DC. Patients were vaccinated with monocyte-derived DC loaded with MHC-class I-binding neoantigens (mutated Caspase-5 and TGF-βRII) and carcinoembryonic antigen (CEA). With our bioassay, we detected SKILs that were able to migrate to the antigen-challenged site, recognize their targets (neoantigens) and exert effector functions shown by high amounts of interferon-γ upon stimulation with neoantigen-loaded target cells. No severe adverse events were detected. Our data emphasize the potency of DC-based immunotherapy to enhance the hosts antitumor immunity. Furthermore, this study paved the way for vaccination aiming at cancer prevention in Lynch syndrome mutation carriers. We recently started a clinical study with the here developed dendritic cells in these lynch syndrome mutation carriers. To date, promising immunological results are noted. Citation Format: Jolanda de Vries, Gerty Schreibelt, Kalijn F. Bol, Harm Westdorp, Steve Boudewijns, Winald R. Gerritsen, Nicoline Hoogerbrugge, Carl G. Figdor. Cancer prevention: Dendritic cell enhanced immune responses towards neoantigens in patients with Lynch syndrome. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA44.

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters.

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients’ age, but not with patients’ gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients’ age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.