Cancer Risk In Lynch Syndrome Research Articles

Ability of a polygenic risk score to refine colorectal cancer risk in Lynch syndrome

BackgroundPolygenic risk scores (PRSs) have been used to stratify colorectal cancer (CRC) risk in the general population, whereas its role in Lynch syndrome (LS), the most common type of hereditary...

Screening and risk reducing surgery for endometrial or ovarian cancers in Lynch syndrome: a systematic review

ObjectiveLynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to...

Colorectal Cancer Risk in Lynch Syndrome: Of Genes and More

Colorectal Cancer Risk in Lynch Syndrome: Of Genes and More

Body Weight, Physical Activity, and Risk of Cancer in Lynch Syndrome.

Simple SummaryLifestyle modifies cancer risk in the general public. How lifestyle modifies cancer risk in individuals carrying the inherited pathogenic gene variants in DNA mismatch repair genes (Lynch syndrome) remains understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, physical activity, and cancer risk among Finnish Lynch syndrome carriers (n = 465, 54% women). The results of our study indicated that longitudinal weight gain increases cancer risk, whereas being highly physically active during adulthood could decrease cancer risk in men. Further, women were observed to be less prone to lifestyle-related risk factors than men. The results emphasize the role of weight maintenance and high-intensity physical activity throughout the lifespan, especially in men with Lynch syndrome.Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00–1.04) and CRC (HR 1.03, 1.01–1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92–0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15–0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.

Ovarian cancer risk in Lynch syndrome: it's time to individualise.

Our understanding of cancer risks associated with Lynch syndrome (LS) has evolved since Dr. Warthin first identified family G in 1913. The current study by Ryan et al provides insight into provider and patient knowledge about gynecologic cancer care options in LS and found that counseling, surveillance, and risk reduction (RR) for these patients vary widely across providers in the UK (BJOG 2020 xxxx). The current study highlights two important points regarding care in LS.

Benefit from extended surveillance interval on colorectal cancer risk in Lynch syndrome.

Although patients with Lynch syndrome have an increased risk of developing colorectal cancer, surveillance can reduce morbidity and mortality. Whether or not affected individuals benefit from lifetime surveillance depends on individual factors and patient adherence, and these may vary, complicating risk modelling. The aim of this study was to identify individual factors which influence patient adherence to surveillance programmes and whether extended surveillance interval influenced their risk of developing colorectal cancer. Demographics and survival data were obtained from patients (n=1223) with Lynch syndrome, identified by interrogating the Danish Hereditary Non-Polyposis Colorectal Cancer Register. These data were linked to patient surveillance interval data which had been divided into three subsets (<27months, adherent to the recommended biennial programme; >27months, extended surveillance interval; and no surveillance) to estimate the cumulative risks and hazard ratios (HRs) for colorectal cancer. In all, 147 colorectal cancers (99 first; 48 metachronous) were identified in 1223 patients. Factors associated with adherence to surveillance were female sex, a previous history of cancer and age <75years. The cumulative incidence for colorectal cancer was 38% (95% CI 27%-50%) for surveillance intervals <27months, 48% (95% CI 29%-67%) for intervals >27months and 72% (95% CI 61%-83%) with no surveillance. Adjusted HRs were 0.22 for surveillance intervals <27months and 0.32 for surveillance intervals >27months. Extended surveillance intervals >27months had a non-significant benefit with an HR of 1.51 (95% CI 0.83-2.75) compared to surveillance intervals <27months. This study demonstrates that adherence to colonoscopic surveillance in Lynch syndrome varies with age, sex and cancer historyand demonstrates a consistent benefit from colorectal cancer surveillance, though it might be lower for individuals with extended intervals.

828 – What's My Risk of Cancer Doctor? Interval Colorectal Cancer Risk in Lynch Syndrome: Results from the New Zealand National Registry

828 – What's My Risk of Cancer Doctor? Interval Colorectal Cancer Risk in Lynch Syndrome: Results from the New Zealand National Registry

Metachronous colorectal cancer risk in Lynch syndrome patients-should the endoscopic surveillance be more intensive?

Regular follow-up for patients with Lynch syndrome (LS) is vital due to the increased risk of colorectal (50-80%), endometrial (40-60%), and other cancers. However, there is an ongoing debate concerning the best interval between colonoscopies. Currently, no specific endoscopic follow-up has been decided for LS patients who already have an index colorectal cancer (CRC). The aim of this study was to evaluate the risk of metachronous cancers (MC) after primary CRC in a LS population and to determinate if endoscopic surveillance should be more intensive. A prospective cohort of patients with a confirmed diagnosis of hereditary CRC since 2009 was included. Patients with LS and a primary CRC were the cohort of choice. One hundred twenty-one patients were included with a median age of 44years(16-70). At least one MC occurred in 39 patients (32.2%), with a median interval of 67months (6-300) from index cancer. Fifteen (38.5%) developed two or more MCs during follow-up, with a median number of two (2-6) tumors occurring. Metachronous CRC were diagnosed after a median interval of 24 (6-57) months since last colonoscopy and were more commonly seen in MSH2 mutation carriers (58 vs. 35%, p = 0.001). After a median follow-up of 52.9 (3-72) months, no cancer-related deaths were recorded. Patients with LS have an increased risk of MC, especially CRCs. With a median time period of 24months between colonoscopy and metachronous CRC, the interval between surveillance colonoscopies following primary CRC should not exceed 18months, especially in patients with MSH2 mutation.

Hereditary Non-polyposis Colorectal Cancer: Prevention and Therapeutic Options

Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common hereditary colorectal cancer (CRC) syndrome. The first and foremost preventive measure is to identify patients with LS among CRC patients. This requires the screening of colorectal cancer through polymerase chain reaction-based microsatellite instability (MSI) testing or immunohistochemistry to look for a loss of expression of one of the mismatch repair (MMR) proteins and the referral of selected patients to genetic counseling. In LS patients, annual or biannual complete colonoscopy with chromoendoscopy is the only validated way to significantly reduce mortality related to CRC with the greatest quality-adjusted life expectancy benefit compared with prophylactic surgery. In the case of diagnosis of colonic cancer, a subtotal colectomy with an ileo-rectal anastomosis is recommended, in order to decrease the risk of metachronous CRC. However, segmental surgery can be discussed on an individual basis. Chemoprevention with aspirin seems to be efficient in decreasing colorectal cancer risk in LS, but the minimum effective dose and potential adverse events associated with long-term use are not yet known. The option of taking low-dose aspirin might be discussed with mutated gene carriers regarding the benefit and risks of the treatment.

Do lifestyle factors influence colorectal cancer risk in Lynch syndrome?

Lynch syndrome (LS) is one of the inherited colorectal cancer (CRC) syndromes and is due to germline mutations in one of the mismatch repair (MMR) genes. Within LS affected-families the expression of the syndrome varies, which suggests that other factors, such as lifestyle factors, have an influence on the LS phenotype. This review gives an overview of studies that assessed the role of lifestyle factors in the development of CRC in LS. Several published studies investigated smoking habits or body fatness (BMI) in relation to colorectal tumours. Those studies fairly consistently suggest that smoking and a high BMI markedly increase the risk of CRC in persons with LS. Other lifestyle factors, such as physical activity, alcohol or diet have not or only scarcely been studied. Lifestyle factors may indeed affect CRC risk in LS. However, more prospective studies with only confirmed MMR gene mutation carriers should be done to further elucidate the role of all lifestyle factors in CRC and in other types of cancer in persons with LS. Information on the role of lifestyle factors in the development of LS-associated cancers may help in establishing lifestyle and dietary recommendations with the ultimate goal of decreasing cancer risk in persons with LS.

Cancer risk in Lynch Syndrome

Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by inactivating mutations in DNA mismatch repair genes. It accounts for 2-4% of all incident colorectal cancers. Mutation carriers are at risk of early onset colorectal cancer, endometrial cancer, and a spectrum of other tumours. Accurate estimation of cancer risk for mutation carriers is essential for counselling, and establishing appropriate screening guidelines. This study reviews the current data on cancer risk, and emerging risk reduction strategies.

Abstract 4842: Hazard ratio for colorectal cancer risk in Lynch syndrome is inversely associated with age.

Abstract Introduction: Carriers of germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) have a high risk of colorectal and other cancers (Lynch syndrome). Between 30% and 70% of carriers will be develop colorectal cancer by age 70 if they are not screened for the disease. What is not well understood is how the effect of mutations, in absolute and relative terms, varies by age. Methods: We conducted a literature review to identify studies of colorectal cancer that estimated age-specific hazard ratios for colorectal cancer for carriers of a mutation in MLH1 or MSH2 compared with the general population. Studies were excluded if they did not adjust correctly for ascertainment. We conducted a random effects meta-analysis to estimate the average age-specific hazard ratio. Annual risk (incidence) by multiplying the population incidence by the age-specific hazard ratio estimated by the meta-analysis. Results: We identified six studies comprising 673 families (282 MLH1, 391 MSH2). All studies observed that the hazard ratio for colorectal cancer was highest at young ages and decreased with age. This pattern was observed for both males and females and for both MLH1 and MSH2 mutation carriers. Overall, the hazard ratio dropped 6-8 fold over three decades (Table). Incidence of colorectal cancer for carriers increased until age 40 years for males and 50 years for females, and then plateaued (Table). Conclusion: At younger ages, in multiplicative terms, the magnitude of the increased risk conferred by the mutations is substantially greater than at older ages. The reason for this age-dependency is not known. It is, however, consistent with a multi-stage model of carcinogenesis for Lynch syndrome. These findings add to the complement of factors that complicate risk estimation for Lynch syndrome including: polygenic effects, non-genetic risk modifiers, and the possibility of a parent-of-origin effect. There is still much to learn about the clinical implications and carcinogenesis of Lynch syndrome. Meta-analysis estimates of hazard ratios and incidences for colorectal cancer by age group. 30-39 year olds 40-49 year olds 50-59 year olds 60-69 year olds Hazard ratio (95%CI): Risk of colorectal cancer in carriers/risk for the general population. Males 120 (60-243) 95 (39-226) 33 (14-78) 14 (4.2-51) Females 80 (42-154) 70 (35-139) 28 (19-41) 14 (7.4-26) Incidence: Proportion of carriers diagnosed with colorectal cancer per year. Males 1 in 146 1 in 50 1 in 39 1 in 38 Females 1 in 490 1 in 135 1 in 69 1 in 61 Citation Format: Mark A. Jenkins, Aung Ko Win, James G. Dowty, John D. Mathews, John L. Hopper. Hazard ratio for colorectal cancer risk in Lynch syndrome is inversely associated with age. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4842. doi:10.1158/1538-7445.AM2013-4842

Elevated Risk of Prostate Cancer Among Men With Lynch Syndrome

Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous studies quantifying prostate cancer risk in LS have provided conflicting results. We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population. Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03). The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.

Genetic modifiers of cancer risk in Lynch syndrome: a review

The report by Aldred Scott Warthin in 1913 of a cancer family history and expanded on by Henry T. Lynch demonstrated one of the most enduring traits observed in patients with Lynch syndrome. The recognition of a variety of malignancies occurring at differing ages within a single family suggested the role of genetic variance on disease expression in an autosomal dominantly inherited genetic condition. With the identification of the genetic basis of Lynch syndrome and the subsequent collection of families and their medical records it has become possible to identify subtle genetic effects that influence the age at which disease onset occurs in this cancer predisposition. Knowledge about genetic modifiers influencing disease expression has the potential to be used to personalise prophylactic screening measures to maximise the benefits for family members and their carers.

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative riskLSca<45_AA=2.90; 95% confidence interval=1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.

Chromosome 8q23.3, 10p14 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome – a combined analysis of the Australian, Dutch and Polish Lynch syndrome cohorts

Background For a decade researchers have been searching for modifier genes in individuals with a molecular diagnosis of Lynch syndrome but the task has proven difficult as discordant results seem to be the rule rather than the exception. Recently, two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome patients irrespective of which gene was mutated. In a combined study of CRC risk in Australian and Polish Lynch syndrome patients only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three datasets was performed to better define this association.

Report From the Jerusalem Workshop on Lynch Syndrome-Hereditary Nonpolyposis Colorectal Cancer

A Workshop was held in Jerusalem, Israel, on October 26 and 27, 2009 to discuss the management of Lynch syndrome-hereditary nonpolyposis colorectal cancer (CRC), with the primary goal to develop consensus for the optimal management of this disease. A second goal was to identify areas of research with the potential to advance the clinical management of Lynch syndrome. The perspectives and recommendations from the workshop are meant to be a platform for discussion and deliberation. The Workshop was organized by Moshe Shike (Memorial Sloan Kettering Cancer Center, New York) and sponsored by The Colon Cancer Foundation. More details of each presentation are available in an on-line supplement.

Abstract A124: Genome-wide association identified susceptibility loci as modifiers of colorectal cancer risk in Lynch syndrome

Abstract Purpose: The purpose of this study was to determine whether 5 common low-penetrance variants identified in recent genome-wide association studies (GWAS) for colorectal cancer modify colorectal cancer risk in people with Lynch syndrome. People with Lynch syndrome are genetically predisposed to colorectal cancer owing to an inherited DNA mismatch repair (MMR) gene mutation; however, disease expression varies, pointing to the role of modifying factors. A study of Dutch Lynch syndrome families (Wijnen et al., 2009) examined 6 GWAS-identified markers and found that 2 of them—rs16892766 (8q23.3) and rs3802842 (11q23.1)—were associated with colorectal cancer risk. However, other risk variants have yet to be characterized in Lynch syndrome. A replication study of 3 markers in subjects enrolled irrespective of whether they were MMR gene mutation carriers (Poynter et al., 2007) found that 2 risk variants in the 8q24 region (rs10505477 and rs6983267) and 1 variant in the 9p24 region (rs719725) were associated with colorectal cancer risk. Methods: In a retrospective cohort study, we analyzed 278 people with Lynch syndrome and a confirmed MMR gene mutation from the M. D. Anderson Lynch syndrome registry. We genotyped the 5 aforementioned risk variants—rs16892766, rs3802842, rs10505477, rs6983267, and rs719725—and analyzed the association between each risk variant and colorectal cancer using Cox proportional hazards regression while adjusting for sex, MMR gene mutation status, and familial correlation. Results: Of the 278 subjects from 128 families with 11,702 person years of follow-up, 146 subjects had colorectal cancer, and the remaining subjects were unaffected. In a codominant model, rs16892766 was significantly associated with colorectal cancer (hazard ratio [HR]: 1.61; 95% confidence interval [CI]: 1.10–2.35). Similarly, rs3802842 exhibited a marginally significant trend in an additive model (Ptrend = 0.07), and the association was most clearly evident among carriers of mutations in the MLH1 MMR gene in a codominant model (HR: 1.98; 95% CI: 1.18–3.33). Conclusion: Our study replicates the previous finding of an association between 2 GWAS-identified susceptibility loci and risk of colorectal cancer in people with Lynch syndrome. Although people with Lynch syndrome have a strong predisposition to colorectal cancer due to the underlying MMR mutation, these common genetic variants may further modify their colorectal cancer risk, particularly in carriers of multiple risk alleles. These and other low-penetrance susceptibility loci are likely to have future application in personalized risk prediction in identifying individuals who are most susceptible so that they can be provided more rigorous cancer-prevention strategies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A124.

Genome wide association identified colorectal cancer susceptibility loci and colorectal cancer risk in Lynch syndrome

Background Recent genome-wide association studies (GWAS) have identified several common low-risk variants for colorectal cancer. Although some of the GWAS were enriched for young onset and family history positive colorectal cancer cases, it is not clear if these variants modify colorectal cancer risk for people with Lynch syndrome. In a case-unaffected sibling analysis of population and clinic based sibships, a study by Poynter et al. (2007) found a stronger association for risk variants in the 8q24 region (rs10505477 and rs6983627) with microsatellite instability (MSI)-high tumors. MSI-high tumors are characteristic of Lynch syndrome. Therefore we hypothesize that these variants may also influence colorectal cancer risk in Lynch syndrome. Recently Wijnen et al. (2009) have reported on some of the GWAS risk variants in Dutch Lynch syndrome families and although they did not find an association between rs6983627 and colorectal cancer risk, other risk variants in 8q24 and 9p24 have yet to be characterized in Lynch syndrome.

Small bowel cancer risk in Lynch syndrome

<h3>Background</h3> Paraneoplastic neurological syndromes are usually associated with small cell lung cancer, gynaecological, lymphomas and renal cell carcinomas. A few studies report the association of neurological syndromes with squamous cell...