Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Yurgelun

CA A Cancer J Clinicians

2018

136

106

The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

Section: Epidemiology Of Lynch Syndromementioning

confidence: 97%

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

Yurgelun

CA A Cancer J Clinicians

2018

136

106

“…Recent molecular advances have made it possible to distinguish another group of MSI‐H cancers designated as Lynch‐like syndrome (LLS) . Neither MLH1 promoter methylation nor germline mutations (LS) explain LLS tumors; instead, two somatic mutational events inactivating a given MMR gene are detectable in more than half of LLS tumors . Apart from MMR genes, the broader somatic mutational profiles of LLS tumors are unknown and only limited information is available of the clinicopathological characteristics and the incidence of LLS in the population …”

Section: Introductionmentioning

confidence: 99%

Epidemiological, clinical and molecular characterization of Lynch‐like syndrome: A population‐based study

Porkka

Lahtinen

Ahtiainen

et al. 2019

Intl Journal of Cancer

Colorectal carcinomas that are mismatch repair (MMR)‐deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch‐like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000–2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer‐relevant genes. Among 107 MMR‐deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E‐negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP‐positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population‐based study design. Significantly more frequent CIMP‐positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1‐methylated colorectal carcinomas with CIMP‐positive phenotype.

Journal of Genetic Counseling

“…These cancers include colorectal, endometrial, ovarian, urothelial, small intestine, stomach, hepatobiliary, brain, and sebaceous cancers (Win et al, ). Prevalence of LS in the general population also varies, but it has been estimated that 1/200–1/400 individuals may carry a germline MMR pathogenic variant (Chen et al, ; Haraldsdottir et al, ). Identifying indviduals with LS to implement cancer surveillance such as routine colonoscopy and opportunities for preventative surgery, including prophylactic hysterectomy and bilateral salpingoophorectomy, is important (Gupta et al, ).…”

Section: Introductionmentioning

confidence: 99%

The impact of health anxiety on perceptions of personal and children’s health in parents with Lynch syndrome

Albiani

McShane

Holter

et al. 2019

This study examined the differences in perceptions of one's health and one's child's health between parents with Lynch syndrome (LS) characterized with high versus low health anxiety. Twenty‐one parents completed semistructured telephone interviews about their perceptions of their own health and the health of their children. Qualitative content analysis using a template coding approach examined the differences between parents with high and low health anxiety. Findings revealed that the most prevalent difference emerged on perceptions of personal health, showing individuals with high health anxiety reported more extreme worries, were more hypervigilant about physical symptoms, experienced the emotional and psychological consequences of LS as more negative and severe, and engaged in more dysfunctional coping strategies than those with low health anxiety. Unexpectedly, with regards to perceptions of their children, parents in the high and low health anxiety groups exhibited similar worries. However, high health anxiety parents reported using dysfunctional coping about their children's health more frequently than those with low health anxiety. The findings suggest that health anxiety is of clinical significance for individuals with LS. Accurately identifying and treating health anxiety among this population may be one avenue to reduce the distress experienced by LS carriers.