Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome

Hemminger, Jessica; Pearlman, Rachel; Haraldsdóttir, Sigurdís; Knight, Deborah; Jonasson, Jón G.; Pritchard, Colin C.; Hampel, Heather; Frankel, Wendy L.

doi:10.1016/j.humpath.2018.04.017

Cited by 30 publications

(25 citation statements)

References 25 publications

(41 reference statements)

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“… and our study) or histological (Refs. and our study) grounds. The novel epigenetic and genetic features we describe for LLS colorectal carcinomas can aid in the recognition of LLS as a separate entity.…”

Section: Discussionsupporting

confidence: 63%

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

Porkka

Lahtinen

Ahtiainen

et al. 2019

Intl Journal of Cancer

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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.

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Section: Discussionsupporting

confidence: 63%

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

Porkka

Lahtinen

Ahtiainen

et al. 2019

Intl Journal of Cancer

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“…Additionally, as previously reported, there are no clinical or histopathological characteristics that can help differentiate between potentially hereditary or sporadic cases [10,26]; neither family history nor age at diagnosis can differentiate between cases, and with no accepted and validated molecular tool for making this distinction, LLS patients and families must be managed as a group. Moreover, in previous studies that also used somatic mutations to classify LLS patients as hereditary or sporadic, authors did not find any clinical or pathological characteristics that were able to differentiate between the two populations [27,28].…”

Section: Discussionmentioning

confidence: 91%

Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome

Picó

Sánchez-Heras

Castillejo

et al. 2020

Cancers

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Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

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“…Biallelic somatic MMR mutations cannot be differentiated from LS using tumor pathology, MSI analysis, or IHC staining, so patients with UMMRD introduce challenges to risk assessment and clinical recommendations (Haraldsdottir et al, ; Hemminger et al, ). However, next‐generation sequencing has led to more frequent utilization of tumor profiling to identify somatic mutations (Hampel et al, ; Pritchard et al, ; Varga, Chao, & Yeager, ) and can be applied to LS tumors as an additional risk assessment tool.…”

Section: Introductionmentioning

confidence: 99%

Somatic mismatch repair testing in evaluation of Lynch syndrome: The gap between preferred and current practices

Williams

Vilar

Hashmi

et al. 2020

Journal of Genetic Counseling

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Lynch syndrome (LS) is a hereditary cancer predisposition syndrome primarily defined by increased risk for colorectal and uterine cancers. Individuals with germline pathogenic variants in the mismatch repair (MMR) genes (MLH1, MSH2/EPCAM, MSH6, and PMS2) are diagnosed with LS and recommended high-risk screening protocols to increase prevention and early detection of LS-related cancers. Tumor testing can help identify those at high risk for LS, but sometimes creates uncertainty with discordant screening and germline results, or unexplained mismatch repair deficiency (UMMRD). Somatic testing for MMR genes may help resolve UMMRD, potentially clarifying LS status and modifying cancer surveillance. However, guidelines for such testing are currently limited. This survey of cancer genetic counselors (GCs) aimed to examine current versus preferred ordering practices and interpretation of somatic MMR testing results in LS evaluation. Two hundred eligible GCs practicing in the United States and Canada were recruited from the National Society of Genetic Counselors. Participants answered questions regarding ordering practices, barriers to somatic MMR testing, theoretical scenarios, and desire for further guidelines. Statistical analysis was performed using chi-square, Fisher's exact, and Wilcoxon rank-sum tests, while themes were identified from free-text responses. Most respondents did not include somatic MMR testing in the LS work-up, despite three-quarters reporting they were 'somewhat comfortable' or 'extremely comfortable' with interpreting these results. Approximately half of participants indicated interest in ordering concurrent somatic MMR and germline testing for each of the four theoretical scenarios. Over three-quarters of individuals reported barriers to ordering somatic MMR testing, with cost and coordinating tissue samples most commonly cited. The frequently reported laboratory-and insurance-related barriers may contribute to the gap between preferred and current ordering practices for somatic MMR testing. Nearly all respondents endorsed additional guidelines for this testing, which could reduce barriers and inform screening recommendations for patients with UMMRD and their family members.

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Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome

Cited by 30 publications

References 25 publications

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

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

Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome

Somatic mismatch repair testing in evaluation of Lynch syndrome: The gap between preferred and current practices

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