Multiple colorectal adenomas in Lynch syndrome

Jain, Ayushi; Alimirah, Maryam; Hampel, Heather; Pearlman, Rachel; Ma, Jianing; Peng, Jing; Kalady, Matthew F.; Stanich, Peter P.

doi:10.3389/fonc.2022.1038678

Cited by 3 publications

(3 citation statements)

References 14 publications

(17 reference statements)

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“…Elevated adenoma burden has been shown in about 6% of LS patients, and multiple cumulative adenomas are particularly observed in carriers of pathogenic MSH6 and PMS2 gene variants as well as individuals with CMMRD ( 8 , 34 , 35 ). Understanding the history of adenomas of LS patients is important as those with > 10 cumulative adenomas are much likelier to develop advanced neoplasia ( 8 , 34 ). Familial risk for tumor multiplicity has been proposed before and some polygenic factors have been identified ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…The Amsterdam criteria, used as an aid in the clinical diagnosis of LS, draws heavily on the family history of CRC, but additionally states the need for the absence of polyps to distinguish LS from familial adenomatous polyposis (FAP) (3,4). Although the cumulative lifetime adenoma burden of LS patients generally stays below ten, recent data has shown that LS may manifest with an elevated polyp count, and that individuals with pathogenic germline variants in different genes may undergo gene-specific tumorigenesis (5)(6)(7)(8)(9), creating difficulties for diagnosis. LS patients with an elevated adenoma count are additionally significantly more likely to have an advanced colorectal neoplasia (8).…”

Section: Introductionmentioning

confidence: 99%

“…Although the cumulative lifetime adenoma burden of LS patients generally stays below ten, recent data has shown that LS may manifest with an elevated polyp count, and that individuals with pathogenic germline variants in different genes may undergo gene-specific tumorigenesis (5)(6)(7)(8)(9), creating difficulties for diagnosis. LS patients with an elevated adenoma count are additionally significantly more likely to have an advanced colorectal neoplasia (8).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

Olkinuora,

Mäki-Nevala,

Ukwattage

et al. 2024

Front. Oncol.

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BackgroundLynch syndrome (LS) is an autosomal dominant multi-organ cancer syndrome with a high lifetime risk of cancer. The number of cumulative colorectal adenomas in LS does not generally exceed ten, and removal of adenomas via routine screening minimizes the cancer burden. However, abnormal phenotypes may mislead initial diagnosis and subsequently cause suboptimal treatment.AimCurrently, there is no standard guide for the care of multiple colorectal adenomas in LS individuals. We aimed to shed insight into the molecular features and reasons for multiplicity of adenomas in LS patients.MethodsWe applied whole exome sequencing on nine adenomas (ten samples) and three assumed primary carcinomas (five samples) of an LS patient developing the tumors during a 21-year follow-up period. We compared the findings to the tumor profiles of two additional LS cases ascertained through colorectal tumor multiplicity, as well as to ten adenomas and 15 carcinomas from 23 unrelated LS patients with no elevated adenoma burden from the same population. As LS associated cancers can arise via several molecular pathways, we also profiled the tumors for CpG Island Methylator Phenotype (CIMP), and LINE-1 methylation.ResultsAll tumors were microsatellite unstable (MSI), and MSI was present in several samples derived from normal mucosa as well. Interestingly, frequent frameshift variants in RNF43 were shared among substantial number of the tumors of our primary case and the tumors of LS cases with multiple tumors but almost absent in our control LS cases. The RNF43 variants were completely absent in the normal tissue, indicating tumor-associated mutational hotspots. The RNF43 status correlated with the mutational signature SBS96. Contrary to LS tumors from the reference set with no elevated colorectal tumor burden, the somatic variants occurred significantly more frequently at C>T in the CpG context, irrespective of CIMP or LINE-1 status, potentially indicating other, yet unknown methylation-related mechanisms. There were no signs of somatic mosaicism affecting the MMR genes. Somatic variants in APC and CTNNB1 were unique to each tumor.ConclusionFrequent somatic RNF43 hot spot variants combined with SBS96 signature and increased tendency to DNA methylation may contribute to tumor multiplicity in LS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

Olkinuora,

Mäki-Nevala,

Ukwattage

et al. 2024

Front. Oncol.

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Biopsie colique et pathologie néoplasique épithéliale en pratique

Chatelain

2023

Revue Francophone des Laboratoires

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Understanding tumour endothelial cell heterogeneity and function from single-cell omics

et al. 2023

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Anti-angiogenic therapies (AATs) are used to treat different types of cancers. However, their success is limited due to insufficient efficacy and resistance. Recently, single-cell omics studies of tumour endothelial cells (TECs) have provided new mechanistic insight. Here, we overview the heterogeneity of human TECs of all tumour types studied to date, at the single cell level. Notably, most human tumour types contain varying numbers but only a small population of angiogenic TECs, the presumed targets of AATs, possibly contributing to the limited efficacy of and resistance to AATs. In general, TECs are heterogeneous within and across all tumour types, but comparing TEC phenotypes across tumours is currently challenging, due to lack of a uniform nomenclature for endothelial cells and consistent single cell analysis protocols, urgently raising the need for a more consistent approach. Nonetheless, across most tumour types, universal TEC markers (ACKR1, PLVAP, IGFBP3) can be identified. Besides angiogenesis, biological processes such as immunomodulation and extracellular matrix (ECM) organization are among the most commonly predicted enriched signatures of TECs across different tumour types.While angiogenesis and ECM targets have been considered for AAT (without the hoped success), the immunomodulatory properties of TECs have not been fully considered as a novel anti-cancer therapeutic approach. Therefore, we also discuss progress, limitations, solutions and novel targets for AAT development.

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Multiple colorectal adenomas in Lynch syndrome

Cited by 3 publications

References 14 publications

Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

Novel insights into tumorigenesis revealed by molecular analysis of Lynch syndrome cases with multiple colorectal tumors

Biopsie colique et pathologie néoplasique épithéliale en pratique

Understanding tumour endothelial cell heterogeneity and function from single-cell omics

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