Noncoding Aberrations in Mismatch Repair Genes Underlie a Substantial Part of the Missing Heritability in Lynch Syndrome

Paske, Iris B A W Te; Mensenkamp, Arjen R.; Neveling, Kornelia; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J. L.; Voer, Richarda M. de; Baert‐Desurmont, Stéphanie; Claes, Kathleen; Leeneer, Kim De; Elze, Lisa; Heuvel, Simone van den; Post, Rachel S. van der; Twuijver, Yvonne van; Ham, Tjakko J. van; Wagner, Anja; Jong, Mirjam M. de; Leter, Edward M; Nielsen, Maartje

doi:10.1053/j.gastro.2022.08.041

Cited by 13 publications

(20 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, long-range sequencing later detected an intronic PV c.2458 + 976A>G in this patient (patient LLP004). 17 These innovative diagnostics also resulted in MLH1 PV c.306 + 1001_307-642delinsTA detection in patient 1947 (patient LP0032). 17 …”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Unexplained mismatch repair deficiency: Case closed

Eikenboom

Moen

Leeuwen

et al. 2023

Human Genetics and Genomics Advances

Self Cite

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

“… 17 These innovative diagnostics also resulted in MLH1 PV c.306 + 1001_307-642delinsTA detection in patient 1947 (patient LP0032). 17 …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Unexplained mismatch repair deficiency: Case closed

Eikenboom

Moen

Leeuwen

et al. 2023

Human Genetics and Genomics Advances

Self Cite

View full text Add to dashboard Cite

“…In the past this would mean that first-degree relatives should be offered a LS-like surveillance scheme. We suggest using new techniques to look for a missed germline variant, such as ultra-long-read sequencing to look for deep intronic variants (or exon deletions), which were recently described as an explanation for part of the missing heritability in up to almost 20% of LS-like cases ( 63 ). If such analyses also fail to reveal a germline variant, we would not advise additional screening of the colon or endometrium for relatives as the explanation of the dMMR would most likely be somatic.…”

Section: Presentmentioning

confidence: 99%

“…As mentioned in discussion of Case 5, new methods of MMR gene analyses are now available. Ultra-long-read sequencing with reads up to 100 kb could increase the proportion of LS families identified through more efficient detection of both larger deletions and noncoding, deep intronic variants ( 63 – 65 ). The introduction of these strategies is very relevant for PMS2 because it makes circumvention of pseudogenes much more straightforward ( 66 ).…”

Section: Futurementioning

confidence: 99%

PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

Self Cite

View full text Add to dashboard Cite

Carriers of any pathogenic variant in one of the MMR genes (path_MMR carriers) were traditionally thought to be at comparable risk of developing a range of different malignancies, foremost colorectal cancer (CRC) and endometrial cancer. However, it is now widely accepted that their cancer risk and cancer spectrum range notably depending on which MMR gene is affected. Moreover, there is increasing evidence that the MMR gene affected also influences the molecular pathogenesis of Lynch syndrome CRC. Although substantial progress has been made over the past decade in understanding these differences, many questions remain unanswered, especially pertaining to path_PMS2 carriers. Recent findings show that, while the cancer risk is relatively low, PMS2-deficient CRCs tend to show more aggressive behaviour and have a worse prognosis than other MMR-deficient CRCs. This, together with lower intratumoral immune infiltration, suggests that PMS2-deficient CRCs might have more in common biologically with sporadic MMR-proficient CRCs than with other MMR-deficient CRCs. These findings could have important consequences for surveillance, chemoprevention and therapeutic strategies (e.g. vaccines). In this review we discuss the current knowledge, current (clinical) challenges and knowledge gaps that should be targeted by future studies.

show abstract

Associations between pathological features and risk of metachronous colorectal cancer

Zhang,

Win,

Makalic

et al. 2024

Intl Journal of Cancer

View full text Add to dashboard Cite

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.

show abstract

Noncoding Aberrations in Mismatch Repair Genes Underlie a Substantial Part of the Missing Heritability in Lynch Syndrome

Cited by 13 publications

References 12 publications

Unexplained mismatch repair deficiency: Case closed

Unexplained mismatch repair deficiency: Case closed

PMS2-associated Lynch syndrome: Past, present and future

Associations between pathological features and risk of metachronous colorectal cancer

Contact Info

Product

Resources

About