The coding microsatellite mutation profile of PMS2-deficient colorectal cancer

Broeke, Sanne W. Bajwa ten; Ballhausen, Alexej; Ahadova, Aysel; Suerink, Manon; Bohaumilitzky, Lena; Seidler, Florian; Morreau, Hans; Wezel, Tom van; Krzykalla, Julia; Benner, Axel; Miranda, Noel F C C de; Doeberitz, Magnus von Knebel; Nielsen, Maartje; Kloor, Matthias

doi:10.1016/j.yexmp.2021.104668

Cited by 10 publications

(6 citation statements)

References 25 publications

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“…Secondly, as discussed above, the role of dPMS2 in tumour development seems to be confirmed by molecular studies and could result in increased adenoma progression to CRC ( 50 ). For the moment, the clinical and molecular characteristics together support the existence of colonoscopy guidelines for path_PMS2 carriers.…”

Section: Pastmentioning

confidence: 80%

“…Investigations of cancer-preventive effects of the FSP vaccine in LS carriers remain to be planned, but recent results from a LS mouse model demonstrated that FSP vaccines can reduce tumour burden and improve survival (73). The presence of a similar cMSI spectrum, and thus of FSPs for dPMS2 tumours (as compared to dMLH1 or dMSH2 tumours), could be reassuring for the expected efficacy of FSP-based vaccines (50). However, the effect of lower immune infiltration remains to be seen.…”

Section: Vaccination Strategiesmentioning

confidence: 99%

“…Another approach to investigate differences between molecular pathways in the different subgroups of path_MMR carriers is to study the coding microsatellite instability (cMSI) spectrum ( 50 ). Our group therefore performed a second tumour study analysing 16 dPMS2 CRCs from confirmed path_PMS2 carriers.…”

Section: Pastmentioning

confidence: 99%

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PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

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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.

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Section: Pastmentioning

confidence: 80%

Section: Vaccination Strategiesmentioning

confidence: 99%

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PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

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“…Consistent with PPd, which is characterized by a very high mutation load [ 41 ], both tumors were ultra-mutated (TMB: 278 and 319 Mut/Mb for the brother’s and sister’s tumor, respectively). In addition, both tumors have a high proportion of short-tandem-repeat variants, i.e., 27% and 23% for the brother’s and sister’s tumor, respectively, which is typical for ( PMS2 -associated) MSI tumors [ 41 , 42 ] ( Figure 3 A,B). A high contribution of signature SBS20 in both tumors (38% and 15% in the brother‘s and sister’s tumor, respectively) is in agreement with combined MMR and Pol δ proofreading deficiency ( Figure 3 C).…”

Section: Resultsmentioning

confidence: 99%

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

et al. 2022

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Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol ẟ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd.

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“…The probabilities for such crypts persisting, disappearing or developing into infiltrating cancers are not known. The biology of CRC in path_PMS2 carriers may be different from carriers of the pathogenic variants of the other genes [26,27].…”

Section: Discussionmentioning

confidence: 99%

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Møller

Seppälä

Dowty

et al. 2022

Hered Cancer Clin Pract

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Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

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The coding microsatellite mutation profile of PMS2-deficient colorectal cancer

Cited by 10 publications

References 25 publications

PMS2-associated Lynch syndrome: Past, present and future

PMS2-associated Lynch syndrome: Past, present and future

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

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