Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report
Seppälä, T. T., Ahadova, A., Dominguez-Valentin, M., Macrae, F., Evans, D. G., Therkildsen, C., Sampson, J., Scott, R., Burn, J., Möslein, G., Bernstein, I., Holinski-Feder, E., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepistö, A., Lautrup, C. K., Lindblom, A., Plazzer, J.-P., Winship, I., . . . Møller, P. (2019). Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report. Hereditary Cancer in Clinical Practice, 17, Article 8. https://doi.org/10.1186/s13053-019-0106-8
Julkaistu sarjassaHereditary Cancer in Clinical Practice
© The Author(s). 2019
Background Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5–2.5, 2.5–3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers. ...
JulkaisijaBioMed Central Ltd.
tähystys colonoscopy colorectal cancer hereditary cancer hereditary nonpolyposis colorectal cancer microsatellite instability mismatch repair over-diagnosis screening syöpätaudit perinnölliset taudit suolistosyövät Lynchin oireyhtymä diagnostiikka seulontatutkimus endoskopia koloskopia DNA mikrosatelliitit tarkkailu
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The “unnatural” history of colorectal cancer in Lynch syndrome : lessons from colonoscopy surveillance Ahadova, Aysel; Seppälä, Toni T.; Engel, Christoph; Gallon, Richard; Burn, John; Holinski‐Feder, Elke; Steinke‐Lange, Verena; Möslein, Gabriela; Nielsen, Maartje; ten Broeke, Sanne; Laghi, Luigi; Dominguez‐Valentin, Mev; Capella, Gabriel; Macrae, Finlay; Scott, Rodney; Hüneburg, Robert; Nattermann, Jacob; Hoffmeister, Michael; Brenner, Hermann; Bläker, Hendrik; von Knebel Doeberit,z Magnus; Sampson, Julian R.; Vasen, Hans; Mecklin, Jukka‐Pekka; Møller, Pål; Kloor, Matthias (Wiley, 2021)Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is ...
Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance Ahadova, Aysel; Pfuderer, Pauline Luise; Ahtiainen, Maarit; Ballhausen, Alexej; Bohaumilitzky, Lena; Kösegi, Svenja; Müller, Nico; Tang, Yee Lin; Kosmalla, Kosima; Witt, Johannes; Endris, Volker; Stenzinger, Albrecht; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Renkonen-Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin, Jukka-Pekka; Seppälä, Toni T.; Kloor, Matthias (MDPI AG, 2021)Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident ...
Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer Mäki‐Nevala, Satu; Ukwattage, Sanjeevi; Olkinuora, Alisa; Almusa, Henrikki; Ahtiainen, Maarit; Ristimäki, Ari; Seppälä, Toni; Lepistö, Anna; Mecklin, Jukka‐Pekka; Peltomäki, Päivi (John Wiley & Sons, 2021)Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis‐associated colorectal carcinomas ...
DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression Mäki-Nevala, Satu; Valo, Satu; Ristimäki, Ari; Sarhadi, Virinder; Knuutila, Sakari; Nyström, Minna; Renkonen-Sinisalo, Laura; Lepistö, Anna; Mecklin, Jukka-Pekka; Peltomäki, Päivi (Elsevier BV, 2019)Background DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR ...
Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants : a Prospective Lynch Syndrome Database report Dominguez-Valentin, Mev; Crosbie, Emma J.; Engel, Christoph; Aretz, Stefan; Macrae, Finlay; Winship, Ingrid; Capella, Gabriel; Thomas, Huw; Nakken, Sigve; Hovig, Eivind; Nielsen, Maartje; Sijmons, Rolf H.; Bertario, Lucio; Bonanni, Bernardo; Tibiletti, Maria Grazia; Cavestro, Giulia Martina; Mints, Miriam; Gluck, Nathan; Katz, Lior; Heinimann, Karl; Vaccaro, Carlos A.; Green, Kate; Lalloo, Fiona; Hill, James; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Strauß, Hans-Georg; Tecklenburg, Johanna; Holinski-Feder, Elke; Steinke-Lange, Verena; Mecklin, Jukka-Pekka; Plazzer, John-Paul; Pineda, Marta; Navarro, Matilde; Vidal, Joan Brunet; Kariv, Revital; Rosner, Guy; Piñero, Tamara Alejandra; Gonzalez, María Laura; Kalfayan, Pablo; Ryan, Neil; ten Broeke, Sanne W.; Jenkins, Mark A.; Sunde, Lone; Bernstein, Inge; Burn, John; Greenblatt, Marc; de Vos tot Nederveen Cappel, Wouter H.; Della, Valle Adriana; Lopez-Koestner, Francisco; Alvarez, Karin; Büttner, Reinhard; Görgens, Heike; Morak, Monika; Holzapfel, Stefanie; Hüneburg, Robert; von Knebel, Doeberitz Magnus; Loeffler, Markus; Rahner, Nils; Weitz, Jürgen; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Auranen, Annika; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane M.; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane C.; Thibodeau, Stephen N.; Therkildsen, Christina; Okkels, Henrik; Ketabi, Zohreh; Denton, Oliver G.; Rødland, Einar Andreas; Vasen, Hans; Neffa, Florencia; Esperon, Patricia; Tjandra, Douglas; Möslein, Gabriela; Sampson, Julian R.; Evans, D. Gareth; Seppälä, Toni T.; Møller, Pål (Nature Publishing Group, 2021)Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. Methods The ...