Dataset Information

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

ABSTRACT:

Purpose

Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.

Methods

We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

Results

There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.

Conclusion

Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

SUBMITTER: Dominguez-Valentin M

PROVIDER: S-EPMC7371626 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Dominguez-Valentin Mev M Sampson Julian R JR Seppälä Toni T TT Ten Broeke Sanne W SW Plazzer John-Paul JP Nakken Sigve S Engel Christoph C Aretz Stefan S Jenkins Mark A MA Sunde Lone L Bernstein Inge I Capella Gabriel G Balaguer Francesc F Thomas Huw H Evans D Gareth DG Burn John J Greenblatt Marc M Hovig Eivind E de Vos Tot Nederveen Cappel Wouter H WH Sijmons Rolf H RH Bertario Lucio L Tibiletti Maria Grazia MG Cavestro Giulia Martina GM Lindblom Annika A Della Valle Adriana A Lopez-Köstner Francisco F Gluck Nathan N Katz Lior H LH Heinimann Karl K Vaccaro Carlos A CA Büttner Reinhard R Görgens Heike H Holinski-Feder Elke E Morak Monika M Holzapfel Stefanie S Hüneburg Robert R Knebel Doeberitz Magnus von MV Loeffler Markus M Rahner Nils N Schackert Hans K HK Steinke-Lange Verena V Schmiegel Wolff W Vangala Deepak D Pylvänäinen Kirsi K Renkonen-Sinisalo Laura L Hopper John L JL Win Aung Ko AK Haile Robert W RW Lindor Noralane M NM Gallinger Steven S Le Marchand Loïc L Newcomb Polly A PA Figueiredo Jane C JC Thibodeau Stephen N SN Wadt Karin K Therkildsen Christina C Okkels Henrik H Ketabi Zohreh Z Moreira Leticia L Sánchez Ariadna A Serra-Burriel Miquel M Pineda Marta M Navarro Matilde M Blanco Ignacio I Green Kate K Lalloo Fiona F Crosbie Emma J EJ Hill James J Denton Oliver G OG Frayling Ian M IM Rødland Einar Andreas EA Vasen Hans H Mints Miriam M Neffa Florencia F Esperon Patricia P Alvarez Karin K Kariv Revital R Rosner Guy G Pinero Tamara Alejandra TA Gonzalez María Laura ML Kalfayan Pablo P Tjandra Douglas D Winship Ingrid M IM Macrae Finlay F Möslein Gabriela G Mecklin Jukka-Pekka JP Nielsen Maartje M Møller Pål P

Genetics in medicine : official journal of the American College of Medical Genetics 20190724 1

<h4>Purpose</h4>Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.<h4>Methods</h4>We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were ...[more]

PMID: 31337882

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Project description:BackgroundThe Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.MethodsThe PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.FindingsGynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.InterpretationIn path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome.FundingWe acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Dataset Information

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Purpose

Methods

Results

Conclusion

Publications

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

Similar Datasets

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