Dataset Information

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

ABSTRACT:

Purpose

Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.

Patients and methods

Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.

Results

A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years.

Conclusion

Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

SUBMITTER: Durno C

PROVIDER: S-EPMC8407605 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

Durno Carol C Ercan Ayse Bahar AB Bianchi Vanessa V Edwards Melissa M Aronson Melyssa M Galati Melissa M Atenafu Eshetu G EG Abebe-Campino Gadi G Al-Battashi Abeer A Alharbi Musa M Azad Vahid Fallah VF Baris Hagit N HN Basel Donald D Bedgood Raymond R Bendel Anne A Ben-Shachar Shay S Blumenthal Deborah T DT Blundell Maude M Bornhorst Miriam M Bronsema Annika A Cairney Elizabeth E Rhode Sara S Caspi Shani S Chamdin Aghiad A Chiaravalli Stefano S Constantini Shlomi S Crooks Bruce B Das Anirban A Dvir Rina R Farah Roula R Foulkes William D WD Frenkel Zehavit Z Gallinger Bailey B Gardner Sharon S Gass David D Ghalibafian Mithra M Gilpin Catherine C Goldberg Yael Y Goudie Catherine C Hamid Syed Ahmer SA Hampel Heather H Hansford Jordan R JR Harlos Craig C Hijiya Nobuko N Hsu Saunders S Kamihara Junne J Kebudi Rejin R Knipstein Jeffrey J Koschmann Carl C Kratz Christian C Larouche Valerie V Lassaletta Alvaro A Lindhorst Scott S Ling Simon C SC Link Michael P MP Loret De Mola Rebecca R Luiten Rebecca R Lurye Michal M Maciaszek Jamie L JL MagimairajanIssai Vanan V Maher Ossama M OM Massimino Maura M McGee Rose B RB Mushtaq Naureen N Mason Gary G Newmark Monica M Nicholas Garth G Nichols Kim E KE Nicolaides Theodore T Opocher Enrico E Osborn Michael M Oshrine Benjamin B Pearlman Rachel R Pettee Daniel D Rapp Jan J Rashid Mohsin M Reddy Alyssa A Reichman Lara L Remke Marc M Robbins Gabriel G Roy Sumita S Sabel Magnus M Samuel David D Scheers Isabelle I Schneider Kami Wolfe KW Sen Santanu S Stearns Duncan D Sumerauer David D Swallow Carol C Taylor Leslie L Thomas Gregory G Toledano Helen H Tomboc Patrick P Van Damme An A Winer Ira I Yalon Michal M Yen Lee Yi LY Zapotocky Michal M Zelcer Shayna S Ziegler David S DS Zimmermann Stefanie S Hawkins Cynthia C Malkin David D Bouffet Eric E Villani Anita A Tabori Uri U

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20210504 25

<h4>Purpose</h4>Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.<h4>Patients and methods</h4>Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, ...[more]

PMID: 33945292

Similar Datasets

Project description:BackgroundConstitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family.Case presentationThe proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband's family pedigree displays multiple relatives with cancers including a likely case of 'true' Turcot syndrome.ConclusionsConstitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.

Dataset Information

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

Purpose

Patients and methods

Results

Conclusion

Publications

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

Similar Datasets

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