Universität zu Köln

Schamschula, Esther ORCID: 0000-0002-8874-1713, Kinzel, Miriam, Wernstedt, Annekatrin, Oberhuber, Klaus, Gottschling, Hendrik, Schnaiter, Simon, Friedrichs, Nicolaus, Merkelbach-Bruse, Sabine, Zschocke, Johannes, Gallon, Richard and Wimmer, Katharina (2022). Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase delta Proofreading Deficiency in Tumorigenesis. Biomolecules, 12 (10). BASEL: MDPI. ISSN 2218-273X

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Abstract

Simple Summary Colorectal cancer (CRC) in adolescents and young adults (AYA) is rare. Genetic causes include autosomal recessive and dominant monogenic disorders due to pathogenic variants (PVs) in genes involved in DNA repair. However, the genetic etiology of the majority of AYA-CRC remains unidentified. In two teenage siblings with CRC, we show to our knowledge for the first time that AYA-CRC cases can be caused by digenic inheritance of each a heterozygous pathogenic variant (PV) in the mismatch-repair (MMR) gene PMS2 and the proofreading polymerase (PP) Pol delta gene POLD1. With the aim to elucidate how the constitutional polymerase proofreading defect and the high propensity to MMR deficiency (MMRd) interact, we performed a comprehensive tumor analysis of the two siblings' tumors. Results indicate that tumorigenesis is initiated by MMRd and the inherited POLD1 PV contributes to fast tumor progression reflected by an ultra-high tumor mutational burden (TMB) and specific mutational signatures. 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 delta 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schamschula, Esther UNSPECIFIED orcid.org/0000-0002-8874-1713 UNSPECIFIED Kinzel, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Wernstedt, Annekatrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Oberhuber, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Gottschling, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Schnaiter, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedrichs, Nicolaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Zschocke, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Gallon, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Wimmer, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-676672
DOI:	10.3390/biom12101350
Journal or Publication Title:	Biomolecules
Volume:	12
Number:	10
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2218-273X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language YOUNG; ASSOCIATION; ADOLESCENTS; PREVALENCE; VARIANTS; GENETICS; PMS2 Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67667