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 (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant <i>MLH1</i> and <i>MSH2</i> 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 <i>PMS2</i> exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited <i>POLD1</i> variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (&amp;gt;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 δ 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 <i>PMS2</i> 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 <i>PMS2</i> and <i>POLD1.</i> Analysis of their CRCs supports that <i>POLD1</i>-mutated tumors acquire hypermutation only with concurrent MMRd.