Del(20q) As a Somatic Gene Rescue in Adult Patients: Can Germline Mutations Other Than SBDS be Found in Affected Patients?
Authors: Orland Mark , Kubota Yasuo , Dima Danai , Bravo-Perez Carlos , Guarnera Luca , Gurnari Carmelo , Maciejewski Jaroslaw P. , Visconte Valeria 
Published: December 2023

Deletions involving chromosome 20 (20q-) are present in up to 5-8% of myeloid neoplasms (MN) and have been associated with either myelodysplastic (MDS) or myeloproliferative (MPN) features, chiefly myelofibrosis. Theoretically, any chromosomal deletion may result in haploinsufficient expression of tumor suppressor genes (TSGs) or in loss of a protective allele in heterozygous carriers of germline (GL) variants or heterozygous somatic (SM) mutations. However, deletions have also been implicated as a maladaptive somatic gene rescue (SGR) event in carriers of GL bone marrow failure (BMF) genes such as SAMD9 and SBDS. The latter is found in Shwachman-Diamond syndrome whereby the upregulated EIF6 gene, responsible for hematopoietic dysfunction, is clonally removed by SM 20q deletion event.
We identified an interesting 35-years-old patient with mild cytopenia and 20q- in which a cryptic homozygous SBDSc.A148T GL mutation was found. This prompted us to search in other adult patients with 20q deletion for: i) other cases with SBDS gene alteration (both hetero and homozygous), ii) other GL variants which could be clonally relieved by compensatory 20q- or, iii) disease-prone GL variants on 20q, whereby either disease-prone suppressive allele is included in the deleted region.
Within a cohort of 5,308 cases with various MN, 215 patients with 20q- were identified. WES results were available for 350 patients. We applied a stringent bioanalytic algorithm to identify unique GL alterations (not deposited in SM databases) in genes expressed in hematopoietic tissues and involved in BMF and cancer, and a population allelic frequency of &lt;1% which were classified as pathogenic (P), likely pathogenic (LP), and VUS with particular level of clinical suspicion (sVUS). In 76 of 215 patients with 20q-, 346 GL mutations in genes of potential interest were identified and further analyzed. No P/LP variants were detected on genes within commonly deleted region on chr.20q, and no additional carriers of SBDS variants were found. However, we identified 9 pathogenic GL variants in potentially pertinent genes including GL alterations in DDX41, STAG2 and TP53 which have been described in the context of MN. However, these gene variants were also present in patients with diploid 20q. The remaining 6 variants included heterozygous P/LP GL alterations in 3 different Fanconi anemia genes ( FANCA, FANCM, FANCD2), SUZ12, and TINF2. The latter, TINF2, a telosome gene, known to be mutated in dyskeratosis congenita (DC), carried an LOF c.605-1G&gt;A in a patient with MDS/MPN with a family history of cancer who later developed 20q-. The patient did not show any symptoms of DC-like features, which usually present at an early age. Since FANCA LOF with SGR via overepression of EIF6 has previously been described 1, we investigated and did not identify any cases in our cohort of EIF6 SGR resultant overexpression.
While occasional patients with no previously diagnosed SBDS can be found among MDS with 20q-, screening for SBDS genes demonstrates that such a genetic configuration among adult patients with 20q is very rare. In addition, only 9 out of 215 patients with 20q- carried other pathogenic GL variants in non-recurrent genes which appear to be likely coincidental. This suggests that del20q is not a SGR in response to a GL mutation, but rather a SGR due to other aforementioned mechanisms, which are currently being explored in our cohort of patients.
References:
1. Gueiderikh A, Maczkowiak-Chartois F, Rouvet G, Souquère-Besse S, Apcher S, Diaz JJ, Rosselli F. Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis. Sci Adv. 2021 Jan 1;7(1):eabb5414. doi: 10.1126/sciadv.abb5414. PMID: 33523834; PMCID: PMC7775781.