Deleterious Germline Variants, Especially in the DNA Repair Pathway, Are Common in Patients with Non-Related Multiple Cancers, One of Them Being Hematological Malignancy
Authors: Singhal Deepak , Hahn Christopher N , Moma Luke D , Wee Li Yan A , Chhetri Rakchha , Babic Milena , Kutyna Monika M , Hiwase Smita , Parker Wendy T , Feng Jinghua , Schreiber Andreas W , Geoghegan Joel , Arts Peer , Gowda Raghu , Singhal Nimit , Brown Anna L , D'Andrea Richard J , Lewis Ian D , Scott Hamish S , Godley Lucy A , Hiwase Devendra K 
Published: November 2019

Approximately 8% of un-selected pediatric (Zhang et al, NEJM 2015) and adult (Huang et al, Cell 2018) cancer patients have a deleterious germline (GL) variant. However, the frequency in patients with >2 non-related cancers, a combination of different hematological malignancies (HM) or a HM and a non-hematological malignancy, is not known. We hypothesize that genetic predisposition is higher in patients with multiple cancers, compared to historical literature for patients with a single cancer.
Method: Clinical and laboratory information on 213 cancer patients, enrolled in the South Australian MDS (SA-MDS) registry (n=90) and University of Chicago clinic (n=123) were analyzed. Germline variants were identified by sequencing paired bone marrow and germline samples for 217-300 cancer related genes and annotated using American College of Medical Genetics (ACMG) 2015 guidelines as pathogenic or likely pathogenic (i.e. deleterious). Additionally, somatic mutations in 240 genes were identified in the SA-MDS cohort (n=90).
Results: The median age at diagnosis was 64 years (interquartile range, 61-76 years). One-hundred and five patients had therapy-related myeloid neoplasm (T-MN), following treatment with chemo- and/or radiotherapy for an unrelated prior malignancy. While 100 patients had non-related multiple cancers (MC) one of them being HM without prior exposure to chemotherapy or radiotherapy, and, 8 patients had only myelodysplastic syndrome or acute myeloid leukemia.
Overall, 20.5% (42/205) patients harbored 46 deleterious GL variants, annotated according to ACMG guidelines (Fig 1A). Most GL variants were in DNA repair pathway (26/46, 57%) followed by TP53, telomere maintenance and drug transport pathways (4/46, 9% each; Fig 1B). Three DDX41 variants were also seen.
The frequency of patients with deleterious GL variants was similar in T-MN (21/105; 20%) and MC (21/100, 21%; Fig 1C). Similarly, the frequency of patients with deleterious GL variants in DNA repair pathways was also similar in T-MN (13/105, 12%) and MC (11/100, 11%).
Of the patients with available cytogenetic data, complex cytogenetics were more frequent in patients with a deleterious GL variant compared to those without (11/28, 39% vs 28/125, 22%; p=0.06).
At the time of analysis, somatic and germline mutation data on 240 genes was available in the SA-MDS cohort only (n=90). Somatic TP53 mutations were frequent in patients with deleterious
GL variant (8/15, 53%) compared to patients without deleterious GL variant (11/75, 15%; p=0.003) (Fig 1D). Interestingly, 80% (4/5) patients with deleterious GL variant in a DNA repair pathway had a somatic TP53 mutation compared to 40% (4/10) with deleterious GL variant in non-DNA repair pathways.
Conclusions: Our results from a large cohort show that patients with >2 non-related cancers have a higher frequency of deleterious germline variants compared to previous reports from patients with single cancer (20.5% vs 8%). Variants in the DNA repair pathway are the most common. The presence of deleterious germline variants is associated with genetic instability as evidenced by high frequency of complex karyotypes and somatic TP53 mutations.

Disclosures
Scott: Celgene: Honoraria. Godley:UpToDate, Inc.: Patents & Royalties: receives royalties from a coauthored article on inherited hematopoietic malignancies ; Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees.