Page 66 - Read Online

Page 196 Feusier et al. J Transl Genet Genom 2021;5:189-99 https://dx.doi.org/10.20517/jtgg.2021.05

were also diagnosed with solid cancers: prostate, gastrointestinal, gynaecological, and lung cancer
[Figure 1B]. The only published article with THSD7B and any cancer is a GWAS study that identified a
-6
common variant (rs13405020, P < 7 × 10 ) outside of the SGS region in THSD7B in Korean patients with
[49]
non-small cell lung cancer .

A small case-control gene-panel sequencing study of sporadic CLL included CXCR4, and identified a
common variant in CXCR4 (rs2228014, MAF = 0.04) that was increased in CLL cases (uncorrected P =
0.0015) . The association of this variant with CLL was not replicated in a second, larger case-control study
[50]
(P = 0.84) . However, one rare truncating variant and one missense variant were observed in CXCR4 in
[51]
two CLL cases with positive family history which was absent from controls (not statistically significant) .
[51]
Truncating germline mutations in the C-terminus of CXCR4 have been shown to act as gain-of-function
mutations and cause WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis),
and Waldenström’s macroglobulinemia .
[52]
Our analysis was limited to the autosome, a restriction of the current SGS algorithm. None of the six
previously proposed CLL risk genes from direct-to-sequencing or CNV analyses in family-based designs are
[13]
[11]
[10]
located on the sex chromosomes. These are ITGB2 , POT1, TERF2IP, ACD , DLEU7 and IRF4 . All
remain to be replicated. Attempts to replicate recurrence of ITGB2 rs2230531 in families or association in
[12]
sporadic case-control designs have not been successful . We did not find significant or suggestive evidence
[53]
of segregation of any of these loci in our pedigree, although we are limited by investigating only one family.
In summary, we have studied a single six-generation high-risk CLL pedigree and identified a genome-wide
significant region at 2q22.1 shared by seven CLL cases and two obligate carriers with hematological
malignancies. The 0.9 Mb region replicates and narrows a previously proposed linkage locus for CLL. In a
complex field which has lacked in replication of family-based findings thus far, this result is extremely
encouraging. Within the shared region, CXCR4 is a compelling candidate. The seven haplotype carriers in
the pedigree provide a valuable resource for pursuing the functionally relevant variant/s (coding or
regulatory) that reside on the shared haplotype. Future work will elucidate if, in fact, CXCR4 plays a role in
inherited risk, as implicated here.

DECLARATIONS
Acknowledgments
We thank the participants and their families who make this research possible. Data collection was made
possible, in part, by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR).
Computations were supported by the University of Utah’s Center for High Performance Computing. We
thank the University of Utah Health Science Center Flow Cytometry and Genomics Cores, and the staff at
the UPDB for their support in the identification of the CLL pedigrees. We greatly appreciate Rob Sargent
for technical and programming support performing the SGS analyses.

Authors’ contributions
Designed the study and wrote the manuscript: Feusier JE, Camp NJ
Contributed to method development: Feusier JE, Madsen MJ, Avery BJ, Camp NJ
Performed data curation and processing: Madsen MJ, Williams JA
Performed analyses: Feusier JE, Madsen MJ, Avery BJ
Provided biological and clinical perspective: Stephens DM, Hu B, Osman AEG, Glenn MJ,
Figures and tables were generated: Feusier JE, Madsen MJ, Avery BJ