Fig. 2: Genetic linkage of strain-specific variants to cancer genes undergoing LOH confound cancer genome analyses.

a, b Trp53;Nlrp1 haplotype reconstruction by WES-based SNP analysis in germline and tumors of KPC mice (a: KPC-5, b: KPC-6). Genomic regions with heterozygous SNPs contain two distinct alleles: one C57BL/6J- and one 129S-specific haplotype (SNP frequencies: ~0.5; light blue background in SNP-plots). Conversely, regions with SNP frequencies of ~1.0 are pure 129S. Regions without values perfectly match the C57BL/6J reference genome (homozygous C57BL/6J). a In the germline, heterozygous SNPs confirm presence of two haplotypes: (1) Trp53^ENG-129S;Nlrp1^129S (engineered Trp53^R172H allele; strain-specific Nlrp1^129S variant) and (2) Trp53^WT;Nlrp1^C57BL/6J. In the tumor, the Trp53^WT;Nlrp1^C57BL/6J haplotype is lost through CN-LOH (reflecting selective pressure to lose Trp53^WT). Homozygosity of the Trp53^ENG-129S;Nlrp1^129S haplotype in the tumor manifests as a Nlrp1 locus deletion when compared to germline (right; CNV plot based on WES with Nlrp1 locus zoom-in). b In the germline, the Trp53;Nlrp1 haplotype is S129-derived on both copies of chr11. The Nlrp1^129S variant is already homozygous in the germline. CNV analyses relying on tumor/germline comparisons thus fail to detect the Nlrp1 alteration in the tumor (right; CNV plot based on WES with Nlrp1 locus zoom-in). c Germline SNP analysis of mouse KPC-7 backcrossed to C57BL/6J for fourteen generations. High SNP densities persist in genomic proximity of engineered alleles. d Germline CNV profiles at the Skint locus in three inbred mouse strains as compared to C57BL/6J. Red dots, aCGH probes within Skint locus alteration (data from ref. ⁶). e Upper panel: Skint locus CNV profile in primary pancreatic cancer cell culture (compare to germline Skint alterations in Fig. 2d). Lower panels: WES-based Cdkn2a;Skint haplotype reconstruction as in Fig. 2a, b. In the germline, heterozygous SNPs confirm presence of two haplotypes: (1) Cdkn2a;Skint^C57BL/6J and (2) Cdkn2a;Skint^129S. During tumor evolution, the Cdkn2a locus is first somatically deleted (Cdkn2a^Δ) on the chromosome carrying the Skint^129S variant (Cdkn2a^Δ;Skint^129S) followed by CN-LOH of the Cdkn2a^Δ;Skint^129S allele, reflecting selective pressure to lose Cdkn2a^WT. Homozygosity of Skint^129S in the tumor manifests as a Skint locus deletion when compared to germline (right; CNV plot based on WES with Skint locus zoom-in).