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Supplementary Figure from The Genomics of Colorectal Cancer in Populations with African and European Ancestry

Black people have a higher incidence of colorectal cancer and worse survival rates when compared with white people. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer microsatellite instability–high (MSI-H) tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations, specifically KRASG12D and KRASG13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, and RET). In patients with young-onset colorectal cancer (APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of the diverse U.S. population.Significance:KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC.See related commentary by Eng and Holowatyj, p. 1187.This article is highlighted in the In This Issue feature, p. 1171

Black people have a higher incidence of colorectal cancer and worse survival rates when compared with white people. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer microsatellite instability–high (MSI-H) tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations, specifically KRASG12D and KRASG13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, and RET). In patients with young-onset colorectal cancer ( Significance: KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC. See related commentary by Eng and Holowatyj, p. 1187. This article is highlighted in the In This Issue feature, p. 1171

Purpose Tumor mutation load is an emerging prognostic and diagnostic marker for many cancers. Sensitivity to immunotherapeutic agents, which stimulate an antitumor immune response by selectively inhibiting immunosuppressive cell surface ligands, is known to correlate with high mutation load in the tumor. Numerous somatic and germline defects can cause genomic instability, including alterations affecting the mismatch repair pathway, DNA polymerases, and cell cycle regulators. We describe here the discovery of previously unreported mutations in the promoter of the PMS2 gene that are associated with significantly increased tumor mutation load. Methods Comprehensive genomic profiling by hybridization capture of exonic regions from either 236 or 315 cancer-related genes and select introns from 19 genes commonly rearranged in cancer was used to characterize more than 60,000 clinical FFPE cancer specimens. At least 50 ng of extracted DNA was analyzed per sample and the constructed libraries were sequenced to high, uniform median coverage (>500x). Samples were assessed for base substitutions, short insertions and deletions, copy number alterations and gene fusions/rearrangements. Mutation load is assessed as the number of somatic coding point mutations per megabase of targeted territory. Results Mutation load from targeted cancer gene analysis recapitulates previous results evaluating whole exome and whole genome mutation load in tumors and cell lines. A novel mutation hotspot was identified in the promoter of PMS2, which codes for the PMS2 protein, a dimerization partner of MLH1 and integral to the DNA mismatch repair complex. Promoter mutations were found in 7.5% of melanoma specimens (n = 101/1348) and 17% of skin squamous cell carcinomas (n = 30/175). In both diseases, PMS2 promoter mutations are the most significant genomic correlate of high mutation load. In melanoma, PMS2 promoter mutant specimens have 4x the median mutation load of the general melanoma population. Skin squamous cell carcinomas show a 2.5-fold increase. Functional characterization is underway to support the hypothesis that these mutations lead to modified PMS2 transcriptional activity, which is known to cause hypermutation. Conclusions The growing corpus of cancer genome data continues to enable novel discoveries in cancer biology. Non-coding and regulatory mutations have not been the target of focused study, and our findings extend the small set of regulatory mutations thought to affect tumor development. Our discovery highlights the power of large-scale genomic analysis to uncover additional disease mechanisms, and furthers our understanding of how cells maintain genome integrity. With the documented association of mutation load and immunotherapy sensitivity, investigation into the response of PMS2 promoter mutant tumors is warranted. Citation Format: Zachary R. Chalmers, Franklin W. Huang, Laurie M. Gay, Siraj M. Ali, Roman Yelensky, Juliann Chmielecki, Jeffery S. Ross, Vincent A. Miller, Philip J. Stephens, Levi A. Garraway, Garrett M. Frampton. Broad analysis of recurrent somatic mutations in cancer reveals a common novel non-coding mutation in the promoter of PMS2 associated with greatly increased tumor mutation load. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3576.

Magnetic resonance imaging (MRI) is a computerized method of depicting the morphology of anatomic structures in cross-section. The basic principles of this technique were discovered by two American physicists, Felix Bloch and Edward Purcell, in 1946, who were subsequently awarded the Nobel Prize in Physics in 1952 for their work. The difficulties inherent in developing the necessary technology to construct the large magnets with excellent field uniformity delayed the clinical application of MRI until 1979.

A retrospective study of spinal epidural abscess spanning 10 years and encompassing 40 patients was done. Epidemiology, clinical features, laboratory findings, radiographic imaging, therapy, and outcome were examined and compared with previous series. An increasing incidence of the disease (up to 1.96 patients per 10,000 admissions per year) and an older, more debilitated population (67% having factors predisposing them to infection) were discovered. Over half of the population was studied with magnetic resonance imaging, which was found to be equally as sensitive (91%) as myelography with computed tomography (92%). Magnetic resonance imaging offers the advantages of being noninvasive and able to delineate other entities, which makes it the imaging modality of choice. Preoperative paralysis and neurological deterioration from normal were identified as poor prognostic features. Of 7 patients with preoperative paralysis, 5 died, and the rest failed to recover neurological function. Eleven patients with initially normal neurological exams deteriorated in the hospital before surgical intervention. Eight of these patients were being treated with appropriate antibiotics; 2 became paralyzed despite more than 3 weeks of antibiotic therapy. Only 3 of these 11 patients recovered fully. Immediate surgical decompression combined with antibiotics remains the treatment of choice.

Magnetic resonance imaging (MRI) may demonstrate disease activity in a number of ways in patients with multiple sclerosis. Newly appearing MRI lesions, gadolinium-enhancing lesions, and enlargement of preexisting lesions are frequently taken as evidence of disease activity. Furthermore, serial MRI studies have been stated to be more sensitive than repeated neurologic examinations in detecting disease activity. We assessed the validity of using lesion enlargement as a measure of disease activity by repeatedly measuring the area of all MRI lesions in four patients with multiple sclerosis. The size-frequency distribution in all patients was similar, with 80% of the lesions measuring less than 0.67 cm2. The median coefficient of variation for three successive lesion measurements was inversely related to lesion area, ranging from 22.6% for the more common smaller lesions (less than 0.67 cm2) to 12.1% for larger lesions. Based on these coefficients of variation, a change in a particular lesion exceeding 45.2% for a baseline lesion smaller than 0.67 cm2 and 24.2% for a baseline lesion greater than or equal to 0.67 cm2 should be required to exclude a change due to measurement variability. It remains necessary to determine the number of lesions that must change when multiple lesions are present in the baseline MRI to reliably exclude chance occurrence when establishing MRI-evident disease activity. Guidelines for determining these criteria are presented, as are the limitations inherent in the statistical model employed to make these determinations.