Association of tumor genomic factors and efficacy for metastasis-directed stereotactic body radiotherapy for oligometastatic colorectal cancer.

PURPOSE/OBJECTIVE(S): To report tumor genomic factors associated with overall survival (OS) and local failure (LF) for patients with colorectal cancer (CRC) who received metastasis-directed stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: This was a retrospective review of patients with CRC who received metastasis-directed SBRT. Tumor genomic alterations were identified through KRAS, BRAF, or a 50-gene next generation sequencing panel. OS and LF were estimated using Kaplan-Meier and competing-risk methods. RESULTS: Eighty-five patients and 109 lesions were treated between 2008 and 2018. The median patient follow-up was 50 months (IQR: 28-107). The median and 5-year OS was 34 months and 26% (95% CI: 16-41%), respectively. The 2-year cumulative incidence of LF was 30% (95% CI: 23-41%). Univariate associates with OS included patient age ≥60 years, bone metastasis, increasing tumor size, KRAS mutation, and combined KRAS and TP53 mutation, while increasing tumor size, bone metastasis, biologically effective dose <100 Gy, and combined KRAS and TP53 mutation were associated with LF. Multivariate associates with OS included patient age ≥60 years (HR: 2.4, 95% CI: 1.2-4.8, p = 0.01), lesion size per 1 cm (HR: 1.3, 95% CI: 1.1-1.5, p < 0.01), and KRAS mutation (HR: 2.2, 95% CI: 1.2-4.3, p < 0.01), while no multivariable model for LF retained more than a single variable. CONCLUSION: Genomic factors, in particular KRAS and TP53 mutation, may assist in patient selection and radiotherapeutic decision-making for patients with oligometastatic CRC. Prospective validation, ideally with genomic correlation of all irradiated metastases, is warranted.

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

BACKGROUND: Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. METHODS: Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety-three unaffected controls were also sequenced. RESULTS: Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC,MLH1,MSH2,MSH6, or multiple pathogenic MUTYH mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations. CONCLUSIONS: Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.

The Genetic Counselor's Role in Managing Ethical Dilemmas Arising in the Laboratory Setting.

Ethical dilemmas are encountered commonly in the setting of the clinical genetic testing laboratory due to the complexity of genetic testing and the number of relevant stakeholders involved in the genetic testing process. Based on their clinical training and role within the laboratory, genetic counselors are uniquely equipped to identify and facilitate management of ethical dilemmas. This paper reviews the historical context of ethical theory and its application to the field of genetic counseling. Theoretical and applied ethics are explored in the context of dilemmas arising in the laboratory setting, with a focus on the role of the laboratory genetic counselor in managing ethical dilemmas. Two illustrative case examples are provided.

Isolated trisomy 2 in bone marrows of patients with suspected hematopoietic malignancies.

Isolated trisomy 2 in hematopoietic malignancies is rare, having been reported in only eight cases. Of these cases, the majority are older males. The underlying hematologic malignancies range from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). The molecular pathogenesis and prognostic significance of isolated trisomy 2 remains unknown. Herein, we report 11 cases of isolated trisomy 2 in hematologic disorders seen in the Mayo Clinic Cytogenetics laboratory from 1996-2012. The majority were older males between the ages of 63-93 years. The underlying bone marrow pathologic diagnoses ranged from no diagnostic features of malignancy to AML. Our data suggest that isolated trisomy 2 could represent an age-related phenomenon since all 11 cases were age 63 and over. It appears that isolated trisomy 2 harbors little prognostic significance and that, instead, the prognostic significance is driven by the underlying pathologic diagnosis. For example, whereas 3 of the cases with AML survived only 7-10 weeks post-bone marrow biopsy, 1 of the cases without diagnostic features of malignancy survived 10 additional years. Therefore, trisomy 2 as a sole abnormality should not be considered as definitive evidence for a myeloid neoplasm in the absence of diagnostic morphologic criteria.