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Family still matters: Counseling patients with complex family histories of colon and endometrial cancers.

ABSTRACT: BACKGROUND:There are no national guidelines for the management of patients with a family history consistent with Lynch syndrome (LS) but a negative genetic test. To determine current management practices, genetic counselors' (GCs) recommendations were assessed. METHODS:A survey of GCs using five hypothetical pedigrees was posted to National Society of Genetic Counselors (NSGC) discussion forums. Descriptive statistics were used. RESULTS:One-hundred and fifteen surveys were completed. A pedigree with a first-degree relative (FDR) with early-onset colorectal cancer (CRC) and a family history of CRC and endometrial cancer (EC) prompted 83% (n = 95) of respondents to recommend early and frequent colonoscopies, based on family history. When the CRCs and ECs occurred in family members removed from the proband, 96% (n = 110) of GCs said they would screen based on family history. However, only 52% (n = 60) suggested CRC screening should begin earlier and occur more often, and 43% (n = 50) suggested CRC screening should follow standard age and frequency guidelines. CONCLUSION:Concordance of opinion among GCs for the management of patients with negative genetic test results exists when FDRs are affected. However, when affected relatives are more distant, GCs disagreed on screening recommendations. These data suggest a need for guidelines for patients with a family history of cancer and a negative genetic test.

SUBMITTER: Gemmell AP

PROVIDER: S-EPMC6732297 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Family still matters: Counseling patients with complex family histories of colon and endometrial cancers.

Gemmell Amber P AP Mauer Caitlin B CB Reys Brian D BD Pirzadeh-Miller Sara S Ross Theodora S TS

Molecular genetics & genomic medicine 20190726 9

<h4>Background</h4>There are no national guidelines for the management of patients with a family history consistent with Lynch syndrome (LS) but a negative genetic test. To determine current management practices, genetic counselors' (GCs) recommendations were assessed.<h4>Methods</h4>A survey of GCs using five hypothetical pedigrees was posted to National Society of Genetic Counselors (NSGC) discussion forums. Descriptive statistics were used.<h4>Results</h4>One-hundred and fifteen surveys were ...[more]

PMID: 31347304

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Project description:Background & aimsPatients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing.MethodsWe analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established.ResultsTwenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase.ConclusionsSome patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.

Project description:Microsatellite-unstable (MSI) cancers have distinct genetic and clinical features from microsatellite-stable cancers, but the molecular functional differences between MSI cancers originating from different tissues or organs have not been well studied because the application of usual differentially expressed gene (DEG) analysis is error-prone, producing too many noncancer-specific normally functioning genes. To maximize therapeutic efficacy, biomarkers reflecting cancer-specific differences between MSI cancers of different tissue origins should be identified. To identify functional differences between MSI colon and endometrial cancers, we combined DEG analysis and biclustering instead of DEG analysis alone and refined functionally relevant biclusters reflecting genuine functional differences between the 2 tumors. Specifically, using The Cancer Genome Atlas and genome-tissue expression as data sources, gene ontology (GO) enrichment tests were performed after routinely identifying DEGs between the 2 tumors with the exclusion of DEGs identified in their normal counterparts. Cancer-specific biclusters and associated enriched GO terms were obtained by biclustering with enrichment tests for the preferences for cancer type (either colon or endometrium) and GO enrichment tests for each cancer-specific bicluster, respectively. A novel childness score was developed to select functionally relevant biclusters among cancer-specific biclusters based on the extent to which the enriched GO terms of the biclusters tended to be child terms of the enriched GO terms in DEGs. The selected biclusters were tested using survival analysis to validate their clinical significance. We performed multiple sequential analyses to produce functionally relevant biclusters from the RNA sequencing data of MSI colon and endometrial cancer samples and their normal counterparts. We identified 3066 cancer-specific DEGs. Biclustering analysis revealed 153 biclusters and 41 cancer-specific biclusters were selected using Fisher exact test. A mean childness score over 0.6 was applied as the threshold and yielded 8 functionally relevant biclusters from cancer-specific biclusters. Functional differences appear to include gland cavitation and the TGF-β receptor, G protein, and cytokine pathways. In the survival analysis, 6 of the 8 functionally relevant biclusters were statistically significant. By attenuating noise and applying a synergistic contribution of DEG results, we refined candidate biomarkers to complement tissue-specific features of MSI tumors.

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Family still matters: Counseling patients with complex family histories of colon and endometrial cancers.

Publications

Family still matters: Counseling patients with complex family histories of colon and endometrial cancers.

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