Regional differences in awareness and attitudes regarding genetic testing for disease risk and ancestry

Little is known about the lay public’s awareness and attitudes concerning genetic testing and what factors influence their perspectives. The existing literature focuses mainly on ethnic and socioeconomic differences; however, here we focus on how awareness and attitudes regarding genetic testing differ by geographical regions in the US. We compared awareness and attitudes concerning genetic testing for disease risk and ancestry among 452 adults (41% Black and 67% female) in four major US cities, Norman, OK; Cincinnati, OH; Harlem, NY; and Washington, DC; prior to their participation in genetic ancestry testing. The OK participants reported more detail about their personal ancestries (p = 0.02) and valued ancestry testing over disease testing more than all other sites (p < 0.01). The NY participants were more likely than other sites to seek genetic testing for disease (p = 0.01) and to see benefit in finding out more about one’s ancestry (p = 0.02), while the DC participants reported reading and hearing more about genetic testing for African ancestry than all other sites (p < 0.01). These site differences were not better accounted for by sex, age, education, self-reported ethnicity, religion, or previous experience with genetic testing/counseling. Regional differences in awareness and attitudes transcend traditional demographic predictors, such as ethnicity, age and education. Local sociocultural factors, more than ethnicity and socioeconomic status, may influence the public’s awareness and belief systems, particularly with respect to genetics

Engagement and return of results preferences among a primarily African American genomic sequencing research cohort.

Genomics researchers are increasingly interested in what constitutes effective engagement of individuals from underrepresented groups. This is critical for longitudinal projects needed to inform the implementation of precision medicine. Return of results is one opportunity for engagement. The aims of this study were to determine participant perspectives on optimal engagement strategies and priorities for return of results and the extent to which focus groups were an effective modality for gathering input on these topics. We conducted six professionally moderated focus groups with 49 participants in a genomics research study. Transcripts from audio-recorded sessions were coded by two researchers and themes were discussed with the wider research team. All groups raised the issue of mistrust. Individuals participated nonetheless to contribute their perspectives and benefit their community. Many group members preferred engagement modalities that are offered to all participants and allow them to share the nuances of their perspectives over the use of participant representatives and surveys. All groups created a consensus ranking for result return priorities. Results for life-threatening conditions were the highest priority to return, followed by those related to treatable conditions that affect physical or mental health. We advocate for engagement strategies that reach as many participants as possible and allow them to share their perspectives in detail. Such strategies are valued by participants, can be effective for developing return of results policies, and may help institutions become more trustworthy

Preferences for and acceptability of receiving pharmacogenomic results by mail: A focus group study with a primarily African-American cohort.

Although genetic counseling is traditionally done through in-person, one-on-one visits, workforce shortages call for efficient result return mechanisms. Studies have shown that telephone and in-person return of cancer genetic results are equivalent for patient outcomes. Few studies have been conducted with other modes, result types or racially diverse participants. This study explored participants' perspectives on receiving pharmacogenomic results by mail. Two experienced moderators facilitated six focus groups with 49 individuals who self-identified primarily as African-American and consented to participate in a genome sequencing cohort study. Participants were given a hypothetical pharmacogenomic result report (positive for c.521T>C in SLCO1B1). An accompanying letter explained that the result was associated with statin intolerance along with a recommendation to share it with one's doctor and immediate relatives. Participants reacted to the idea of receiving this type of result by mail, discussing whether the letter's information was sufficient and what they predicted they would do with the result. Two researchers coded the focus group transcripts and identified themes. Many participants thought that it was appropriate to receive the result through the mail, but some suggested a phone call alerting the recipient to the letter. Others emphasized that although a letter was acceptable for disclosing pharmacogenomic results, it would be insufficient for what they perceived as life-threatening results. Most participants found the content sufficient. Some participants suggested resources about statin intolerance and warning signs be added. Most claimed they would share the result with their doctor, yet few participants offered they would share the result with their relatives. This exploratory study advances the evidence that African-American research participants are receptive to return of certain genetic results by approaches that do not involve direct contact with a genetic counselor and intend to share results with providers. ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study (NCT00410241)

CDH1 Missense Variant c.1679C>G (p.T560R) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site.

Disease-causing germline mutations in CDH1 cause Hereditary Diffuse Gastric Cancer (HDGC). For patients who meet the HDGC screening criteria, the identification and classification of the sequence variants found in CDH1 are critical for risk management of patients. In this report, we describe a germline CDH1 c.1679C>G (p.T560R) variant identified in a 50 year old man who was diagnosed with gastric cancer with a strong family history of gastric cancer (one living brother was diagnosed with gastric cancer at 63 and another brother died of gastric cancer at 45). cDNA analysis, involving fragment analysis and cloning, indicated that the p.T560R mutation created a novel 5' splice donor site, which led to a novel transcript with a 32 nucleotide deletion in exon 11. This abnormal transcript putatively produces a truncated CDH1 protein (E-cadherin) of 575 amino acids instead of 882. We also demonstrated that the variant completely abolishes normal splicing as the mutant allele does not generate any normal transcript. Furthermore, the CDH1 c.1679C>G (p.T560R) variant segregated with gastric cancer in all three family members affected with gastric cancer in this family. These results support the conclusion that CDH1 c.1679C>G (p.T560R) variant is a pathogenic mutation and contributes to HDGC through disruption of normal splicing

Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients With Hereditary Diffuse Gastric Cancer

Background and Aims: Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Methods: Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Results: Of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients aged less than 45 years had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. Conclusion: In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected and most subjects were aged less than 45 years. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404

<i>In silico</i> prediction of the <i>CDH1</i> p.T560R variant.

<p>Prediction of the potential effects of the <i>CDH1 c</i>.<i>1679 C>G</i> (p.T560R) alteration on normal mRNA splicing. Top panel: reference sequence; bottom panel: mutated sequence. The text at the left of each panel represents the names of the tools used to predict splice site strength. The number ranges indicate the strength of each target sequence in each prediction tool with the upper range being the perfect match. The reference sequence and mutated sequences are shown at the bottom of each panel with nucleotide positions indicated above. Blue vertical bars indicate 5’ (donor) site. The height of each bar is proportional to the maximum possible score computed by the corresponding algorithm.</p

Patient pedigree, <i>CDH1</i> mutation and H&E image of diffuse gastric cancer.

<p>(A) The patient (indicated with the arrow head) is a 50 year old man who was diagnosed with gastric cancer at the age of 50. In his generation, three members were diagnosed with gastric cancers (one brother died of gastric cancer at 45, another brother was diagnosed with gastric cancer at 63). All three brothers affected with gastric cancer were determined to have the <i>CDH1 c</i>.<i>1679 C>G</i> p.T560R variant. (B) our patient’s germline <i>CDH1</i> sequencing demonstrating the <i>CDH1 c</i>.<i>1679C>G</i> variant. (C) Haematoxylin and eosin stain (H&E stain) of patient’s biopsy specimen showing infiltrating adenocarcinoma poorly differentiated with mucinous and signet ring cell features. The signet ring cells are characteristic of hereditary diffuse gastric cancer (HDGC). They contain large amount of mucin which pushes the nucleus to the cell periphery (see arrows).</p

<i>CDH1 c</i>.<i>1679 C>G</i> (p.T560R) mutant allele creates a novel splice site that results in a 32 nucleotide deletion of the 3’ end of exon 11.

<p>(A) Sequence adjacent to wild type allele, <i>CDH1 c</i>.<i>1679 C</i>, indicating normal splice site. Electropherogram data of normally spliced cDNA with wild type allele highlighted in blue. (B) Sequence adjacent to mutant allele, <i>CDH1 c</i>.<i>1679 G</i>, indicating aberrant splice site produced by mutant allele (solid lines) and location of normal splice site (dashed lines). Electropherogram data of aberrantly spliced cDNA with the mutant allele highlighted in light blue.</p