Germline variants and phenotypic spectrum in a Canadian cohort of individuals with diffuse gastric cancer.

Background: CDH1 pathogenic variants (pvs) cause most cases of inherited diffuse gastric cancer (dgc), but have low detection rates and vary geographically. In the present study, we examined hereditary causes of dgc in patients in Ontario. Methods: CDH1 testing through single-site or multi-gene panels was conducted for patients with dgc meeting the 2015 International Gastric Cancer Linkage Consortium (igclc) criteria, or with isolated dgc at less than 50 years of age, or with a strong family history of cancer identified at the Zane Cohen Centre (zcc). All CDH1-positive patients at zcc, regardless of cancer history, were summarized. Results: In 15 of 85 patients with dgc (17.6%), a pv or likely pv was identified through CDH1 single-site (n = 43) or multi-gene panel (n = 42) testing. The detection rate was 9.4% overall (8 of 85) and 11% using igclc criteria (7 of 65). No CDH1 pvs were identified in patients with isolated dgc at less than 40 years of age, but 1 pv was identified in a patient with isolated dgc at less than 50 years of age. Multi-gene panels identified 9 pvs (21.4%), including CDH1, STK11, ATM, BRCA2, MLH1, and MSH2. Review of 81 CDH1 carriers identified 10% with dgc (median age: 48 years; range: 38-59 years); 41% were unaffected (median age: 53 years; range: 26-89 years). Observed malignancies other than dgc or lobular breast cancer (lbc) included colorectal, gynecologic, kidney or bladder, prostate, testicular, and ductal breast cancers. Lobular-breast cancer was seen only in 3 families. Conclusions: In Ontario, the detection rate of CDH1 pvs in patients with dgc was low: no pvs were identified in patients with isolated dgc at less than 40 years of age, and 1 was identified in a patient with isolated dgc at less than 50 years of age. Isolated lbc with no dgc was observed in CDH1-positive families, as were pathology-confirmed nondgc or non-lbc malignancies, which had not previously been reported. Given a phenotype that overlaps with other hereditary conditions, multi-gene panels are recommended for all patients with dgc at less than 50 years of age and for those meeting igclc criteria.

Long-term psychosocial and behavioral adjustment in individuals receiving genetic test results in Lynch syndrome.

A cross-sectional study of 155 participants who underwent genetic testing for Lynch syndrome (LS) examined long-term psychosocial and behavioral outcomes. Participants completed standardized measures of perceived risk, psychosocial functioning, knowledge, and a questionnaire of screening activities. Participants were on average 47.3 years and had undergone testing a mean of 5.5 years prior. Eighty four (54%) tested positive for a LS mutation and 71 (46%) negative. For unaffected carriers, perceived lifetime risk of colorectal cancer was 68%, and surprisingly, 40% among those testing negative. Most individuals demonstrated normative levels of psychosocial functioning. However, 25% of those testing negative had moderate depressive symptoms, as measured by the Center for Epidemiologic Studies for Depression Scale, and 31% elevated state anxiety on the State-Trait Anxiety Inventory. Being female and a stronger escape - avoidant coping style were predictive of depressive symptoms. For state anxiety, similar patterns were observed. Quality of life and social support were significantly associated with lower anxiety. Carriers maintained higher knowledge compared to those testing negative, and were more engaged in screening. In summary, most individuals adapt to genetic test results over the long term and continue to engage in screening. A subgroup, including some non-carriers, may require added psychosocial support.

Efficacy of an educational intervention on family physicians' risk assessment and management of colorectal cancer.

We developed a point-of-care tool indicating risk categories for colorectal cancer (CRC) based on family history (FH) and management recommendations tailored to risk. The study objective was to determine if this CRC Risk Triage/Management Too would enable family physicians (FPs) to appropriately triage and make screening and genetics referral recommendations for patients with CRC FH. Baseline questionnaires were mailed to a random sample of FPs in Ontario and Newfoundland, Canada. Participants were asked to use the tool for 3 months and then complete a follow-up questionnaire. The primary outcomes were correct responses to questions regarding CRC risk category, screening method, starting age, frequency, and decision to refer to genetics, for eight clinical vignettes. The study was completed by 75/121 (62 %) participating FPs. Most (77 %) agreed they routinely recommended fecal occult blood testing for average risk patients age ≥50. This did not change significantly following the intervention. There was a significant increase in confidence in CRC risk assessment (52 % pre; 88 % post; p < 0.001), correct management recommendations for patients with CRC FH (51 % pre; 84 % post; p < 0.001), and improvement in total mean scores on outcome measures for all vignettes. Most (90 %) agreed the tool would improve practice. Receipt of the CRC Risk Triage/Management Tool was associated with improvement in FPs' CRC risk assessment, screening, and genetics referral recommendations for clinical vignettes. This demonstrates the value of point-of-care tools and illustrates a process for development, evaluation, and dissemination of tools needed by FPs if potential impacts of genomic advances are to be achieved.

Development and validation of an instrument to measure the impact of genetic testing on self-concept in Lynch syndrome.

A positive genetic test result may impact on a person's self-concept and affect quality of life. The purpose of the study was to develop a self-concept scale to measure such impact for individuals carrying mutations for a heritable colorectal cancer Lynch syndrome (LS). Two distinct phases were involved: Phase 1 generated specific colorectal self-concept candidate scale items from interviews with eight LS carriers and five genetic counselors, which were added to a previously developed self-concept scale for BRCA1/2 mutation carriers, Phase II had 115 LS carriers complete the candidate scale and a battery of validating measures. A 20-item scale was developed with two dimensions identified through factor analysis: stigma/vulnerability and bowel symptom-related anxiety. The scale showed excellent reliability (Cronbach's α = 0.93), good convergent validity by a high correlation with impact of event scale (r(102) = 0.55, p < 0.001) and Rosenberg self-esteem scale (r(108) = -0.59, p < 0.001), and a low correlation with the Fear questionnaire (r(108) = 0.37, p < 0.001). The scale's performance was stable across participant characteristics. This new scale for measuring self-concept has potential to be used as a clinical tool and as a measure for future studies.