Province-Wide Ascertainment of Lynch Syndrome in Manitoba.

BACKGROUND & AIMS: We describe the experience of Lynch syndrome (LS) diagnosis in the province of Manitoba, Canada, over the past 20 years. METHODS: We performed a retrospective review of charts from the provincial Genetics Clinic from January 1, 2000, to May 31, 2023. We extracted data on individuals identified to carry a germline pathogenic or likely pathogenic LS gene variant, the mode of ascertainment, family history, and cascade genetic testing (CGT). Data were stratified and compared before and after the year of implementation (October 2013) of the provincial LS screening program (LSSP) and ascertainment by the LSSP vs clinic referrals (CRs). RESULTS: Between 2014 and 2021, 50 of 101 (49.5%) index cases were identified by the LSSP compared with 51 of 101 (50.5%) from CRs. The proportion of PMS2 variants was 34% (17 of 50) for LSSP index cases compared with 21.6% (11 of 51) for CRs from 2014 to 2021 (P < .001). Among CRs from 2014 to 2021, 24 of 51 (47.1%) families met the Amsterdam criteria, compared with 11 of 50 (22.0%) for the LSSP (P = .01). CGT occurred among 46.8% (95 of 203; average, 1.9 relatives/index) of first-degree relatives of CR index cases vs 36.5% (84 of 230; average, 1.7 relatives/index) of first-degree relatives of LSSP index cases (P = .03). Daughters were most likely to undergo CGT. CONCLUSIONS: A tumor screening program is more effective at detecting individuals with lower penetrant gene variants and families who do not meet traditional family history-based criteria. Cascade genetic testing is higher among clinic referrals compared with the screening program. These findings suggest a complementary role of these 2 ascertainment methods for Lynch syndrome.

A Canadian Provincial Screening Program for Lynch Syndrome.

INTRODUCTION: Manitoba implemented the first Canadian provincial program of reflex screening through mismatch repair immunohistochemistry (MMR-IHC) for all colorectal cancers diagnosed at age 70 years or younger in December 2017. We evaluated compliance to universal reflex testing and for referrals to Genetics for individuals with MMR-deficient tumors. METHODS: We searched the provincial pathology database with "adenocarcinoma" in the colorectal specimen pathology reports between March 2018 and December 2020. We cross-referenced with paper and electronic records in the Program of Genetics and Metabolism to determine whether patients with MMR-deficient tumors had been referred for Genetic assessment and what proportion of patients and first-degree relatives accepted an appointment and genetic testing. We performed logistic regression analysis to identify predictors of testing. RESULTS: We identified 3,146 colorectal adenocarcinoma specimens (biopsies and surgical resections) from 1,692 unique individuals (mean age 68.66 years, male 57%). Of those aged 70 years or younger (n = 936), 89.4% received MMR-IHC screening. Individual pathologists (categorized by the highest, average, and lowest screening rates) were the biggest predictors of MMR-IHC screening on multivariable analysis (highest vs lowest: odds ratio 17.5, 95% confidence interval 6.05-50.67). While only 53.4% (n = 31) of 58 screen-positive cases were referred by pathologists for genetic assessment, other clinicians referred an additional 22.4% (n = 13), resulting in 75.8% overall referral rate of screen-positive cases. Thirteen (1.4%) patients (1.1%, aged 70 years or younger) were confirmed to experience Lynch syndrome through germline testing, and 8 first-degree relatives (an average of 1.6 per patient) underwent cascade genetic testing. DISCUSSION: The first Canadian Lynch syndrome screening program has achieved high rates of reflex testing.

Telephone versus in-person colorectal cancer risk and screening intervention for first-degree relatives: A randomized controlled trial.

BACKGROUND: Having a first-degree relative (FDR) with colorectal cancer (CRC) is a significant risk factor for CRC. Counseling for FDRs regarding CRC risk factors and personalized risk is important to improve knowledge and screening compliance. METHODS: A 3-arm randomized controlled trial compared tailored in-person and telephone CRC counseling interventions with controls among FDRs who were not mutation carriers for known hereditary cancer syndromes, but who were considered to be at an increased risk based on family history. It was hypothesized that both telephone and in-person approaches would increase CRC knowledge, screening adherence, perceived risk accuracy, and psychosocial functioning compared with controls. The authors anticipated greater satisfaction with the in-person approach. CRC knowledge, risk perception, psychosocial functioning, and intention to screen were assessed at baseline and at 2-week and 2-month follow-ups (primary endpoint). RESULTS: A total of 278 FDRs (mean age, 47.4 years, standard deviation, 11.38 years) participated. At baseline, participants reported low to moderate CRC knowledge and overestimations of risk. Screening adherence was 73.7%. At 2 months, participants in the in-person arm and telephone arm demonstrated improvements in knowledge and perceived risk and were not found to be statistically different from each other. However, when comparing each intervention with controls, knowledge in the in-person arm was found to be statistically significantly higher, but the difference between the telephone and control arms was not. Cancer-related stress reduced over time in all groups. Intervention benefits were maintained at 1 year. Baseline screening intent/adherence were high, and therefore did not reach statistically significant improvement. CONCLUSIONS: Tailored in-person or telephone formats for providing CRC risk counseling, incorporating behavioral interventions, appear to improve knowledge and risk perceptions, with high client satisfaction.

Psychosocial Impact of Lynch Syndrome on Affected Individuals and Families.

INTRODUCTION: Lynch syndrome is the most common hereditary colorectal cancer syndrome, conferring a heightened risk not only of colon cancer but also of various extracolonic tumors. Studies in hereditary breast cancer have shown a negative psychological impact for patients testing positive for BRCA1 or BRCA2 mutations, but there is a paucity of literature looking at psychosocial impact of LS testing for probands and families. METHODS: A literature search of PubMed English-language articles was performed using the keywords "Lynch syndrome" combined with "psychological impact," "depression," and "anxiety." RESULTS: Lynch syndrome mutation carriers, whether or not they have had cancer, suffer a transient increase in depression and anxiety scores post-disclosure, which seem to normalize by 6-12 months. Younger patients with higher colorectal cancer risk perception, higher education level, married, and employed are more likely to accept genetic testing. Major motivators for testing are predicting one's own risk of cancer and risk to offspring. Carrier status influences family planning, and there is growing interest for preimplantation genetic diagnosis. CONCLUSIONS: Psychosocial ramifications of LS mutation positivity need to be explored further.

Moderators of cancer-related distress and worry after a pancreatic cancer genetic counseling and screening intervention.

OBJECTIVES: Although the hereditary breast and ovarian cancer literature has demonstrated short-term gains in psychological adjustment following genetic counseling, there has been limited research examining long-term outcomes and moderators. Moreover, there has been minimal research into the psychological effects of this intervention in populations at high risk for pancreatic cancer. This study examines the long-term effects of pancreatic cancer screening and genetic counseling on cancer-related distress and cancer worry in a high-risk population at 1-year follow-up. Additionally, this study explores potential moderators of the effectiveness of this intervention. METHODS: One hundred twenty-nine participants with familial pancreatic cancer or with the BRCA2 gene mutation completed a baseline questionnaire prior to their first pancreatic cancer screening and genetic counseling session. Participants also completed questionnaires at 3- and 12-month follow-up. RESULTS: Cancer-related intrusive thoughts decreased significantly over time, whereas cancer-related worry decreased at 3 months and showed a small but significant increase at 1 year. Age and baseline distress exhibited moderator effects. Younger individuals showed a significant decrease in cancer-related intrusive thoughts, cancer-related avoidant thoughts, and cancer worry. Additionally, individuals with greater baseline distress showed a significant decrease in cancer-related intrusive thoughts over time. CONCLUSIONS: Analysis of the long-term effects of pancreatic cancer screening and genetic testing reveal psychological gains that are maintained at 1-year follow-up. This intervention is particularly effective for younger participants and individuals with greater baseline distress.

Management of pancreatic adenocarcinoma in Ontario, Canada: a population-based study using novel case ascertainment.

BACKGROUND: Pancreatic adenocarcinoma (PA) is largely incurable, although recent progress has been made in the safety of surgery for PA and in adjuvant and palliative chemotherapy. The purpose of this study was to describe the management of PA in Ontario, Canada. METHODS: The Pathology Information Management System (PIMS), which uses electronic pathology reporting (E-path), was used to rapidly identify and recruit patients based on a pathologic diagnosis of PA between 2003 and 2006. Patients were mailed questionnaires for additional data. RESULTS: The patient participation rate was 26% (351 of 1325). Nonresponders were more likely to be older than 70 years (43% v. 28%, p < 0.001) and to have received treatment in nonacademic centres (53% v. 34%, p < 0.001). Fifty-four percent of responders underwent a potentially curative operation, and most (77%) were 70 years or younger (p = 0.03). Completed resections were documented in 83% of patients who underwent exploratory surgery with curative intent; 17% of patients had unresectable and/or metastatic disease at laparotomy. Of the completed resections, 24% were performed in nonacademic centres with a 32% positive margin rate; 76% were performed in academic centres with a 29% positive margin rate (p = 0.84). Resections with curative intent were less frequently aborted in academic centres (10% v. 33%, p < 0.001). Of the patients who responded to our questionnaire, 43% received chemotherapy and 7% participated in clinical trials. CONCLUSION: Despite using PIMS and E-path, the response rate for this study was low (< 30%). Nonresponders were older and more commonly treated in nonacademic centres. Patients undergoing surgery in academic centres had higher resection rates. The rate of adjuvant and palliative chemotherapy was stage-dependent and low.

Immune Checkpoint Inhibition as Primary Adjuvant Therapy for an IDH1-Mutant Anaplastic Astrocytoma in a Patient with CMMRD: A Case Report-Usage of Immune Checkpoint Inhibition in CMMRD.

Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive hereditary cancer syndrome due to biallelic germline mutation involving one of the four DNA mismatch repair genes. Here we present a case of a young female with CMMRD, homozygous for the c.2002A>G mutation in the PMS2 gene. She developed an early stage adenocarcinoma of the colon at the age of 14. Surveillance MRI of the brain at age 18 resulted in the detection of an asymptomatic brain cancer. On resection, this was diagnosed as an anaplastic astrocytoma. Due to emerging literature suggesting benefit of immunotherapy in this patient population, she was treated with adjuvant dual immune checkpoint inhibition, avoiding radiation. The patient remains stable with no evidence of progression 20 months after resection. The patient's clinical course, as well as the rational for considering adjuvant immunotherapy in patients with CMMRD are discussed in this report.

Hereditary colorectal cancer screening: A 10-year longitudinal cohort study following an educational intervention.

Family history (FH) of a first-degree relative with colorectal cancer (CRC) is associated with two to fourfold increased risk, yet screening uptake is suboptimal despite proven mortality reduction. We developed a FH-based CRC Risk Triage/Management tool for family physicians (FPs), and educational booklet for patients with CRC FH. This report describes physician referral and patient screening behavior 5 and 10 years post-educational intervention, and factors associated with screening. Longitudinal cohort study. FPs/patients in Ontario and Newfoundland, Canada were sent questionnaires at baseline (2005), 5 and 10 years (2015) following tool/booklet receipt. FPs were asked about CRC screening, patients about FH, screening type and timing. "Correct" screening was concordance with tool recommendations. Results reported for 29/121 (24%) FPs and 98/297 (33%) patients who completed all 3 questionnaires. Over 10 years 2/3 patients received the correct CRC screening test at appropriate timing (baseline 75%, 5-year 62%, 10-year 65%). About half reported their FP recommended CRC screening (5-year 51%, 10-year 63%). Fewer than half the patients correctly assessed their CRC risk (44%, 40%, 41%). Patients were less likely to have correct screening timing if female (RR 0.78; 95% CI 0.61, 0.99; p = 0.045). Patients were less likely to have both correct test and timing if moderate/high CRC risk (RR 0.66; 95% CI 0.47, 0.93; p = 0.017) and more likely if their physician recommended screening (RR1.69; 95% CI 1.15, 2.49; p = 0.007). Physician discussion of CRC risk and screening can positively impact patient screening behavior. Efforts are particularly needed for women and patients at moderate/high CRC risk.

Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.

Although the association of germline BRCA2 mutations with pancreatic adenocarcinoma is well established, the role of BRCA1 mutations is less clear. We hypothesized that the loss of heterozygosity at the BRCA1 locus occurs in pancreatic cancers of germline BRCA1 mutation carriers, acting as a "second-hit" event contributing to pancreatic tumorigenesis. Seven germline BRCA1 mutation carriers with pancreatic adenocarcinoma and nine patients with sporadic pancreatic cancer were identified from clinic- and population-based registries. DNA was extracted from paraffin-embedded tumor and nontumor samples. Three polymorphic microsatellite markers for the BRCA1 gene, and an internal control marker on chromosome 16p, were selected to test for the loss of heterozygosity. Tumor DNA demonstrating loss of heterozygosity in BRCA1 mutation carriers was sequenced to identify the retained allele. The loss of heterozygosity rate for the control marker was 20%, an expected baseline frequency. Loss of heterozygosity at the BRCA1 locus was 5/7 (71%) in BRCA1 mutation carriers; tumor DNA was available for sequencing in 4/5 cases, and three demonstrated loss of the wild-type allele. Only 1/9 (11%) sporadic cases demonstrated loss of heterozygosity at the BRCA1 locus. Loss of heterozygosity occurs frequently in pancreatic cancers of germline BRCA1 mutation carriers, with loss of the wild-type allele, and infrequently in sporadic cancer cases. Therefore, BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and individuals with these mutations may be considered for pancreatic cancer-screening programs.

The prevalence of BRCA2 mutations in familial pancreatic cancer.

Mutations in the BRCA2 gene have been implicated in pancreatic cancer susceptibility through studies of high-risk breast and ovarian cancer families. To determine the contribution of mutations in BRCA2 to familial pancreatic cancer, we screened affected probands from 151 high-risk families identified through pancreatic cancer clinics for germ-line BRCA2 mutations. Of these families, 118 had two or more first- and second-degree relatives with pancreatic cancer, and an additional 33 had two or more affected second-degree relatives. The average age of onset for pancreatic cancer was 62.8 years. Five BRCA2 truncating mutations were identified, three in families with two or more first- and second-degree relatives with pancreatic cancer. Three of the families with mutations had a history of breast cancer but not ovarian cancer. Four of five families with mutations were identified through probands with early-onset (<55 years) pancreatic cancer. The results of this study were combined with those from a BRCA2 mutation study of 29 other families from the same Johns Hopkins University National Familial Pancreatic Tumor Registry to estimate the frequency of BRCA2 mutations. A total of 10 carriers from 180 families were identified, suggesting that BRCA2 mutations account for 6% of moderate and high-risk pancreatic cancer families.

Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.

BACKGROUND: Pancreatic adenocarcinoma is the fourth leading cause of cancer death. METHODS: A prospective cohort study was undertaken between 2003 and 2011 at a tertiary care centre in Toronto, Canada. Two hundred and sixty-two subjects were enrolled based on an elevated estimated lifetime risk for pancreatic cancer due to known genetic mutations and/or cancer family history. Subjects underwent annual magnetic resonance imaging, followed by additional investigations if abnormal findings were detected. Evidence of malignancy or suspicious macroscopic abnormalities prompted referral for surgical intervention. RESULTS: Average length of follow-up was 4.2 years, during which 84/262 (32%) subjects demonstrated pancreatic abnormalities. Three participants developed pancreatic adenocarcinoma (one 1.5-cm tumor was resected but recurred, while the other two subjects developed metastatic cancer), and a fourth participant developed a pancreatic neuroendocrine tumor that was resected. Fifteen subjects had radiologic evidence of branch-duct intraductal papillary mucinous neoplasms, of which two underwent surgical resection. Sixty-five subjects had simple pancreatic cysts that have remained stable. CONCLUSION: Magnetic resonance imaging can detect small pancreatic tumors and cystic lesions, but further improvement in sensitivity is needed. An understanding of the natural history of pre-invasive lesions in members of high-risk families is necessary for developing a more effective screening program.

Pancreatic cancer risk counselling and screening: impact on perceived risk and psychological functioning.

Individuals at increased risk for pancreatic cancer who undergo screening can experience psychological and emotional distress. The objective of this study is to determine whether individuals participating in a pancreatic cancer screening program experience disruptions in risk perception, cancer-related anxiety or emotional distress. A pretestposttest design was used to examine perceived risk and psychological functioning of individuals participating in a pancreatic cancer screening protocol. The screening protocol includes genetic counselling, transcutaneous abdominal ultrasound, magnetic resonance imaging, and blood collection and eligible participants included individuals with a family history of pancreatic cancer or BRCA2 mutation carriers. At baseline, participants (n = 198) showed low to moderate levels of risk perception, pancreatic cancer-related anxiety, and general distress. Participants with familial pancreatic cancer (FPC) (n = 131) endorsed higher risk perception of pancreatic cancer than the BRCA2 carriers (n = 67) (perceived lifetime risk 42 vs. 15%), but did not differ on cancer worry or general distress prior to the first study appointment. From baseline to 3 months follow-up, no significant time or time by group interactions emerged on risk perception or general distress, but cancer worry decreased over time for the FPC group regardless of the number of affected relatives. Our findings indicate that participation in a pancreatic cancer screening program does not lead to a significant increase in risk perception, cancer worry, or general distress and that participants with high baseline levels of risk perception and distress may benefit from a more comprehensive risk assessment and psychological support.

The P239S palladin variant does not account for a significant fraction of hereditary or early onset pancreas cancer.

The P239S palladin variant has recently been suggested to play a role in hereditary pancreatic cancer. We estimated the contribution of the P239S variant, and surrounding sequence, to familial and early-onset pancreatic cancer. The P239S germline variant was identified in one of 84 high-risk cases and one of 555 controls. The case reported an elderly relative with pancreas cancer. We conclude that this variant does not appear to account for a significant fraction of hereditary or early-onset pancreas cancer.

Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation.

Heterozygous germline DNA mismatch repair gene mutations are typically associated with hereditary nonpolyposis colorectal cancer. The molecular hallmark of this syndrome is high-frequency microsatellite instability in the tumors. Rare childhood cases with homozygous or compound heterozygous DNA mismatch repair gene mutations have a described predisposition to leukemia, lymphoma, and brain tumors but not to gastrointestinal cancer. We have now characterized a family in which 2 children with a homozygous germline DNA mismatch repair gene mutation developed early-onset gastrointestinal cancers. The 11-year-old proband had café-au-lait macules and developed metastatic duodenal adenocarcinoma that arose in a tubulovillous adenoma. His 9-year-old sister with café-au-lait macules and axillary freckling presented with malignant colon polyps. A 6-year-old sister with café-au-lait macules, hairy nevi, and a plexiform neurofibroma of the tongue has no malignancies to date. The family history did not fulfill the Amsterdam criteria for hereditary nonpolyposis colorectal cancer, but 2 relatives in their 60s had gastric cancer and colorectal cancer, whereas the parents, who are first cousins, remain cancer free. The proband's metastatic duodenal cancer and his sister's malignant colon polyps had high-frequency microsatellite instability but had detectable MLH1, MSH2, and MSH6 proteins by immunohistochemistry. Because some germline DNA mismatch repair gene deficiencies are associated with apparently intact immunohistochemical DNA mismatch repair gene expression in tumors, we proceeded to DNA sequencing, which showed that all 3 children had a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGG-->TGG), whereas both parents were heterozygous for this mutation.