Recruitment of participants

Responses to recruitment are shown in Supplementary Table 1. Approximately two-thirds of non-PV carriers (477 of 756, 63.1%) wished to know their genomic results, even though they were not notified of the names of genes to be returned or of disease risks. The invitation letter was sent to 238 PV carriers (HBOC: 167, LS: 71). A reminder letter regarding the response was sent exclusively to PV carriers. After the second round of reminder letters, 129 PV carriers (HBOC: 85, LS: 44) accepted the invitation and a study information session was arranged for them at the nearest local assessment center (Supplementary Table 1). Of the 129 PV carriers who accepted the invitation, 113 attended the study information session in person and 112 consented to participate in the study (Fig. 2). The remaining 16 individuals who accepted the invitation were unable to attend the information session due to various personal reasons. One male BRCA1 PV carrier refused to participate in the study despite having attended an information session. Blood sampling for single-site analysis and the first QS were conducted after IC was obtained. The results of the single-site analysis were verified with those of the WGS and were returned to the participants in person.

Fig. 2

Overview of the study participants. The number of participants and their responses to the study process are presented. QS: questionnaire survey

The results of non-PV carriers who accepted the invitation were sent by mail. We provided an outline of the study, including the technical limitations of WGS. We also provided a URL (https://www.megabank.tohoku.ac.jp/activity/localhealth/rogr/movie) of an educational video for non-PV carriers that we originally created and uploaded on social media.

Individual variant and cancer incidence

The list of PVs and number of participants with HBOC and LS are shown in Supplementary Tables 2 and 3, respectively. There were 28 and 51 PV carriers of BRCA1 and BRCA2, respectively. Among them, 11 BRCA1 and BRCA2 PV carriers had a history of cancer. Three PVs, BRCA1 c.188 T > A, BRCA2 c.5576_5579del TTAA, and BRCA2 c.6592 C > T, which are frequently found in Japanese HBOC patients (ref. [25,26,27]), had more than 10 carriers (Supplementary Table 2). Five and nine PVs of BRCA1 and BRCA2, respectively, were not identified in our previous dataset from 3 352 participants (3.5KJPNv2) (ref. [28]), in a report using samples from the Biobank Japan (7 051 breast cancer patients and 11 241 controls) (ref. [25]), in the HBOC registration system of Japan reported in 2018 (127 and 115 BRCA1 and BRCA2 PV carriers, respectively) (ref. [26]), and in Japanese ovarian cancer patients (ref. [27]). The number of PV carriers of MLH1, MSH2, MSH6, and PMS2 were six, one, nine, and five, respectively. Eight patients had a history of cancer. There were three PV carriers for MSH6 c.3226 C > T and ≤2 for other PVs (Supplementary Table 3). None of the PVs, except MLH1 c.199 G > A, were reported in the variants in a previous study (ref. [29]) involving 2 501 Japanese cancer patients or in data from the Japanese Society of Cancer of the Colon and Rectum reported in 2017 (ref. [30]).

Although the results of single-site analysis of all BRCA1 and BRCA2 variant carriers matched those of WGS, there was a discrepancy between the single-site analysis and WGS in four variants of the 12 LS participants (Supplementary Fig. 1). Three individuals with the MLH1 variant c.2080 G > T (p.E694*) had another variant in an adjacent nucleotide (c.2081 A > C) in the same allele, resulting in the missense variant c.2080_2081inv (p.E694S). This variant has been previously reported and annotated as VUS (ref. [31]). In addition, three PVs from nine participants were not identified in the single-site analysis. All of these were the variants in or adjacent to the homopolymer regions that were supposed to be challenging for WGS-based screening. We informed participants of the unanticipated results and the inherent limitations of WGS technology. Besides, we performed single-site analysis for the MSH2 c.942 + 3 A > T variant on 23 individuals using DNA samples stored in our biobank, rather than freshly-prepared blood samples. This was done because these individuals had accepted the invitation but were not scheduled for the study information session at that time. As none of these samples tested positive for the variant, we did not arrange an information session for these participants. Instead, their results were communicated via postal mail.

Outline of the participants

The age group and sex of 112 PV carriers (HBOC: 79, LS: 33) who consented to participate in the study are shown in Table 1. At present, 108 individuals, including 12 non-PV carriers of LS, continue participation, whereas 4 participants (HBOC: 3, LS: 1) withdrew consent or discontinued contact. Thirty-seven males (HBOC: 25, LS: 12) and 75 females (HBOC: 54, LS: 21) participated in this study. Non-PV carriers of LS were 6 each for males and females. The median ages of HBOC and LS PV carriers were 41 and 62 years, respectively. There was a bimodal age distribution for both syndromes, and the difference of median ages between the syndromes was not statistically significant (P = 0.30, Mann-Whitney test). Most participants in their 40 s participated in the TMM Birth and Three-Generation Cohort Study (ref. [32]), whereas those in their 70 s participated in the TMM Community-Based Cohort Study (ref. [33]).

Table 1 Profiles of study participantsParticipants’ comprehension levels and cancer worry

Participants’ comprehension levels of the study information and cancer worry were assessed in the first QS. As shown in Fig. 2, 99 PV carriers (HBOC: 78, LS: 21) responded to the QS, and the results were examined using correlation analysis. The items, choices, and ratios of correct answers on the comprehension test are shown in Supplementary Table 4 Although all items were communicated to the participants in person, the ratio of correct answers varied from 42 to 100%. The mean and standard deviation of the total scores of correct answers was 6.2 and 1.4, respectively. The total score on the comprehension test significantly correlated with participants’ age and sex (Fig. 3A). The mean score of participants aged <60 years was significantly greater than that of participants aged ≥60 years (6.48 ± 1.03 vs. 5.64 ± 1.68; P = 0.0026). When the mean score of younger (<60) and older (≥ 60) participants was compared in females and males separately, the difference was significant in females (6.60 ± 0.93 vs. 5.85 ± 1.50; P = 0.013) and non-significant in males (5.75 ± 1.39 vs. 5.42 ± 1.87; P = 0.659). The mean score of younger females was significantly higher than that of younger (P = 0.030) and older males (P = 7.7 × 10-4). None of the factors other than age and sex was significantly correlated with the comprehension test score.

Fig. 3

Related analysis of the comprehension test, CWS-J, K6, and cancer history. A Distribution of the comprehension test score. Participants were divided into two age groups ( < 60 and ≥ 60), and the scores are shown separately. B Frequency of the answers to items #1 to #8 of the CWS-J. Dark and light colored bars indicate answers from participants who had cancer (n = 28) and those who never had cancer (n = 71), respectively. *, **, ns: comparison of the frequency of answers “often” and “always” from the cancer experienced vs. never had cancer groups. *: P < 0.05, **: P < 0.01, ns: not significant. C Distribution of the K6 (upper panel) and CWS-J (lower panel) scores. Scores and number of participants are indicated. D Average CWS-J scores of the four participant groups. The participants were grouped according to the K6 score ( < or ≥2) and cancer experience. The number of participants in each group is shown at the bottom. E Distribution of the K6 (upper panel) and CWS-J (lower panel) score changes over 12 months. Differences in scores (QS2-QS1) are indicated

The CWS-J items are listed in Supplementary Table 5. The answers for each item of the participants with a history of cancer (n = 28) and those who never had cancer (n = 71) are shown in Fig. 3B. In all items except item #3, the frequencies of the answer “often” or “always” were higher in participants with a history of cancer than in those who never had cancer. The differences were statistically significant for items #1, #4, #5, #6, and #8 (Fig. 3B). When the answers “rarely,” “occasionally,” “often” and “always” were scored as 0, 1, 2, and 3, respectively, the average total scores of participants with a history of cancer (mean ± standard deviation: 9.5 ± 5.3) were significantly greater than those of participants never had cancer (6.0 ± 3.9, P = 3.8 × 10-4).

In the first QS, the K6, which might be influenced by general psychological distress, was conducted in conjunction with the CWS-J. The histograms of the K6 and CWS-J scores are shown in Fig. 3C. The average score was 2.1 ± 2.4 and 2.5 ± 2.7 for with and without cancer history, respectively (P = 0.542). Although the average score was not affected by the cancer history, the individual K6 score was significantly correlated with the CWS-J score (correlation coefficient: 0.283, P = 0.0046). A variance analysis of the CWS-J with factors including age, sex, K6 score, and cancer history suggested a synergistic effect of the K6 score and cancer history (P = 0.017 for the interaction term). When participants were divided into four groups according to the K6 score and cancer experience, the mean CWS-J score was the highest in participants with a high K6 score and positive cancer history (Fig. 3D). Moreover, it is noteworthy that none of the examined factors—including disease type, age, sex, comprehension level, CWS-J score, K6 score, and cancer history—correlated with participants’ attitudes toward addressing their genomic risks at the hospital. We analyzed the scores of the comprehension test, CWS-J, and K6 from PV carriers of BRCA1/2 and MMR-related genes separately to test for any differences between these groups. Interestingly, the average K6 score was significantly higher in participants with HBOC compared to those with LS (2.67 ± 2.8 vs 1.19 ± 2.8, P = 0.022; t-test). However, the average CWS-J score was comparable between participants with HBOC and LS. Notably, the number of participants who had previously had cancer was higher in the LS group than in the HBOC group. Therefore, we surmise that the higher K6 scores in HBOC participants were not directly influenced by their cancer genetic risks. No significant difference was observed in the comprehension test scores between HBOC and LS participants.

We evaluated K6 and CWS-J scores at two time points: at the time of obtaining IC (first time point) and 12-month following the ROGR (second time point). Of 96 PV carriers who received the second QS, 81 individuals completed both assessments for K6 and CWS-J. The correlation coefficient between the first and second assessment were 0.758 (P = 2.7 × 10-16) for K6 and 0.525 (P = 4.7×10-7) for CWS-J. The means and standard deviations of the K6 scores were 2.37 ± 2.69 at the first time point and 2.47 ± 3.82 at the second time point, with a P-value of 0.72. For the CWS-J scores, the means and standard deviations were 7.44 ± 4.68 at the first time point and 7.04 ± 5.52 at the second time point, with a P-value of 0.467. Figure 3E shows a histogram of the difference in scores between the two time points for K6 and CWS-J. The highest columns were between −2 and −1 in both K6 and CWS-J. These results suggest that knowing their genetic results had little impact on participants’ mood and worry about cancer.

Participant follow-up in medical institutes

All participants who underwent the ROGR session (HBOC:77, LS: 20) were advised to visit TUH. For four and three HBOC and LS participants, respectively, who had cancer and were followed up in other medical institutes, we directly created a patient referral document with genetic information for an attending doctor. Fifty-eight and thirteen HBOC and LS participants were referred to TUH, respectively (Fig. 4). Nineteen participants (HBOC: 15, LS: 4) refused to visit any medical institute. We asked participants to provide reasons for refusing hospital visits, allowing multiple responses. Six of them had once accepted to visit TUH but canceled thereafter or could not be contacted. Other participants stated several reasons for not visiting hospitals: nine of them raised personal reasons, such as old age, being busy with work, or raising children; six raised the burden of medical expenses; and five stated that TUH was too far from their place. Three participants who never had cancer believed that medical surveillance may not necessarily be valuable for themselves.

Fig. 4

Clinical management of participants at Tohoku University Hospital. The number of participants who had the ROGR session and clinical management at Tohoku University Hospital is shown. The profiles of HBOC female participants who had breast and/or ovarian cancer are shown in Supplementary Table 4

Of the 58 HBOC participants who visited TUH, 15 were males and 43 were females. There were 21 and 37 PV carriers of BRCA1 and BRCA2, respectively. Most females visited both the Breast and Endocrine Surgical Oncology and Gynecology and Obstetrics departments on the same day. All males visited only the Breast and Endocrine Surgical Oncology department. Seventeen HBOC patients who visited TUH had various types of cancer, two of whom had multiple cancers. The profiles of 14 HBOC participants with breast and/or ovarian cancer are shown in Supplementary Table 6. Six breast cancer participants had contralateral risk reducing mastectomy. One participant (#4) decided to have a contralateral risk reducing mastectomy that was motivated by participating in this study. Similarly, two participants (#7 and #8) were motivated to undergo a risk reducing salpingo‒oophorectomy (RRSO) by the study participation. In addition, three participants who never had cancer underwent RRSO (Fig. 4). Two participants were diagnosed with cancer (#13: ovarian cancer and #14: right breast cancer) and received treatment. Of the 13 LS participants who visited TUH, four were male and nine were female. The numbers of PV carriers for MLH1, MSH2, MSH6, and PMS2 were five, one, five, and two, respectively. Six of the thirteen participants had a history of cancer and four had multiple types of cancer (Fig. 4). None of the participants or their families were diagnosed with LS. One participant was diagnosed with colon cancer and underwent treatment. Twelve participants (HBOC: 6, LS: 6) were referred to the Department of Gastroenterology for surveillance. Following the first visit to TUH, 5 and 7 HBOC and LS participants, respectively, were referred to other hospitals, and 59 (HBOC: 53, LS: 6) had a second appointment at TUH (Fig. 4).

Family history of cancer and sharing genomic results with relatives

The cancer types identified in the relatives of HBOC participants who visited TUH are shown in Fig. 5A. Stomach cancer was the most common type of cancer, followed by breast cancer. The 58 HBOC participants were asked whether information about genetic risk was shared with their family members (Fig. 5B). The results revealed that the offsprings were more informed about genetic risks by the participants than their parents (P = 9.9 × 10-6), and females were more informed than males (P = 0.014). However, only one female offspring decided to undergo genetic counseling and single-site analysis at the Department of Medical Genetics. She visited there 2 months after the first consultation at a clinical oncologist. According to the information from TUH, no other relatives underwent genetic counseling and single-site analysis at TUH.

Fig. 5

Family history of cancer and sharing genomic results with relatives in HBOC carriers. A Number of first- and second-degree relatives who had certain types of cancers as indicated. B Number of first-degree relatives with whom the participants shared or did not share genomic results. The first-degree relatives are shown separately according to sex and generation. n: the number of accessible relatives