M.E. Velthuizen

Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk

PURPOSEnThe clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.nnnMETHODSnData were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.nnnRESULTSnThe cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.nnnCONCLUSIONnCRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.

Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study

Purpose: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). Experimental Design: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. Results: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001). Conclusions: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).

Effect of Routine Assessment of Specific Psychosocial Problems on Personalized Communication, Counselors' Awareness, and Distress Levels in Cancer Genetic Counseling Practice: A Randomized Controlled Trial

PURPOSEnThis study evaluated the efficacy of a cancer genetics–specific questionnaire in facilitating communication about, awareness of, and management of psychosocial problems, as well as in lowering distress levels.nnnMETHODSnIndividuals referred to genetic counseling for cancer at two family cancer clinics in The Netherlands were randomly assigned to an intervention or a control group. All participants completed the psychosocial questionnaire before counseling. In the intervention group, the counselors received the results of this questionnaire before the counseling session. All sessions were audiotaped for content analysis. Primary outcomes were the frequency with which psychosocial problems were discussed, the genetic counselors’ awareness of these problems, and their management. Secondary outcomes included cancer worries and psychological distress, duration and dynamics of the counseling, and satisfaction.nnnRESULTSnThe frequency with which psychosocial problems were discussed with 246 participating counselees was significantly higher in the intervention group (n = 127) than in the control group (n =119; P = .004), as was the counselors’ awareness of psychosocial problems regarding hereditary predisposition (P < .001), living with cancer (P = .01), and general emotions (P < .001). Counselors initiated more discussion of psychosocial problems in the intervention group (P < .001), without affecting the length of the counseling session. No significant differences were found on management (P = .19). The intervention group reported significantly lower levels of cancer worries (p = .005) and distress (p = .02) after counseling.nnnCONCLUSIONnThe routine assessment of psychosocial problems by questionnaire facilitates genetic counselors’ recognition and discussion of their clients’ psychosocial problems and reduces clients’ distress levels.

Active approach for breast cancer genetic counseling during radiotherapy: long‐term psychosocial and medical impact

Genetic counseling and DNA testing (GCT) for breast cancer is increasingly being actively offered to newly diagnosed patients. Little is known about the consequences of such an approach. Therefore, the long‐term psychosocial and medical impact of referring breast cancer patients for GCT during an early phase of treatment was studied. A group of 112 breast cancer patients who had been actively offered GCT during adjuvant radiotherapy 7–14u2009years earlier, returned a self‐report questionnaire. We compared their experiences with a group of 127 breast cancer patients who had not met the criteria for GCT. In total, 239 women participated in this long‐term follow‐up study (72% response rate). Nearly 75% of them had received regular mammography surveillance in the past 3u2009years. Preventive surgery was reported more often in the counseling group (specifically in the BRCA1/2 mutation carriers). Like the comparative group, only a minority of patients who had received GCT were experiencing high levels of depression (5%) or psychological distress (14%). Breast cancer patients can be actively approached and referred for GCT at the beginning of their radiotherapy without a threat to psychological functioning in the long term.

Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer: contributions from the Dutch Lynch syndrome registry

The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.

Routine assessment of psychosocial problems after cancer genetic counseling : Results from a randomized controlled trial

Approximately 70% of counselees undergoing cancer genetic counseling and testing (CGCT) experience some degree of CGCT‐related psychosocial problems. We evaluated the efficacy of an intervention designed to increase detection and management of problems 4u2009weeks after completion of CGCT. In this randomized, controlled trial, 118 participants completed a CGCT‐related problem questionnaire prior to an – audiotaped – telephone session with their counselor 1u2009month after DNA‐test disclosure. For those randomized to the intervention group (nu2009=u200963), a summary of the questionnaire results was provided to the counselor prior to the telephone session. Primary outcomes were discussion of the problems, counselors awareness of problems, and problem management. Secondary outcomes included self‐reported distress, cancer worries, CGCT‐related problems, and satisfaction. Counselors who received a summary of the questionnaire were more aware of counselees problems in only one psychosocial domain (practical issues). No significant differences in the number of problems discussed, in problem management, or on any of the secondary outcomes were observed. The prevalence of problems was generally low. The telephone session, combined with feedback on psychosocial problems, has minimal impact. The low prevalence of psychosocial problems 1u2009month post‐CGCT recommends against its use as a routine extension of the CGCT procedure.

Migrant breast cancer patients and their participation in genetic counseling : results from a registry-based study

Certain ethnic groups seem to have less access to cancer genetic counseling. Our study was to investigate the participation in cancer genetic counseling among migrant breast cancer patients of Turkish and Moroccan origin. Hospital medical records of Turkish and Moroccan and of a comparative group of non-Turkish/Moroccan newly diagnosed breast cancer patients were studied. All women were diagnosed between 2007 and 2012. Eligibility for genetic counseling was assessed with a checklist. A total of 156 Turkish/Moroccan patients were identified, and 321 patients were assigned to the comparative group. About one third (35xa0%) of the Turkish/Moroccan patients fulfilled criteria for breast cancer genetic counseling, compared to 21xa0% of the comparative group (Pxa0=xa00.001); this was largely due to a relatively young age at diagnosis in the migrant group (26xa0% <40xa0years vs 5xa0% in the comparative group, Pxa0=xa00.0001). Uptake of genetic counseling among eligible patients was 47xa0% in the migrant group and 56xa0% in the comparative group; differences in uptake were seen among the patients diagnosed before 40xa0years of age (48xa0% in the migrant group vs 81xa0% in the comparative group; Pxa0=xa00.021). When adjusted for age at diagnosis, ethnicity was associated with discussing referral to genetic counseling and its actual uptake. The Turkish/Moroccan ethnicity appears to be associated with a lower uptake of genetic counseling, mainly caused by the lower uptake in the young age-group. The major barrier to participation in genetic counseling seems to lie within the referral process.

Referral to cancer genetic counseling: do migrant status and patients’ educational background matter?

Participation rates in cancer genetic counseling differ among populations, as patients with a lower educational background and migrant patients seem to have poorer access to it. We conducted a study to determine the present-day educational level and migrant status of counselees referred to cancer genetic counseling. We assessed personal characteristics and demographics of 731 newly referred counselees. Descriptive statistics were used to describe these characteristics. The results show that about 40% of the counselees had a high educational level and 89% were Dutch natives. Compared to the Dutch population, we found a significant difference in educational level (pxa0=xa0<xa00.01) and migrant status (pxa0=xa0<xa00.001). This suggests disparities in cancer genetic counseling and as a result of that, suboptimal care for vulnerable groups. Limited health literacy is likely to pose a particular challenge to cancer genetic counseling for counselees with a lower education or a migrant background. Our study points to considerable scope for improvement in referring vulnerable groups of patients for cancer genetic counseling.

Breast cancer genetic counseling among Dutch patients from Turkish and Moroccan descent: participation determinants and perspectives of patients and healthcare professionals

Lower participation rates in cancer genetic counseling are observed among different ethnic minorities. The goal of our study is to gain insight into determinants of Turkish and Moroccan patients’ participation in breast cancer genetic counseling and DNA testing, from the point of view of healthcare professionals and patients. Questionnaire-based telephone interviews about awareness, perceptions, and reasons for (non-) participation in cancer genetic counseling were conducted with 78 Dutch breast cancer patients from Turkish and Moroccan descent. The interviews were held in Arabic, Berber, Turkish, or Dutch by bilingual research assistants. Additionally, 14 breast cancer patients participated in one of two focus group meetings, and two focus groups were held with 11 healthcare professionals. SPSS and QSR Nvivo were used to examine the quantitative and qualitative data, respectively. Half of the total group of patients (Nxa0=xa078) and 79% of patients eligible for genetic counseling and testing (Nxa0=xa033) were aware of the possibility of genetic counseling. The most important determinants for nonparticipation in genetic counseling were experienced difficulties in patient-doctor communication, cultural factors (e.g., social norms), limited health literacy, limited knowledge of the family cancer history, and anxiety about cancer. Religious beliefs and knowing personal and family members’ breast cancer risks were motives to obtain genetic counseling. Despite the fact that our study showed that Moroccan and Turkish women reported several personal motives to obtain genetic counseling and testing (GCT), patients and healthcare professionals experience significant language and health literacy difficulties, which make it harder to fully access health care such as genetic counseling and testing.

Genetic counselling of young women with breast cancer for Li–Fraumeni syndrome: a nationwide survey on the experiences and attitudes of genetics professionals

Germline TP53 mutations are associated with an increased risk of early-onset breast cancer. Traditionally, it was not standard practice to offer TP53 genetic testing due to the low mutation detection rate and limited options regarding preventive screening. Recent guidelines recommend that all women diagnosed with breast cancer before the age of 31, irrespective of family history, should be offered TP53 genetic testing. This study aims to gain more knowledge on the attitudes and experiences among genetics professionals regarding the timing and content of genetic counselling of young breast cancer patients for Li–Fraumeni syndrome (LFS). We conducted a nationwide online survey among genetics professionals who provide cancer genetic counselling in the Netherlands. Fifty-seven professionals completed the questionnaire (response rate overall 54%, clinical geneticists 70%). Most respondents reported that they discuss the option of TP53 genetic testing—simultaneously with BRCA 1/2—during the initial counselling visit, especially in case of referral for treatment-focused genetic counselling. There was a general consensus about ten information items that should be discussed during counselling. Sixty-one percent of genetics professionals did not encounter difficulties in providing genetic counselling for LFS, but a substantial minority (29%) did. This study offers valuable insight, which will be useful for clinical practice. Studies which address young breast cancer patients’ attitudes and preferences regarding the timing and content of counselling are warranted to further determine the most appropriate genetic counselling strategy for these women.