Parents' expectations, preferences, and recall of germline findings in a childhood cancer precision medicine trial.

BACKGROUND: Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child's and family's future cancer risk. Understanding parents' perspectives of germline genome sequencing is critical to successful clinical implementation. METHODS: A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child's results, including clinically relevant germline findings (received by 13% of parents). Parents' expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth. RESULTS: At trial enrollment, most parents (63%) believed it was at least "somewhat likely" that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child's genome sequencing results by their child's clinician. CONCLUSIONS: Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.

Hopes, concerns, satisfaction and regret in a precision medicine trial for childhood cancer: a mixed-methods study of parent and patient perspectives.

BACKGROUND: Paediatric precision oncology aims to match therapeutic agents to driver gene targets. We investigated whether parents and patients regret participation in precision medicine trials, particularly when their hopes are unfulfilled. METHODS: Parents and adolescent patients completed questionnaires at trial enrolment (T0) and after receiving results (T1). Parents opted-in to an interview at T1. Bereaved parents completed a questionnaire 6-months post-bereavement (T1B). We analysed quantitative data with R and qualitative data thematically with NVivo, before integrating all data for interpretation. RESULTS: 182 parents and 23 patients completed T0; 108/182 parents and 8/23 patients completed T1; 27/98 bereaved parents completed T1B; and 45/108 parents were interviewed. At enrolment, participants held concurrent hopes that precision medicine would benefit future children and their child. Participants expressed concern regarding wait-times for receipt of results. Most participants found the trial beneficial and not burdensome, including bereaved parents. Participants reported high trial satisfaction (median scores: parents: 93/100; patients: 80/100). Participants expressed few regrets (parent median scores: parents: 10/100; bereaved parents: 15/100; patient regret: 2/8 expressed minimal regret). CONCLUSIONS: Even when trial outcomes did not match their hopes, parents and patients rarely regretted participating in a childhood cancer precision medicine trial. These data are critical for integrating participants' views into future precision medicine delivery.

Implementing gene curation for hereditary cancer susceptibility in Australia: achieving consensus on genes with clinical utility.

BACKGROUND: The strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles. METHODS: To promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols. RESULTS: Genes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information. CONCLUSION: Through an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.

Technology-Assisted, Group-Based CBT for Rural Adults' Depression: Open Pilot Trial Results.

Purpose: This pilot study assesses the association of Raising Our Spirits Together (ROST), a technology-assisted, group-based cognitive behavioral therapy for depression, with rural adults' depressive symptoms and anxiety. Method: Nine adults from rural Michigan participated in an open pilot of ROST. Clergy facilitated pilot groups. The pilot began in February 2020 in-person. Due to COVID-19, the pilot was completed virtually. Results: Mean depressive symptom scores, based on the PHQ-9, significantly decreased from pre-treatment (M = 14.4) to post-treatment (M = 6.33; t (8) = 6.79; P < .001). Symptom reduction was maintained at 3-month follow-up (M = 8.00), with a significant pattern of difference in depressive symptoms over time (F(2) = 17.7; P < .001; eta-squared = .689). Similar patterns occurred for anxiety based on the GAD-7. Participants attended an average of 7.33 of 8 sessions. Fidelity ratings were excellent. Discussion: ROST is a potentially feasible intervention for rural adults' depressive symptoms. ROST offers a promising model for increasing treatment access and building capacity in rural areas.

The design, implementation, and effectiveness of intervention strategies aimed at improving genetic referral practices: a systematic review of the literature.

PURPOSE: Despite rapid advancements in genetics and genomics, referral practices remain suboptimal. This systematic review assesses the extent to which approaches from implementation science have been applied to address suboptimal genetic referral practices. METHODS: A search of MEDLINE, EMBASE, and PsycINFO generated 7,794 articles, of which 28 were included. Lay barriers were mapped to the Theoretical Domains Framework (TDF) and interventions mapped to behavior change techniques. Use of implementation and behavior change frameworks was assessed, and the Theory and Techniques Tool used to determine theoretical alignment. RESULTS: Knowledge was the most frequent retrospectively TDF-coded barrier, followed by environmental context and resources, and skills. Significant referral improvements occurred in 56% of studies. Among these, the most frequent interventions were clinical data review systems, family history collection and referral tools, and embedding genetics staff into nongenetic specialties. Few studies used implementation frameworks or reported implementation outcomes, though some deployed intuitive strategies that aligned with theory. CONCLUSION: Genetic referral interventions are rarely informed by implementation and/or behavior change theories, limiting opportunities for learning across contexts. Retrospective coding has provided a suite of theoretically linked strategies, which may be useful for informing future efforts. Incorporating these strategies into clinical guidelines may facilitate operationalization within the system.

Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants.

BACKGROUND: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. METHODS: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. RESULTS: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. CONCLUSION: Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

How can Australia integrate routine genetic sequencing in oncology: a qualitative study through an implementation science lens.

PURPOSE: This study sought to determine genetics and oncology specialists' views of integrating BRCA1 and BRCA2 testing in epithelial ovarian and breast cancer into routine practice. METHODS: Qualitative interviews were designed using the Consolidated Framework for Implementation Research. Questions included experiences or views of the BRCA testing processes, implementation needs of oncology health professionals, perceived challenges, and future ideas for interventions to integrate genetic testing into oncology. RESULTS: Twenty-two participants were interviewed from twelve health organizations and four themes were identified: (1) embracing the shift to mainstream genetic testing, with the majority of participants viewing BRCA testing as clinically useful and routine use important for maintaining a patient centered process; (2) the need for communication networks and role delineation to integrate routine genetic testing; (3) factors that influence sustaining routine genetic testing, including ongoing training, resources and funding, real-world adaptation, system complexity, and champions; and (4) variation in system interventions for integrating routine genetic testing align to organizational context. CONCLUSION: Findings illustrate the need for integrating genetic testing into routine oncology, and that adaptation of interventions and processes is essential to sustain a feasible model. An understanding of individual and organizational implementation factors will help to prepare for future integration of routine genetic testing in other cancers.

Families' and health care professionals' attitudes towards Li-Fraumeni syndrome testing in children: A systematic review.

Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by germline TP53 mutations. Genetic testing is not routinely offered in asymptomatic children at risk of the condition as the benefits are debatable and the attitudes of families and health care professionals (HCPs) may vary. This review assessed the attitudes of families and HCPs towards offering genetic testing to children for LFS, with a focus on perceived advantages and disadvantages and involvement of children in the decision-making process. We searched three key databases (Medline, PsycINFO and EMBASE) to identify quantitative and qualitative studies. We screened 729 articles identifying eight studies for detailed review. Most parents perceived TP53 genetic testing to be beneficial in childhood, despite previous lack of surveillance guidelines. Parents raised some concerns, including decreased insurability and diminishing the child's autonomy. Most children tested reported no negative emotional concerns after testing, even if tested positive. Despite generally positive interest clinicians remain hesitant. Most families saw the value in involving children in decision-making. Families' acceptance of TP53 testing in childhood was high. This review highlights the need for research on the long-term psychosocial impacts of testing and the attitudes of families to be reflected in professional guidelines.

"I remember how I felt, but I don't remember the gene": Families' experiences of cancer-related genetic testing in childhood.

BACKGROUND: Genetic testing in children for hereditary cancer predisposition syndromes (CPSs) involves unique psychosocial and family-systems considerations. This retrospective study explored the perspectives and emotional reactions of parents and young adults about cancer-related genetic counseling and testing offered to children in the family. METHODS: Families were eligible if they had considered genetic testing for a child (≤18 years) within the family. Parents and young adults ≥16 years participated in semistructured interviews that we coded and identified key themes. We also quantitively assessed emotional distress, quality of life, impact of receiving genetic cancer risk information, and service-related satisfaction. RESULTS: From 35 interviews (26 parents, nine young adults), we identified themes spanning families' experiences from referral to genetic services to the longer term impact of receiving information about family cancer risk from testing of children. Supported by quantitative data, families generally described positive experiences of genetic services and reported benefits to genetic testing. Nevertheless, families faced unique emotional and relational challenges that changed over the family lifecycle. Those challenges differed according to whether the child was asymptomatic or had a cancer diagnosis at testing. Parents of children with cancer described genetic consultations as a secondary concern to the immediate stressors of their child's treatment. CONCLUSIONS: We conclude that the successful integration of cancer genetics into pediatric cancer care requires specialist pediatric genetic counseling and psychosocial support services that are able to respond to families' changing needs.

Health professional and at-risk BRCA young adult perspectives about information needs: What does Gen Y need to know?

Young adults at risk of a hereditary condition require the provision of accurate information to make an informed decision about genetic testing and risk management options. At-risk young adults' (18- to 40-year olds) preferences for information and resources, and genetic-related health professionals' (GHPs) views on young adults' information needs, are largely unknown in the literature. This study aimed to clarify and compare the information needs of emerging (18- to 25-year olds) and early (26- to 40-year olds) adults. Resource preferences of young adults were also explored. Findings are drawn from two datasets: questionnaires and semi-structured interviews with at-risk young adults from BRCA1 or BRCA2 families (N = 32), and focus groups with GHPs (N = 73) working in Australian familial cancer clinics. Both datasets were analyzed using framework analysis. Emerging adults, particularly those who had not attended a clinic, wanted to know the rationale for genetic testing and basic genetic facts. Early adults were concerned about reproductive issues and cancer risk for future or current children. Information needs reported by young adults but not reported by GHPs include male cancer risk, finding reputable information, understanding test results (e.g., negative), and understanding risk terminology (e.g., lifetime cancer risk). Young adults' satisfaction with current information received was suboptimal, yet uptake of genetic-related resources was generally low. Getting information to this cohort remains a challenge for GHPs. Emerging adults showed a preference to obtain information through technologically-based formats (e.g., websites, social media), whereas early adults used a wider range of formats (e.g., websites, booklets). Awareness of and access to genetic information prior to genetic clinic attendance is needed. A review of the utility of current resources available for at-risk young adults would be helpful.

Talking across generations: Family communication about BRCA1 and BRCA2 genetic cancer risk.

While family communication about a BRCA1 or BRCA2 (BRCA1/2) pathogenic variant can be a catalyst for the uptake of risk-reducing measures in young adults, disseminating information within families and across generations is complex. This study aimed to explore how young adults and their families communicate about a BRCA1/2 pathogenic variant, from a family systems perspective. In-depth family interviews and questionnaires (N = 67 individuals; 21 families) were completed at four metropolitan and regional genetic clinics in Australia. Data involved thematic analysis and interpretation based on family systems theory, including the use of standardized measures. Six key themes were identified and explored: (1) Responsibility to protect, (2) "It's a woman's problem," (3) Family culture influences communication, (4) Adversarial growth and connection, (5) Key events can be relational turning points, and (6) Health professionals can help. Family identities were solidified through the incorporation of a pathogenic variant in family scripts, while members of the family who held differing views to their families expressed less agreeableness and openness to disseminate information. The collective family's experience and perspective toward a pathogenic variant can influence a young adult's decision-making about genetic testing, risk-management, and family planning. The utilization of family therapy skills in routine practice would be helpful in facilitating communication and the inclusion of standardized measures is beneficial to identify individuals needing ongoing psychological support. Understanding relationship difficulties that arise from family members holding divergent views can offer insight into future research inquiry and areas of further training and clinical support.

Family history-taking practices and genetic confidence in primary and tertiary care providers for childhood cancer survivors.

BACKGROUND: There is growing impetus for increased genetic screening in childhood cancer survivors. Family history-taking is a critical first step in determining survivors' suitability. However, the family history-taking practices of providers of pediatric oncology survivorship care and the confidence of these providers to discuss cancer risks to relatives are unknown. PROCEDURE: Fifty-four providers completed semistructured interviews in total, which included eight tertiary providers representing nine hospitals across two countries (63% male, 63% oncologists, 37% nurses) and 46 primary care providers (PCPs) nominated by a survivor (59% male, 35% regional practice). We used content analysis and descriptive statistics/regression to analyze the data. RESULTS: Few tertiary (38%) or primary (35%) providers regularly collected survivors' family histories, often relying on survivors/parents to initiate discussions. Providers mostly took two-generation pedigrees (63% tertiary and 81% primary). Primary providers focused on adult cancers. Lack of time, alternative priorities, and perceived lack of relevance were common barriers. Half of all tertiary providers felt moderately comfortable discussing genetic cancer risk to children of survivors (88% felt similarly discussing risks to other relatives). Most primary providers lacked confidence: 41% felt confident regarding risks to survivors' children and 48% regarding risks to other relatives. CONCLUSIONS: While family history-taking will not identify all survivors suitable for genetics assessment, recommendations for regular history-taking are not being implemented in tertiary or primary care. Additional PCP-targeted genetic education is warranted given that they are well placed to review family histories of pediatric cancer survivors.

Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma.

BACKGROUND: Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH. METHODS: DNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293). RESULTS: Using massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant. CONCLUSIONS: Our studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.

Family Communication, Risk Perception and Cancer Knowledge of Young Adults from BRCA1/2 Families: a Systematic Review.

Understanding challenges in familial communication of cancer risk has informed genetic service delivery. Parent-child interactions have received considerable attention, but few studies focus on young adulthood experiences within BRCA1/2 families. Young adults are approaching, or at a life stage where awareness of hereditary cancer risk is vital for informed choice of risk management options. This review assesses family communication, risk perception and cancer knowledge held by 18-40 year old individuals who have a parent with a BRCA1/2 gene mutation or carry the gene mutation themselves. Thirteen papers met the inclusion criteria. One utilized a 'mixed methods' methodology and the remaining used a qualitative approach. Findings were synthesized into themes and reported narratively. In general, parents are communicating openly about genetic risk with young adult offspring, but there is evidence that some young adults are withholding information from their parents about their own test results. Risk perception is influenced by a family history of cancer, childbearing plans and health providers' advice. Misconceptions about genetic risk appear to be common and gaps in hereditary cancer knowledge are evident. It is unclear whether incorrect knowledge was passed from parents to offspring. Health providers need to provide developmentally appropriate services for emerging adults (18-25 years old), with particular support in navigating through risk management options.

Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

The psychological impact of genetic information on children: a systematic review.

PURPOSE: This review assessed the psychological impact that acquiring personal and familial genetic information has on children. We also examined the concordance between the available empirical data and clinical guidance/perspectives articles. METHODS: We screened 591 abstracts and identified 13 studies, representing 966 children. Ten studies assessed 386 children tested for familial adenomatous polyposis (n = 171), hereditary cardiac disease (n = 134), and other conditions (n = 81). Three studies addressed the impact of BRCA1/2 testing of a family member on 580 children. RESULTS: Serious adverse psychological outcomes were uncommon. Most studies reported no significant increase in mean anxiety, depression, and distress scores (n = 8, 61.5%); however, some children experienced intrafamilial distress, discrimination, and guilt/regret. Some children were more concerned about their own health or their family members' health. There was limited consistency between anticipated adverse impact and empirical data. CONCLUSIONS: The review identified little conclusive evidence of deleterious psychological consequences for children acquiring genetic information. However, there is a lack of data regarding genetic testing for conditions that may not be treatable/modifiable, as well as a dearth of longitudinal studies. Therefore, clinical caution remains essential for the ethical integration of genetic testing into pediatrics. Further research assessing the potential positive and negative effects of genetic testing in childhood is warranted.Genet Med 18 8, 755-762.

Lynch syndrome and cervical cancer.

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age-specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6 fold (95% CI: 2.3-13.8; p = 0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9-10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0-46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p = 0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.

Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer.

We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.

Clinical and pathologic features of familial pancreatic cancer.

BACKGROUND: Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). METHODS: Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC). RESULTS: The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P<.0001), particularly melanoma and endometrial cancer, but not a personal history of EPM. Patients with SPC were more likely to be active smokers, have higher cumulative tobacco exposure, and have fewer multifocal precursor lesions, but these were not associated with differences in survival. Long-standing diabetes mellitus (>2 years) was associated with poor survival in both groups. CONCLUSIONS: FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies.