Under-ascertainment of breast cancer susceptibility gene carriers in a cohort of New Zealand female breast cancer patients.

BACKGROUND: Diagnostic screening for pathogenic variants in breast cancer susceptibility genes, including BRCA1, BRCA2, PALB2, PTEN and TP53, may be offered to New Zealanders from suspected high-risk breast (and ovarian) cancer families. However, it is unknown how many high-risk pathogenic variant carriers in New Zealand are not offered genetic screening using existing triage tools and guidelines for breast (and ovarian) cancer patients. METHODS: Panel-gene sequencing of the coding and non-coding regions of the BRCA1 and BRCA2 genes, and the coding regions and splice sites of CDH1, PALB2, PTEN and TP53, was undertaken for an unselected cohort of 367 female breast cancer patients. A total of 1685 variants were evaluated using the ENIGMA and the ACMG/AMP variant classification guidelines. RESULTS: Our study identified that 13 (3.5%) breast cancer patients carried a pathogenic or likely pathogenic variant in BRCA1, BRCA2, PALB2, or PTEN. A significantly higher number of pathogenic variant carriers had grade 3 tumours (10/13) when compared to non-carriers; however, no other clinicopathological characteristics were found to be significantly different between (likely) pathogenic variant carriers and non-carriers, nor between variant of unknown significance carriers and non-carriers. Notably, 46% of the identified (likely) pathogenic variant carriers had not been referred for a genetic assessment and consideration of genetic testing. CONCLUSION: Our study shows a potential under-ascertainment of women carrying a (likely) pathogenic variant in a high-risk breast cancer susceptibility gene. These results suggest that further research into testing pathways for New Zealand breast cancer patients may be required to reduce the impact of hereditary cancer syndromes for these individuals and their families.

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.

A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10-8 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.

Ten-Year Follow-Up of Women at High Risk for Familial Breast and Ovarian Cancer in Otago and Southland, New Zealand.

BACKGROUND: Care for families affected by Familial Breast and Ovarian Cancer (FBOC) is challenging as a broad range of professions and specialties are involved. The aim was to review management and outcomes for a cohort of women at high risk for familial breast and ovarian cancer. METHODS: Ten-year retrospective follow-up study of individuals in Southern New Zealand  assessed by Genetic Health Service New Zealand to be high risk for FBOC and without a personal cancer diagnosis at time of consultation. RESULTS: Twenty women were identified; twelve underwent genetic testing, and a pathogenic BRCA variant was identified in eleven. Eight women had no testing, as no index case was available. Guidelines had been fully adhered to in 55% of women, regardless of BRCA status. Six did not undergo appropriate breast surveillance. To date, seven of the 11 patients who tested positive for a pathogenic BRCA variant (64%) had risk-reducing surgeries. Two women were diagnosed with breast cancer on surveillance imaging; none were diagnosed with ovarian cancer. Four women were lost to follow-up, one of whom subsequently presented with a symptomatic breast cancer. CONCLUSIONS: To our knowledge, this is the first study providing long-term data for FBOC in New Zealand. Overall, guidelines were followed satisfactorily, but some women did not receive appropriate surveillance or referrals. An integrated interdisciplinary long-term care provision model in New Zealand might help to address gaps in FBOC surveillance and management.

Self-, collateral- and clinician assessment of depression in persons with cognitive impairment.

OBJECTIVES: This investigation examined the associations between self-reports, collateral-source reports and a clinician's diagnosis of depression in persons with cognitive impairment. METHOD: Responses on the Geriatric Depression Scale - 15 (GDS-15) from 162 participants with a diagnosis of Mild Cognitive Impairment (n = 78) or Alzheimer's Dementia and a Mini-Mental State score >or=15 (n = 84) were compared with both their collateral sources' report on either the Neuropsychiatric Inventory Questionnaire (n = 93) and/or the collateral-source GDS-15 (n = 67), or a clinician's diagnosis of Major Depression (MD). RESULTS: Significant differences were seen between self- versus collateral-source reports of depression in these participants. Participants' reports of loss of interest (anhedonia) significantly increased the odds of disagreement with their collateral sources (OR = 3.78, 95% CI: 1.3-11.2) while reports of negative cognitions significantly decreased the odds of such a disagreement (OR = 0.31, 95% CI: 0.1-0.9). The symptom of anhedonia also showed the strongest association with the clinician's diagnosis of MD. CONCLUSION: A motivational symptom like loss of interest was seen to play an important role in depression experienced by those with cognitive impairment.

Antenatal screening for aneuploidy--surveying the current situation and planning for non-invasive prenatal diagnosis in New Zealand.

AIMS: To gauge clinical opinion about the current system and possible changes as well as providing a forum for education about Non-Invasive Prenatal Testing (NIPT). METHODS: A series of workshops for doctors and midwives, supported by the National Screening Unit of the Ministry of Health and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, were held in the main centres of New Zealand. Following a brief education session, a structured evaluation of current screening and future possibilities was undertaken by questionnaire. RESULTS: One hundred and eight maternity carers participated in 5 workshops. Over 40% identified barriers to current screening. More than 60% would support NIPT in the first trimester. The majority of carers provided their own counselling support for women. CONCLUSIONS: The survey has shown general enthusiasm for the introduction of publically funded NIPT into prenatal screening in New Zealand. Barriers to utilisation of the current system have been identified and enhancements to screening performance with guidelines around conditions to be screened for would be supported.

Meeting the challenges of interpreting variants of unknown clinical significance in BRCA testing.

Many BRCA1 and BRCA2 genetic mutations are known to result in an elevated breast cancer risk. Routine BRCA1/2 gene screening is offered to patients thought to have an increased risk of carrying a deleterious mutation. 5-10% of genetic tests identify a variant of unknown clinical significance (VUCS), creating significant challenges to health care providers. Recent advances in sequencing technologies allow more genes to be screened in an increasing number of individuals and at an ever decreasing cost. Significantly more VUCS will be identified, adding to the uncertainty of how to manage these patients. The addition of splicing assays to current variant classification tools may be instrumental towards understanding the disease risk of these variants and improve the reliability of these assays.

Decisions about amniocentesis by advanced maternal age patients following maternal serum screening may not always correlate clinically with screening results: need for improvement in informed consent process.

We evaluated the prenatal diagnosis utilization patterns of advanced maternal age (AMA) patients who underwent serum screening to assess how screening results correlated with their decisions regarding amniocentesis. A 6-year review (1994-1999) of laboratory records identified 2,456 AMA patients who underwent multiple-marker serum screening. The relationship between screening results and patients' decisions on whether or not to undergo amniocentesis was assessed. Among the 841 AMA patients with positive screens, more than half (52%) declined amniocentesis. Of the 1,615 patients with negative serum screening results, 208 (13%) opted for amniocentesis. We concluded that decisions by AMA patients regarding amniocentesis may not always correlate clinically with maternal serum screening results. Possible explanations, including how the state of informed consent may or may not contribute to these decisions, are discussed. It is suggested that understanding the reasons for these decisions may identify opportunities for improving service delivery to all pregnant patients considering prenatal testing. Use of a questionnaire is proposed as one mechanism for gaining a clearer understanding of the possible factors contributing to AMA patient decisions.