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In 2016, we reported a child with bilateral lung cysts and left lung type II pleuropulmonary blastoma (PPB), classic phenotypes of DICER1 syndrome; we identified a DICER1 hotspot mutation c.5425G>A, p.Gly1809Arg in both a lung cyst and PPB, but the variant was absent in other tissues studied. A somatic mutation (c.1966C>T, p.Arg656Ter) was identified in the PPB, and mosaicism was suspected.1 The child has since developed multinodular goitre (MNG) with cystic thyroid nodules. We have now detected p.Gly1809Arg in the thyroid lesions, while various other tissues were negative. The exquisite localisation of the variant confirms mosaicism and strongly suggests it arose in embryonic foregut endoderm between gestational days 16 and 26. Mosaicism is a phenomenon where two genetically distinct populations of cells arise following postzygotic acquisition in one cell of a de novo mutation.2 DICER1 syndrome is a paediatric multitumour predisposition syndrome caused typically by germline loss-of-function DICER1 variants, but some predisposing mosaic DICER1 mutations have also been described.1 3 4 DICER1 encodes an endoribonuclease that processes hairpin precursors into mature microRNAs that, in turn, post-transcriptionally regulate target messenger RNA expression. Syndromic tumours result from acquisition of a somatic, second variant that typically affects DICER1’s critical RNase IIIb cleavage domain. These variants are referred to as ‘hotspot mutations’ and include NM_177438.3: c.5425G>A, p.Gly1809Arg. Common phenotypes of DICER1 syndrome include PPB, MNG, cystic nephroma and Sertoli-Leydig cell tumour. Previously, to assess mosaicism 1 in multiple tissues obtained when the patient’s age ranged from 11 months to age 15 years, DNA was analysed using a Fluidigm Access Array and the HaloPlex HS Target Enrichment System, followed by deep sequencing. However, the results were inconclusive because no completely normal lung tissue was available for study, the p.Gly1809Arg variant was not found in DNA derived from saliva, head hair or blood …

BackgroundThis study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.MethodsLaboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.ResultsTwelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.ConclusionsThe COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.

Heterozygous germline pathogenic variants (GPVs) inSMARCA4, the gene encoding the ATP-dependent chromatin remodelling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcaemic type, atypical teratoid and malignant rhabdoid tumour, and uterine sarcoma. The increase in germline testing ofSMARCA4in recent years has revealed putative GPVs affectingSMARCA4in patients with other cancer types. Here we describe 11 patients with neuroblastoma (NBL), including 4 previously unreported cases, all of whom were found to harbour heterozygous germline variants inSMARCA4. Median age at diagnosis was 5 years (range 2 months–26 years); nine were male; and eight of nine cases had tumour location information in the adrenal gland. Eight of the germline variants were expected to result in loss of function ofSMARCA4(large deletion, truncating and canonical splice variants), while the remaining four were missense variants. Loss of heterozygosity of the wild-typeSMARCA4allele was found in all eight cases where somatic testing was performed, supporting the notion that SMARCA4 functions as a classic tumour suppressor. Altogether, these findings strongly suggest that NBL should be included in the spectrum ofSMARCA4-associated tumours.

ObjectiveUp to 15% of patients with high-grade serous ovarian, tubal, or peritoneal carcinoma harbor a mutation in BRCA genes. Early notion of mutation status may facilitate counseling, predict prognosis, and increase access to Parp-inhibitors. The aim of this study was to examine the rate of germline genetic testing in a retrospective cohort of women with high-grade serous ovarian, tubal, or peritoneal carcinoma to determine if a new pilot project of gynecologic oncologist-initiated genetic testing improved the rate of testing, after 1 year of implementation.MethodsGynecologic oncology-initiated genetic testing was implemented at a single university hospital center with input and collaboration from gynecological oncologists, nurses, and genetic counselors. All patients diagnosed with high-grade serous ovarian, tubal, or peritoneal carcinoma after August 2017 were offered gynecologic oncologist- initiated genetic testing for a panel of 13 hereditary breast and ovarian cancer susceptibility genes. Data from this group was then compared with a historic cohort of patients who received traditional genetic counseling between January 2014 and August 2017 (control group). Patients that had genetic testing through a clinical trial were excluded. The primary outcome was the uptake of genetic testing in both groups. Secondary outcomes included difference in time from diagnosis to genetic result between both cohorts. Data was analyzed using SPSS 25.0 and medians (ranges) were reported.ResultsA total of 152 women with high-grade serous ovarian, tubal, or peritoneal carcinoma were included in this study. Between January 2014 to July 2017 there were 108 patients with high-grade serous ovarian, tubal, or peritoneal carcinoma, among which 50.9% (n=54) underwent genetic testing following referral to genetics. The prevalence of BRCA pathogenic variants was 25.9% (14/54): 9.2% (5/54) in BRCA1 and 16.7% (9/54) in BRCA2. The median time from diagnosis to genetics referral was 53 days (range; 3–751), and median time from diagnosis to test result disclosure was 186 days (range; 15–938). After 1 year of implementation of the gynecologic oncologist-initiated genetic testing model, among 44 women diagnosed with high-grade serous ovarian, tubal, or peritoneal carcinoma, 86.2% underwent genetic testing. The median time from diagnosis to result disclosure decreased to 58 days, representing a reduction of 128 days, or 4.27 months (PBRCA1/2 pathogenic variants was 21% (8/38).ConclusionGynecologic oncologist-initiated genetic testing at the time of high-grade serous ovarian, tubal, or peritoneal carcinoma diagnosis leads to increased uptake and decreased delays in testing compared with referral for traditional genetic counseling.

IntroductionPreventive bilateral salpingo-oophorectomy is the most effective means of reducing the risk of ovarian cancer among women with an inherited BRCA1 or BRCA2 mutation. Some women are diagnosed with an invasive cancer (ovarian or fallopian tube) at the time of preventive surgery, referred to as an ‘occult’ cancer. The survival experience of these women is not known.MethodsWe estimated the 10-year survival for 52 BRCA mutation carriers diagnosed with an occult ovarian or fallopian tube cancer at the time of preventive bilateral salpingo-oophorectomy.ResultsThe mean age at diagnosis was 51.6 (range 33–69) years. All were serous cancers (although 14 were missing information on histologic subtype). Of the 20 cases with information available on stage at diagnosis, 10 were stage I, 1 was stage II, and 9 were stage III (n=32 missing). After a mean of 6.8 years, 12 women died (23%). The 10-year all-cause survival was 74%.ConclusionAlthough based on only 52 cases, these findings suggest a more favorable prognosis for BRCA mutation carriers diagnosed with an occult rather than incident disease.

BRIP1 is one of several DNA damage response genes that have been implicated in both Fanconi Anaemia and hereditary breast and ovarian cancer. BRIP1 binds to the BRCT1 C-Terminus (BRCT) domain and functions in BRCA1-dependent DNA repair and cell cycle control.1 Biallelic mutations in BRIP1 cause Fanconi Anaemia type J.1 Heterozygous mutations in other Fanconi Anaemia genes such as BRCA1 , BRCA2 and PALB2 are associated with an increased risk of breast cancer,2 so it is reasonable to consider BRIP1 as a candidate breast cancer susceptibility gene. BRIP1 is currently included on most commercially available hereditary cancer gene panels, with both breast and ovarian cancers given as indication for testing. The basis for inclusion of BRIP1 as a breast cancer susceptibility gene is a single study of familial breast cancer3 (1212 cases and 2081 controls), in which the relative risk for breast cancer was estimated to be about twofold (p=0.012). Although published in 2006, the results of that study have never been confirmed, and the role of BRIP1 in contributing to breast cancer risk remains unclear. In this issue of JMG , Easton and colleagues,4 using a very large series of cases and controls, report a failure to replicate the association3 between BRIP1 truncating mutations and breast cancer risk. Here, the authors first …

Pineoblastomas occur in RB-1 mutation carriers,1 but are rarely seen in association with other hereditary syndromes.2 Germline DICER1 mutations are associated with embryonal tumours such as pleuropulmonary blastoma (PPB),3 ,4 so we hypothesised that such mutations might also occur in children with pineoblastoma. Here we describe a novel deleterious germline DICER1 mutation in a young child with a highly aggressive pineoblastoma. In addition, we observed loss of heterozygosity (LOH) of the wild-type allele, an event not previously reported in DICER1 associated tumours.5 ,6 Our observations suggest: (1) pineoblastomas are associated with germline DICER1 mutations; and (2) unexpectedly, tumour cells can thrive in the absence of functional DICER1 . The pineal gland, so named by Galen because of its resemblance to a pine nut, is a ∼175 mg midline structure situated on the posterior wall of the third ventricle, deep between the cerebral hemispheres. Pineal gland tumours are often derived from ectopic germ cell tissue, but pineocytomas and pineoblastomas also occur. A pineoblastoma is a supratentorial primitive neuroectodermal tumour arising in the pineal gland. Germline mutations in tumour suppressor genes have rarely been associated with pineoblastomas,1 ,2 but mutations in RB-1 can result in so-called ‘trilateral retinoblastoma’.1 We obtained …

Background Germline mutations in the PALB2 gene have been implicated in both breast cancer and pancreatic cancer susceptibility. The extent to which PALB2 mutations account for cancer susceptibility in breast–pancreas cancer families is unknown. Methods High Resolution Melting analysis and Multiplex Ligation-dependent Probe Amplification were performed to investigate the prevalence of PALB2 mutations in patients with either a personal history of both breast and pancreatic cancer or a personal history of breast cancer and a family history of a first degree relative with pancreatic cancer. Results No PALB2 mutations were identified in 77 breast–pancreas cancer families, which included 22 probands with a personal history of both breast and pancreatic cancer. Conclusion Mutations within the PALB2 gene are rare events that do not account for a substantial proportion of cancer susceptibility in breast–pancreas cancer families. Routine screening of breast–pancreas cancer families for the presence of PALB2 mutations appears to be low yield.

Late-stage ovarian carcinoma is almost universally fatal. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Here we report a remarkable case of cure following platinum-resistant stage III ovarian carcinoma in a woman with a BRCA2 mutation. The patient was subsequently treated with oral melphalan therapy and has not recurred in over 25 years. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib. There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness.

Editor—Germline mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia (MEN) type 2A, 2B, and familial medullary thyroid carcinoma (FMTC). MEN 2A is characterised primarily by medullary thyroid carcinoma (MTC), parathyroid hyperplasia, and phaeochromocytoma. MEN 2B has additional stigmata including a marfanoid habitus, mucosal neuromas, and corneal nerve thickening. In FMTC, the only lesion present is MTC. Although characteristic of MEN 2B, prominent corneal nerves have been noted in subjects with MEN 2A. We have studied a family presenting with MTC and corneal nerve thickening (CNT), but no evidence of MEN 2 related disease outside the thyroid gland (fig 1). The proband (III.1) was found to have prominent corneal nerves on routine ophthalmological examination in his late 30s. No further action was taken and he presented with a palpable thyroid mass at the age of 53. Figure 1 A truncated pedigree of the family is shown. Filled symbols indicate affected subjects. The letters below the symbols refer to the site of cancer, the numbers following the abbreviations indicate age at diagnosis. MTC, medullary thyroid cancer; PSU, primary site unknown; d, age at death; CNT, corneal nerve thickening. MEN 2B was suspected and he was referred for laboratory screening tests for MTC and phaeochromocytoma. Serum calcitonin was raised at 4090 ng/l (normal range

BACKGROUND—The discovery of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has improved our ability to counsel women at increased risk of developing breast and ovarian cancer. The objective of our study was to identify the needs of women who have undergone genetic counselling and testing for BRCA1/2 and to determine the impact of receiving a positive BRCA1/2 result. This is the first study to report on a large group of women who have received positive BRCA1/2 mutation results. METHODS—Questionnaires were distributed to 105 women who had received pre- and post-test genetic counselling for a positive BRCA1/2 result at the University of Toronto or at McGill University in Montreal, Canada between the years of 1994 and 1998. The questionnaire items included patient motivation for seeking genetic services, information needs, screening and prophylactic surgery practices, satisfaction with access to services and support, the desire for a support group, and overall client satisfaction. RESULTS—Seventy nine female carriers were surveyed. The majority of the respondents (77%) were satisfied with the information they received during the genetic counselling process. Women with a previous diagnosis of cancer indicated that they needed more information relating to cancer treatment compared to women without cancer (p=0.05). Nineteen percent of the women felt they needed more support than was received. Fifty eight percent of the women reported that their screening practices had changed since they received their result. Young women (below the age of 50) and women with no previous diagnosis of cancer were most likely to have changed their screening practices. Nearly two thirds of the respondents said they had considered prophylactic surgery of the breasts or ovaries. Twenty eight percent of the women had prophylactic mastectomy and 54% had undergone prophylactic oophorectomy. Women with an educational level of high school or more were more likely to have undergone prophylactic bilateral mastectomy than those with less education (p=0.07) but were less likely to undergo prophylactic oophorectomy (p=0.0007). CONCLUSION—These findings have a direct impact on the counselling and risk management of female BRCA mutation carriers. Age, education, and a previous diagnosis of cancer are important determinants in a woman's decision making after receiving positive genetic test results. Keywords: genetic counselling; BRCA1; BRCA2; cancer genetics

The MSH2*1906G--C mutation was recently shown to be a rare yet highly penetrant mutation leading to colorectal cancer. The mutation was only found among Ashkenazi Jewish individuals and lies on an extended haplotype that is common in that population. This study determined that the mutation probably arose between 11 and 22 generations ago, during the time when the Ashkenazim were living in eastern Europe.

Pancreatic adenocarcinoma is an important cause of death from cancer throughout the developed world. There are few established environmental risk factors, but a previous history of pancreatitis and exposure to tobacco and salted food appear to be the most important. A family history of pancreatic adenocarcinoma is not common in patients with this disease, but recent research has shown that pancreatic adenocarcinoma can be a feature of cancer susceptibility syndromes associated with germline mutations in p16, BRCA1, BRCA2, and APC. This highlights the need for a full family history in apparently sporadic cases. Somatic mutations in p16, BRCA2, and APC have also been reported in pancreatic cancer; however, K-RAS mutations appear to be the commonest oncogenic alteration. Recent advances in our understanding of the basis of hereditary cancer syndromes may be applicable to the diagnosis, treatment, and possibly prevention of pancreatic adenocarcinoma in the future.

Objective To determine the contribution of inheritance to the incidence of squamous cell carcinoma of the head and neck. Design Historical cohort study. First degree relatives of cases with squamous cell carcinoma of the head and neck made up the exposed cohort and first degree relatives of spouses of cases made up the comparison unexposed cohort. Setting Ear, nose, and throat clinic in a large metropolitan teaching hospital. Subjects 1429 first degree relatives of 242 index cases of squamous cell carcinoma of the head and neck; as controls, 934 first degree relatives of the spouses of 156 index cases. Main outcome measures Relative risk of developing squamous cell carcinoma in first degree relatives of cases compared with risk in first degree relatives of spouses. Results The adjusted relative risk for developing head and neck cancer if the index case had squamous cell carcinoma of the head and neck was 3.79 (95% confidence interval 1.11 to 13.0). There were no significantly increased risks associated with a family history of cancer at other sites. The adjusted relative risk for squamous cell carcinoma of the head and neck was 7.89 (1.50 to 41.6) in first degree relatives of patients with multiple primary head and neck tumours. Conclusions These data suggest that genetic factors are important in the aetiology of head and neck cancer, in particular for patients with multiple primary cancers. Given the prolonged exposure of these subjects to carcinogens, these genetic factors may have a role in modifying carcinogen activity or in host resistance to carcinogens. Inherited factors may be important in persons with environmentally induced cancers.

Editor—A report was recently published on the localisation of a chromosome segment at 1p36 which appeared to be linked (two point lod score=4.74) to a large number of families with multiple cases of early onset (mean age at diagnosis of

Objective To compare the survival rates of women with BRCA associated breast cancer who did and did not undergo mastectomy of the contralateral breast. Design Retrospective analysis. Setting 12 cancer genetics clinics. Participants 390 women with a family history of stage I or II breast cancer who were carriers of BRCA1 and BRCA2 mutations and initially treated with unilateral or bilateral mastectomy. 181 patients had mastectomy of the contralateral breast. Patients were followed for up to 20 years from diagnosis. Main outcome measure Death from breast cancer. Results 79 women died of breast cancer in the follow-up period (18 in the bilateral mastectomy group and 61 in the unilateral mastectomy group). The median follow-up time was 14.3 years (range 0.1-20.0 years). At 20 years the survival rate for women who had mastectomy of the contralateral breast was 88% (95% confidence interval 83% to 93%) and for those who did not was 66% (59% to 73%). In a multivariable analysis, controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic features, contralateral mastectomy was associated with a 48% reduction in death from breast cancer (hazard ratio 0.52, 95% confidence interval 0.29 to 0.93; P=0.03). In a propensity score adjusted analysis of 79 matched pairs, the association was not significant (0.60, 0.34 to 1.06; P=0.08). Based on these results, we predict that of 100 women treated with contralateral mastectomy, 87 will be alive at 20 years compared with 66 of 100 women treated with unilateral mastectomy. Conclusions This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy. Given the small number of events in this cohort, further research is required to confirm these findings.

The case of a 59 year old white man who had chronic malabsorption and selective IgA deficiency with severe iron deficiency is reported. In addition, he was deficient in vitamin E and selenium, important antioxidants which protect against lipid peroxidation. He was intolerant of oral iron and when treated with iron-dextran developed symptoms suggestive of polymyositis with evidence of rhabdomyolysis. It is suggested that free iron within iron-dextran activated free radicals, initiating lipid peroxidation and leading to polymyositis, rhabdomyolysis, and myoglobulinuria.

The functions of the breast cancer susceptibility genes BRCA1 and BRCA2 are not fully elucidated, but appear to include the regulation of X chromosome activity. Xist is a non-coding RNA that accumulates on the inactive X chromosome and is required for X chromosome inactivation during the silencing step.1 The RING domain of BRCA1 and Xist interact in mammalian cells and it has been suggested that BRCA1 contributes to the initiation of X chromosome inactivation.2 Women with ovarian cancer possessing germline mutations in BRCA1 have been found to frequently demonstrate non-random X chromosome inactivation.3 In the light of these findings, a recent report by de la Hoya et al is of interest.4 In this study of 68 Spanish breast/ovarian pedigrees they reported that 67% of the children of women who carried a BRCA1 mutation were female. By contrast, only 54% of the offspring of BRCA2 carriers and 52% of the offspring of non-carriers were female. This highly skewed sex ratio in the offspring of BRCA1 carriers from Spain prompted us to ask whether this is true in other populations as well. To address this question, we examined the sex ratios of the offspring of a total of 1040 women (229 BRCA1 carriers, 104 BRCA2 carriers, and 707 non-carriers) from five different studies which were conducted in …

Ovarian cancer is the fifth most common malignancy among North American women and the fourth leading cause of cancer death. Approximately 5 to 13% of all ovarian cancer cases are caused by the inheritance of cancer predisposing genes with an autosomal pattern of transmission.1 Hereditary ovarian carcinoma has been described in association with mutations in four genes, BRCA1 , BRCA2 , MLH1 , and MSH2 , although usually ovarian carcinoma (OC) does not occur in a site specific fashion, but is associated with breast cancer ( BRCA1 and BRCA2 ) or colorectal and endometrial cancer ( MLH1 and MSH2 ). The large majority of hereditary OC is attributable to mutations in BRCA1. While mutations in BRCA1 have been seen in large pedigrees with apparently site specific OC predisposition,2 mutations in BRCA2 that have been associated with site specific OC are rare, and have often been missense mutations.3,4 The biological significance of such mutations can be uncertain. Gayther et al 5 reported that mutations in a 3.3 kb segment of exon 11 of BRCA2 were associated with a higher risk of OC relative to breast cancer than were mutations outside this region (p = 0.0004). They called this region of BRCA2 the ovarian cancer cluster region (OCCR). In an expanded study from the same group, Thompson et al 6 estimated that mutations in the ovarian cancer cluster region (OCCR) of BRCA2 are associated with an OC risk to the age of 70 of 19.5% (95% confidence interval (CI) 11.6 to 31.7), whereas the equivalent risk associated with mutations outside this region has been estimated at 10.9% (95% CI 5.5 to 20.9). Despite the concluding comments of the authors, urging a cautious interpretation of their data, if these estimates were to be used to counsel women who carry BRCA2 mutations, those who …

Edited by Robert B Silvers New York Review Books, $19.95, pp 193 ISBN 0 940322 03 X From Humphry Davy's farewell letter to Samuel Coleridge of 1804 (on the poet's departure for Malta), it is clear that they were close friends. Their correspondence makes plain their joint interest in chemistry and poetry: the word “science” was not widely used at that time and both Davy and Coleridge could be said to be investigating nature. Increasingly since then, science and art seem to have diverged, such that the discourse of the practitioners of one may be quite unintelligible to the other. The New York Review of …

EDITOR, - Aileen Clarke and colleages suggest that female castration should receive the same attention as surgical castration for sexual offenders.1, 2 I have two comments. Firstly, though specific and detailed informed consent is clearly required before oophorectomy during a hysterectomy, male and female castration seem to be fundamentally …