Phenotypes of carriers of two mutated alleles in major cancer susceptibility genes.

PURPOSE: While cancer phenotypes in carriers of a single mutant allele in most major cancer susceptibility genes are well-established, there is a paucity of data on the phenotype of carriers of two pathogenic variants-double heterozygotes (DH) or homozygous carriers. Here, we describe the phenotype of carriers of homozygous and DH pathogenic sequence variants (PSVs) in major cancer susceptibility genes. METHODS: Individuals referred for multigene panel testing at Blueprint Genetics laboratory were included. Ethically approved comparison of cancer type and age at diagnosis between DH, homozygous, and single PSV carriers was performed per gene. RESULTS: Of 6,685 eligible participants, 928 (13.9%) were single heterozygous PSV carriers, 6 (0.09%) were homozygous PSV carriers, and 17 (0.25%) were DH PSV carriers. Mean age at diagnosis of any cancer among single PSV age was 46.8 ± 14.9 years and among DH PSV carriers 37.6 ± 13.0 years (P < 0.0001). Notably, age at diagnosis for breast cancer among single BRCA1 PSV carriers (n = 59) was 43.8 ± 8.7 years (p = 0.7606), among single BRCA2 PSV carriers (n = 52)-47.9 ± 13.0 years (p = 0.2274) compared with 42.3 ± 13.0 years among DH PSV carriers (n = 10- 9 of whom were carriers of either BRCA1 or BRCA2). CONCLUSION: DH for PSV in two cancer susceptibility genes is a rare event, and the mean age at cancer diagnosis is younger in DH PSV carriers compared with single PSV carriers.

Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases.

PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.

Breast cancer screening in BRCA1/2 pathogenic sequence variant carriers during pregnancy and lactation.

OBJECTIVES: Women harboring germline BRCA1/BRCA2 pathogenic sequence variants (PSVs) are at an increased risk for breast cancer. There are no established guidelines for screening during pregnancy and lactation in BRCA carriers. The aim of this study was to evaluate the utility of whole-breast ultrasound (US) screening in pregnant and lactating BRCA PSV carriers. METHODS: Data were retrospectively collected from medical records of BRCA PSV carriers between 2014 and 2020, with follow-up until 2021. Associations between imaging intervals, number of examinations performed and pregnancy-associated breast cancers (PABCs) were examined. PABCs and cancers diagnosed at follow-up were evaluated and characteristics were compared between the two groups. RESULTS: Overall 212 BRCA PSV carriers were included. Mean age was 33.6 years (SD 3.93, range 25-43 years). During 274 screening periods at pregnancy and lactation, eight (2.9 %) PABCs were diagnosed. An additional eight cancers were diagnosed at follow-up. Three out of eight (37.5 %) PABCs were diagnosed by US, whereas clinical breast examination (n = 3), mammography (n = 1) and MRI (n = 1) accounted for the other PACB diagnoses. One PABC was missed by US. The interval from negative imaging to cancer diagnosis was significantly shorter for PABCs compared with cancers diagnosed at follow-up (3.96 ± 2.14 vs. 11.2 ± 4.46 months, P = 0.002). CONCLUSION: In conclusion, pregnant BRCA PSV carriers should not delay screening despite challenges like altered breast tissue and hesitancy towards mammography. If no alternatives exist, whole-breast ultrasound can be used. For lactating and postpartum women, a regular screening routine alternating between mammography and MRI is recommended.

Clinical breast exam contribution to breast cancer diagnosis in BRCA mutation carriers vs. average to intermediate risk women.

PURPOSE: The contribution of clinical breast exam (CBE) to breast cancer diagnosis in average risk women undergoing regular screening mammography is minimal. To evaluate the role of CBE in high-risk women, we compared BC diagnosis by CBE in BRCA mutation carriers undergoing regular BC surveillance to average to intermediate risk women undergoing regular breast cancer screening. METHODS: A retrospective chart review of all consecutive screening visits of BRCA mutation carriers (January 2012-October 2022) and average to intermediate risk women (November 2016-December 2022) was completed. Women with histologically confirmed BC diagnosis were included. Additional CBE yield for BC diagnosis, defined as the percentage of all BC cases detected by CBE alone, was assessed in both groups. RESULTS: Overall, 12,997 CBEs were performed in 1,328 BRCA mutation carriers in whom 134 BCs were diagnosed. In 7,949 average to intermediate risk women who underwent 15,518 CBEs, 87 BCs were diagnosed. CBE contributed to BC diagnosis in 3 (2%) BRCA mutation carriers and 3 (4%) non-carriers. In both groups, over 4,000 CBEs were needed in order to diagnose one cancer. In all 3 BRCA mutation carriers BC was palpated during the surveillance round that did not include MRI. In the average to intermediate risk group, 2 of 3 cancers diagnosed following CBE findings were in a different location from the palpable finding. CONCLUSIONS: The contribution of CBE to BC diagnosis is marginal for all women including BRCA mutation carriers. In BRCA mutation carriers, CBE appears redundant during the MRI surveillance round.

Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥50 years.

PURPOSE: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years. METHODS: Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed. RESULTS: Of 2706 patients with BC (mean age at diagnosis, 54 years; range, 20-92 years) counseled, 515 patients of non-AJ (all four grandparents) descent, diagnosed ≥age 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) of non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants were found in 2.5% of genotyped TNBC and in 3.7% of patients with non-TNBC, including CHEK2 c.499G>A (n = 3), APC c.3920T > A (n = 4), and heterozygous MUTYH c.1187G>A (n = 5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n = 2, c.846+1G>C and c.592+3A>T), ATM c.103C>T (n = 2), and NBN c.966C>G (n = 1). CONCLUSIONS: The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Breast cancer diagnosed after age 70 years in Israeli BRCA1/BRCA2 pathogenic sequence variant carriers: a single institution experience.

PURPOSE: A semi-annual surveillance scheme from age 25 to 30 years is offered to BRCA1/BRCA2 pathogenic sequence variants (PSVs) carriers for early detection of breast cancer (BC). There is a paucity of data on the yield of adhering to this scheme beyond 70 years of age. METHODS: Female BRCA1/BRCA2 PSV carriers followed at the Meirav high-risk clinic, Sheba Medical center, Israel were eligible. Type and frequencies if use of Imaging modalities, breast biopsies and histological outcomes for participants after age 70 years were retrieved and analyzed. RESULTS: Overall, the study encompassed 88 consenting participants (46 BRCA1 carriers) mean age ± SD 73.7 ± 3.3 years (range 70-90 years), followed for an average of 3.8 years (range 1-11 years). Ten carriers (11.3%) were diagnosed with BC after age 70 years (mean age at diagnosis 72 ± 2 years) and an additional case was diagnosed with breast lymphoma. The imaging modality that has led to most diagnoses was MRI (8/11 cases). Eight of these ten cases were previously diagnosed with BC prior to age 70 and in six, BC past 70 years was in the contralateral breast. The lesions size averaged 1.29 ± 0.75 cm, with IDC and DCIS diagnosed in five cases each, and none had lymph node involvement. CONCLUSION: In ~10% of BRCA1/BRCA2 PSV carriers BC is diagnosed by breast imaging after age 70 years. If these results are validated in a larger study, the guidelines for the maximum age for BC surveillance in high risk women should be revisited and set at 75 years.

Bilateral Peters' anomaly, aniridia and Wilms tumour (WAGR syndrome) in monozygotic twins.

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.

Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier.

INTRODUCTION: Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene. OBJECTIVES: Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism. METHODS: A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous melanoma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases, five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome sequencing (WES) identified a rare homozygous missense PV (c.919C>T; p.Arg307Trp) in exon 8 of the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2). CONCLUSIONS: Familial malignant melanoma phenotype may, in fact, be an unusual clinical presentation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC alleles.

Incidental Genetic Finding in a Fetus.

A 37-year-old woman presented with suspected polycystic kidney detected on routine fetal ultrasonography, and an incidental finding of a heterozygous c.501-2 A

Diabetes insipidus nefrogênico: conceitos atuais de fisiopatologia e aspectos clínicos / Nephrogenic diabetes insipidus: actual concepts of fisiopathology and clinical aspects

O diabetes insipidus nefrogênico (DIN) é uma doença rara caracterizada pela incapacidade do rim de concentrar a urina, a despeito de concentrações normais ou aumentadas do hormônio antidiurético arginina-vasopressina (AVP). Recentes avanços da fisiopatologia renal mostraram que, após a ligação do AVP ao seu receptor AVPR2 (receptor de vasopressina tipo 2), uma cascata de eventos culmina com a reabsorção de água no túbulo coletor, por meio de canais permeáveis exclusivamente à água e localizados nas membranas apicais do túbulo coletor, sendo o mais importante deles a aquaporina-2 (AQP2). A identificação, caracterização e análise mutacional dos genes AVPR2 e AQP2 permitiram estabelecer as bases moleculares de vários tipos hereditários de diabetes insipidus nefrogênico. Aproximadamente 90 por cento desses pacientes apresentam mutações do AVPR2, 8 por cento apresentam mutações no AQP2 e o restante não tem causas identificadas. Nessa revisão apresentamos exemplos de alterações genéticas e sugerimos que o uso de técnicas de biologia molecular pode minimizar as complicações dessa doença heterogênea mas com fenótipo bastante semelhante.

Analise de mutações somáticas dos genes APP, presenilina 1 e 2, em tecido encefálico na doença de Alzheimer / Somatic mutationals analysis of genes APP, presenilin 1 and 2, in encephalic tissue in Alzheimer's disease

As bases moleculares da forma esporadica da doenca de Alzheimer (DA) permanecem ainda desconhecidas. Nos formulamos a hipotese de que, em alguns casos esporadicos de DA, uma mutacao somatica nos genes da proteina precursora amiloide (APP), da presenilina 1 (PS-1) e 2 (STM2) (genes envolvidos na DA forma familiar) em uma celula embrionaria comprometida com o desenvolvimento neuronal, pode resultar em fenotipo da DA. Usando a tecnica de PCR, eletroforese em gel de gradiente desnaturante (DGGE), analise de restricao e sequenciamento direto de DNA, nos analisamos esses genes em 99 tecidos encefalicos de pacientes com DA comprovada histologicamente. Uma amostra de tecido encefalico mostrou uma mutacao no gene PS-1 (His 163 Arg), que mais tarde foi demonstrada ser uma mutacao de celulas germinativas. Nenhuma outra anormalidade de migracao foi demonstrada, em qualquer amostra, nos exons 16 ou 17 do gene APP, nos exons codificadores da PS-1 ou qualquer padrao anormal de digestao pela analise de restricao no gene PS-2...