Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

[Clinical Cancer Genetics: A guide for the pathologist]. / Les trois temps de la prise en charge oncogénétique : la consultation, l'analyse en laboratoire et le suivi personnalisé.

It is paramount to identify patients whose cancer is associated with genetic susceptibility to the disease, since their long-term management depends on it. Anatomical and molecular pathologists play a key role in the process. Indeed, their diagnosis supports or even sometimes warrants germline genetic testing. For example, a colorectal cancer with mismatch repair protein expression loss suggests Lynch syndrome, while a rare type of renal cell carcinoma with fumarate hydrate expression loss is highly evocative of hereditary leiomyomatosis and renal cell carcinoma syndrome. Similarly, the presence of the T790M EGFR variant before treatment in a non-small-cell lung carcinoma warrants further testing as the variant is likely of germline origin. Patients with suspected genetic susceptibility to cancer are referred to the nearest clinical cancer genetics clinic. The cancer geneticist, assisted by a genetic counsellor, then collects detailed personal and familial information, sometimes feeds them into bioinformatics tools or clinico-pathological scores, decides whether germline genetic analysis is justified, determines which genes should be analysed and prescribes testing. Germline testing is carried out on a blood sample by expert laboratories using next generation sequencing on panels of cancer susceptibility genes. The cancer geneticists then return the result to the patient. When a pathogenic variant is identified, the patient's management is modified, with recommendations ranging from intensified surveillance to risk-reducing surgery. Treatment is sometimes adapted to the pathogenic variant. In addition, relatives can undergo genetic testing, should they wish to know whether they carry the familial variant. In the near future, we expect clinical cancer genetics to move towards strengthened partnerships with molecular pathologists and medical oncologists. Somatic genetic analyses are now routine, at least in metastatic cancer, and a proportion of the tumoral variants identified are actually of germline origin. As for the oncologists, the development of mainstreaming programs where they are allowed to prescribe germline testing under the supervision of a cancer genetics team is unavoidable.

Lynch syndrome: influence of additional susceptibility variants on cancer risk.

Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.

[Oncogénétique dans les cancers de l'ovaire]. / Genetic susceptibility to ovarian cancers.

GENETIC SUSCEPTIBILITY TO OVARIAN CANCERS About 15% of ovarian cancers are hereditary. Hereditary ovarian cancers are caused by a germline pathogenic variant in a susceptibility gene, mainly BRCA1 and BRCA2. Cumulative risks before age of 80 years are 44% and 17%, respectively, and are high enough to warrant risk-reducing salpingo-annexectomy in asymptomatic carriers before the menopause. Risk of breast cancer is also increased, with an associated recommendation of intensive breast screening with MRI at its core, and a possibility of risk-reducing mastectomy for well-informed patients who might request it. Ovarian and breast cancers associated with a BRCA1/BRCA2 pathogenic variant, can be, under certain conditions, treated with a new class of drugs called poly-(ADP-ribose)-polymerase (PARP) inhibors in addition to surgery and/or chemotherapy. The other ovarian cancer susceptibility genes are RAD51C, RAD51D, PALB2 and the mismatch repair genes (Mismatch repair [MMR] of Lynch syndrome). Cumulative risks are however in general smaller than for BRCA1/BRCA2.

ONCOGÉNÉTIQUE DANS LES CANCERS DE L'OVAIRE Environ 15 % des cancers de l'ovaire sont d'origine héréditaire, c'est-à-dire causés par un variant pathogène constitutionnel dans un gène de prédisposition au cancer de l'ovaire. BRCA1 et BRCA2 sont les principaux gènes, avec un risque cumulé de cancer ovarien avant l'âge de 80 ans de respectivement 44 % et 17 % ; cette prédisposition justifie une annexectomie de réduction de risque avant la ménopause chez les porteuses asymptomatiques. Il existe d'autres implications de l'identification d'un variant pathogène dans BRCA1/BRCA2 : les porteuses ont un excès de risque de cancer du sein motivant un dépistage renforcé par imagerie par résonance magnétique (IRM) mammaire, voire une mastectomie de réduction de risque pour les femmes demandeuses. Par ailleurs, en cas de cancer survenant dans ce contexte génétique, il est possible d'administrer, sous certaines conditions, un traitement ciblé par inhibiteur de poly- (ADP-ribose) polymérase (PARP), en complément de la chirurgie et/ou de la chimiothérapie. RAD51C, RAD51D, PALB2 et les gènes de réparation de mésappariement de base (mismatch repair [MMR] du syndrome de Lynch) sont d'autres gènes de prédisposition au cancer de l'ovaire. Ils sont cependant plus rarement impliqués et sont associés, sauf cas particulier, à des risques cumulés moindres que ceux de BRCA1/ BRCA2.