FH-tumor predisposition syndrome (FH-TPS) is an autosomal dominant cancer predisposition syndrome caused by the fumarate hydratase (FH) gene. FH was initially shown to cause hereditary leiomyomatosis and renal cell cancer (HLRCC), historically called Reed syndrome. More recently, certain germline FH variants have been linked to pheochromocytoma (PHEO) risk in individuals without features of HLRCC. Diagnosis of these apparently non-overlapping conditions, FH-TPS-PHEO and FH-TPS-HLRCC, has increased through application of broad hereditary cancer gene panels. Early HLRCC studies suggested high lifetime RCC risk; however, emerging data suggests RCC risk in FH-TPS-HLRCC is lower than previous estimates. Individuals with likely pathogenic or pathogenic (LPV/PV) FH variants were identified in a large, ethnically diverse health system. Heterozygotes were classified as FH-TPS-PHEO, FH-TPS-HLRCC, or FH-ARC (autosomal recessive carrier for congenital fumarate hydratase deficiency without FH-TPS risk) based on variant phenotype-genotype prediction. Groups were evaluated for demographics, FH testing indications, FH-TPS-HLRCC related clinical features, and RCC. Cumulative RCC incidence was estimated via Aalen-Johansen estimator. Among 279 individuals with LPV/PV in FH, 4 had FH-TPS-PHEO, 111 FH-TPS-HLRCC, and 164 FH-ARC. The FH-TPS-HLRCC and FH-ARC groups were approximately two-thirds female. FH-ARC was less ethnically diverse due to a common variant in Northern Europeans (c.1431_1433dup). One-third of FH-TPS-HLRCC individuals underwent testing for cancer-related indications unrelated to FH-TPS-HLRCC, and nearly 75% of these were women who had uterine leiomyomata suggestive of FH-TPS-HLRCC. One-quarter of FH-TPS-HLRCC individuals were diagnosed via cascade testing, 40% of whom had clinical features of FH-TPS-HLRCC. RCC occurred in nine patients (5 FH-TPS-HLRCC, 3 FH-ARC, 1 FH-TPS-PHEO). All RCCs in FH-TPS-HLRCC were FH-deficient and occurred at earlier average age than the sporadic RCC in other groups. Cumulative RCC incidence by age 70 was 7.3% (95% CI 2.1-15.3%) in FH-TPS-HLRCC and 2.6% (95% CI 0.0-7.1%) in FH-ARC. RCC risk before age 25 in FH-TPS-HLRCC was negligible. FH-TPS-HLRCC is underdiagnosed and RCC risk is lower than earlier HLRCC estimates. Many individuals are identified through broad hereditary cancer gene panel testing and exhibit less obvious manifestations such as uterine leiomyomata. Adult RCC surveillance is warranted in FH-TPS-HLRCC, but the need for pediatric screening merits further study.

Hereditary breast and ovarian cancer (HBOC) confers a markedly increased lifetime risk of breast and ovarian cancers. As no effective surveillance method for early detection of ovarian cancer has been established, risk-reducing salpingo-oophorectomy (RRSO) is recommended for patients with HBOC to prevent disease onset. We evaluated the clinical characteristics of patients with HBOC and the surgical outcomes of RRSO performed at our institution. We retrospectively reviewed women diagnosed with HBOC at our institution between 2018 and 2024. For analyses of surgical outcomes, male patients, patients with prior bilateral adnexectomy, and patients diagnosed with HBOC who did not undergo RRSO were excluded. Clinical data including patient characteristics, surgical procedures, genetic testing, and pathological findings were assessed. A total of 283 women were diagnosed with HBOC, and 43 (15.1%) underwent testing based on the results of affected relatives. After excluding 39 patients with prior bilateral adnexectomy, and 105 who did not undergo RRSO, 139 patients were included in the surgical analysis. The uptake rate of RRSO among female patients with HBOC was 57%. The median age at surgery was 50 years (range, 35-75). Pathogenic BRCA1 variants were identified in 48 patients (34.5%), BRCA2 variants in 90 (64.7%), and both BRCA1 and BRCA2 variants in 1 (0.7%). A history of malignancy was observed in 121 patients (breast cancer, n = 121; pancreatic cancer, n = 1; ovarian cancer, n = 1; others, n = 3). Laparoscopic RRSO was performed in 138 cases, with one additional hysterectomy performed laparoscopically and one via laparotomy. No perioperative complications were observed. All 6 cases before April 2020 were performed outside insurance coverage; after insurance coverage was initiated in April 2020, 16 were non-covered and 117 were covered by insurance. Pathological examination revealed occult high-grade serous carcinoma in 4 patients (2.9%) and serous tubal intraepithelial carcinoma in 5 patients (3.6%). To date, no cases of primary peritoneal carcinoma following RRSO have been identified. RRSO was performed safely at our institution, with the detection rate of intraepithelial and invasive carcinoma comparable to previous reports. Although no cases of primary peritoneal carcinoma have been observed postoperatively to date, the residual risk remains, indicating the need for continued long-term surveillance.

BackgroundColorectal cancer (CRC) is the fourth most common cancer in Pakistan and poses significant public health challenges. While the majority of CRC cases are sporadic, ~ 5–10% are hereditary, linked to germline pathogenic variants (PVs) in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and other susceptibility genes (APC, EPCAM). In Pakistan, small-range PVs in MLH1 and MSH2 account for 34.5% of hereditary nonpolyposis colorectal cancer (HNPCC)/suspected-HNPCC and 1.1% of non-HNPCC cases. However, the contribution of large genomic rearrangements (LGRs) in MLH1, MSH2, MSH6, and the 3′ end of EPCAM remains uncharacterized.MethodsWe comprehensively screened 199 Pakistani CRC patients (HNPCC/suspected-HNPCC:18 and non-HNPCC:181), previously tested negative for small-range PVs in MMR genes. LGRs in MLH1, MSH2, MSH6, and the 3′ end of EPCAM were analyzed using multiplex ligation-dependent probe amplification (MLPA). Deletion breakpoints were characterized using long-range polymerase chain reaction (PCR) and Sanger sequencing.ResultsFive distinct MSH2 deletions (5′ upstream, exons 1–3, exons 1–6, exon 7, and exon 11) were identified in 11.1% (2/18) of HNPCC/suspected-HNPCC and 3.3% (6/181) of non-HNPCC cases. A recurrent 5′ upstream deletion was identified in four unrelated patients, including one suspected-HNPCC and three non-HNPCC cases. Other deletions were identified in patients with variable family histories of cancer. No LGRs were detected in MLH1, MSH6, or the 3′ end of EPCAM. Notably, 87.5% of patients with MSH2 LGRs belonged to Punjabi ethnicity.ConclusionsOur findings demonstrate that MSH2 LGRs occur at a notable frequency among Pakistani CRC patients, with a recurrent 5′ upstream deletion representing a potential Punjabi founder variant. Inclusion of this deletion into targeted genetic testing panels may enhance diagnostic yield and improve risk stratification for CRC in Pakistan.

Multiple polyposis syndromes include Familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), Juvenile polyposis syndrome (JPS), PTEN hamartoma tumor syndrome (PHTS), MUTYH-associated polyposis (MAP), NTHL1-associated polyposis (NAP), Polymerase proofreading-associated polyposis (PPAP), and MBD4-associated polyposis. Common to these syndromes is the presence of polyps in the large intestine and very high risk of developing colorectal cancer (CRC), which can reach up to 100% in the case of FAP. The development of FAP is associated with pathogenic variants of the APC gene. However, pathogenic variants are not always detected in patients with FAP, which poses a significant clinical challenge for both patients and their families, who may be at increased risk for developing the disease. A second strong predisposition to CRC is MAP, characterized by biallelic pathogenic variants in the MUTYH gene, with a phenotype similar to FAP. This mini review focuses on potential approaches to improve the diagnosis of patients in whom pathogenic variants in the APC and MUTYH genes are not detected by routine testing.

Medullary breast cancer is a rare subtype of invasive breast cancer, representing from 0.2% to 6% of all breast carcinomas, with a higher proportion among women with triple-negative breast cancer and among those with a BRCA1 mutation. This review article aims to investigate the frequency of medullary breast cancer among all breast cancers and to assess its association with BRCA1 mutations. We surveyed studies involving patients diagnosed with breast cancer that report both the histology of the breast cancer as well as the presence of BRCA1 mutations. Among women with medullary breast cancer, the proportion of cases that carry a BRCA1 mutation ranges from 3% up to 35.3%, depending on the study. Among BRCA1-mutated breast cancers, the proportion that are medullary ranges from 8 to 20%. Given the notable association between medullary breast cancer and BRCA1 mutations, we propose to consider medullary breast cancer as a criterion for genetic testing in order to improve the identification of a larger number of carriers, thereby enhancing screening and prevention strategies.

BackgroundBreast cancer (BC) is the most common malignancy among Iranian females, accounting for 24.4% of all malignancies. Germ line mutations in DNA repair system-related genes are associated with an increased risk of BC. This study aims to evaluate the frequencies of single nucleotide polymorphisms (SNPs) in the BRCA1, BRCA2, and PALB2 genes in patients with BC from a subset of the Iranian population in the western part of Iran.MethodsBlood samples were collected from 335 patients with BC and 354 healthy matched volunteers. Genomic DNA was extracted using the salting-out method and, after quality control, was genotyped using the multiplex TaqMan allelic discrimination assay for three SNPs: rs80359550 (6174 delT) in the BRCA2 gene, rs180177102 in the PALB2 gene, and rs386833395 (185delAG) in the BRCA1 gene. Statistical analysis was performed to examine allele frequency, odds ratio, and relative risk (genetic association) in a retrospective case-control study.ResultsThe data showed no association between rs386833395 and BC risk in the studied population (odds ratio = 1), whereas rs80359550 and rs180177102 polymorphisms were strongly associated with BC risk in patients (odds ratio = 0.01 for both, with p-values of 0.011 and 0.021, respectively).ConclusionsOur findings suggest no significant association between the rs386833395 polymorphism and BC risk in the Iranian Kurdish population, while rs80359550 and rs180177102 polymorphisms were strongly associated with BC. However, the study has several limitations, including its retrospective design, a relatively small sample size, and the potential lack of generalizability to other ethnic groups within Iran. Future studies involving larger cohorts and more diverse populations are needed to confirm these results.

Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage.

More than 25 years ago, CDH1 pathogenic variants (PVs) were identified as the primary cause of hereditary diffuse gastric cancer (HDGC), an inherited cancer syndrome that increases the lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Since DGC is associated with a poor prognosis, a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers. However, as germline genetic testing becomes more widespread, many CDH1 PV carriers have been identified, including in families with lower penetrance levels or without a history of gastric cancer (GC). When including these families, recent findings suggest that the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13–19%. This lower risk, combined with the fact that around one third of the CDH1 PV carriers decline PTG due to potential lifelong physical and psychological consequences, raises critical questions about the current uniformity in recommending PTG to all CDH1 PV carriers. As a result, there is a growing need to consider alternative strategies, such as endoscopic surveillance. However, despite the currently lower estimated risk of infiltrative (advanced) DGC, almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC. Therefore, the primary goal of surveillance should be to identify atypical, deeper infiltrating lesions rather than every SRC lesion. Understanding the progression from indolent to more infiltrative lesions, and recognizing their endoscopic and histological features, is crucial in deciding the most suitable management option for each individual.

BackgroundHereditary cancer is estimated to account for up to 10% of the worldwide cancer burden; 5% of all thyroid cancers are thought to be genetic. Inheritance of a deleterious mutation in genes associated with a high lifetime risk of developing cancer. Cancer-predisposing genes can promote the initiation and progression of thyroid cancer by enhancing the activation of major signaling pathways through oxidative stress mechanisms.AimIdentification of the possible link between familial susceptibility to cancer and the level of oxidative stress in thyroid cancer patients.MethodsPatients with thyroid cancer (with and without genetic predisposition) were investigated. Study participants were treated in Limited Liability Company (LLC) “Oncology Scientific Research Center” (Tbilisi, Georgia). The study group was collected between 2020 and 2021. In patients’ blood, the thyroid hormones content (free Triiodothyronine (fFT3), free Thyroxine (fFT4), bound Triiodothyronine (FT3), bound Thyroxine (FT4), Thyroid-stimulating hormone (TSH)), and oxidative stress intensity (total activity of non-enzymatic antioxidant system (TAA) and the lipid peroxidation product, malondialdehyde (MDA), content) were investigated.ResultsThe difference in free and bound forms of T3 and T4 levels in the blood serum between patients with thyroid cancer (Group 2 and Group 3) and the control group (Group 1) was not statistically significant (F1,2=0.5, p1,2=0.8, F1,3=2.31, p1,3=0.16). In patients with thyroid cancer the TSH level significantly increased compared to the control group (Group 1) (TSH (mean ± Std error): Group 1– 1.21 ± 0.12, Group 2–2.45 ± 0.11 (F1,2=107, p1,2<0.001), Group 3–2.47 ± 0.17 (F1,3=150, p1,3<0.001)) and the MDA levels increased by 4–5 fold. In patients with thyroid cancer from families with cancer aggregation(Group 2), the level of TAA statistically significantly decreased (F1 − 2=200; p1 − 2<0.001), in patients without genetic predisposition to cancer(Group 3), the level of TAA did not change compared to the control (F1 − 3= 2.13; p1 − 3=0.15),ConclusionsOxidative stress plays a critical role in tumorigenesis, and antioxidant/oxidant imbalance may contribute to the malignant transformation of normal tissue. In patients with familial susceptibility to cancer mutations of several genes, which are involved in the regulation of oxidative metabolism, may contribute to the disruption of the redox balance, increase the level of oxidative stress, and contribute to the development of thyroid cancer.

Current National Comprehensive Cancer Network ® (NCCN ®) guidelines for Colorectal Genetic/Familial High-Risk Assessment provide limited guidance for genetic testing for individuals with already diagnosed hereditary cancer conditions. We are presenting the case of a 36-year-old woman who was diagnosed with Lynch Syndrome at age 23 after genetic testing for a familial variant (c.283del) in the MLH1 gene. The patient had a previous history of Hodgkin Lymphoma at the time of familial variant testing, and she would later develop stage IIIa cecal adenocarcinoma at age 33 and metastatic papillary thyroid carcinoma at age 35. The patient’s family history included a first-degree relative who was diagnosed with colorectal cancer at age 39, multiple second-degree relatives with colorectal, endometrial, and stomach cancer, and third and fourth-degree relatives with breast cancer. In light of her personal and family history, a comprehensive cancer panel was recommended. This panel found a second hereditary cancer predisposition syndrome: a likely pathogenic variant (c. 349 A > G) in the CHEK2 gene. This specific CHEK2 variant was recently reported to confer a moderately increased risk for breast cancer. The discovery of this second cancer predisposition syndrome had important implications for the patient’s screening and risk management. While uncommon, the possibility of an individual having multiple cancer predisposition syndromes is important to consider when evaluating patients and families for hereditary cancer, even when a familial variant has been identified.