Hereditary Cancer in Clinical Practice最新文献

Pathogenic variants in BRCA1 and BRCA2 are associated with an increased risk of developing several types of cancer, including breast cancer. However, the risk varies by other environmental and genetic factors present in carriers of mutation. To understand the value of these factors more clearly, a number of common genetic susceptibility variants have been studied through genome-wide association studies as potential genetic risk modifiers for BRCA1 and BRCA2 pathogenic variants carriers. Several studies have identified specific polymorphisms that may influence the risk of breast cancer development, either by increasing or reducing susceptibility. These variants are implicated in biological pathways such as DNA damage repair, hormonal regulation or cell proliferation. The identification and understanding of key genetic modifiers may provide valuable insights into development of personalized prevention, targeted therapies and screening strategies for high-risk individuals. This review presents the overview of known genetic risk modifiers for carriers of BRCA1 and BRCA2 pathogenic variants, their potential impact on risk, and their functional roles. Furthermore, it highlights the need for further research directions, including understanding the biological role of genetic modifiers in cancer development and the refinement of risk assessment models.

Purpose: While enhanced breast screening of germline pathogenic variant (GPV) carriers results in earlier stage at diagnosis, the impact of tumour biology and GPV on chemotherapy receipt in early-stage disease remains understudied.

Methods: We retrospectively reviewed treatment administered following a first diagnosis of BRCA1/2- and PALB2-associated breast cancer between 2002 and 2022. Chemotherapy receipt was compared according to tumor size, biologic subtype, and GPV. Subgroup analyses were performed in women with T1N0 disease and in those with pre-diagnostic awareness of their GPV.

Results: Overall, 309 affected BRCA1/2 and PALB2 carriers with a median age of 43 years at breast cancer diagnosis (range, 19-80 years) were included; 160 (51.8%) BRCA1, 130 (42.1%) BRCA2, and 19 (6.1%) PALB2 carriers. Chemotherapy was administered in 70.9% of index breast cancer cases and was significantly associated with younger age, tumor size, histologic grade, nodal status, and biologic subtype (all p < 0.05). Chemotherapy receipt was 80.6% in BRCA1-associated breast cancers compared to 56.9% in BRCA2 and 84.2% in PALB2 associated breast cancers (p < 0.001). In subgroup analysis of early stage, T1N0 disease, chemotherapy was administered in 78.9% BRCA1 and 59.5% BRCA2/PALB2 patients (p = 0.04). Pre-diagnostic awareness of a GPV in BRCA1/2 or PALB2 was associated with smaller invasive tumors (%T1, 50% vs. 32.9%; p = 0.002) and node-negative invasive disease (87.1% vs. 72.2%), as well as a reduced likelihood of chemotherapy (59.7% vs. 74.3%, p = 0.02).

Conclusion: Chemotherapy receipt is high in BRCA1/2 and PALB2-associated breast cancers including in early stage, node-negative disease. Pre-diagnostic awareness is associated with a lower likelihood of requiring chemotherapy for a breast cancer diagnosis.

Background: While numerous studies have demonstrated variations in colorectal cancer (CRC) incidence among Lynch Syndrome (LS)-associated germline pathogenic variant (gPV) carriers, limited data are available regarding tailoring surveillance and treatment strategies. The main goal of this study was to estimate whether personalised care could be offered based on the different gPVs (MLH1, MSH2, MSH6 or PMS2). Additionally, the outcome from patient-shared care for early (T1) CRC was investigated.

Methods: The study is performed as a single centre retrospective analysis of our cohort of patients with a LS-associated gPV in MLH1, MSH2, MSH6 or PMS2. Colon surveillance data from between January 1978 to February 2024 were collected. Analyses were performed to identify differences in incidence of precursor lesions and CRC between the different variants and treatment variation for CRC in LS.

Results: From a cohort of 621 LS individuals 496 (133 MLH1, 107 MSH2, 180 MSH6 and 76 PMS2) could be included in this study. Analyses revealed that, despite adequate surveillance intervals and lower adenoma incidence, individuals with a gPV in MLH1 or MSH2 have higher CRC incidences compared to MSH6 or PMS2. Most detected CRC lesions were early stage (T1) CRCs. Treatment for T1 CRC varied considerably; in 68% of the cases deviating from a subtotal colectomy, with nearly equivalent recurrence rates.

Discussion: Based on higher precursor lesion detection and lower CRC incidences in LS individuals with a gPV in MSH6 or PMS2 under biannual endoscopic surveillance, this study supports the potential for extended surveillance intervals in the latter group. As treatment for the detected T1 CRCs varied considerably with nearly equivalent recurrence rates, in selected cases less invasive interventions for LS individuals could be considered.

Background: Breast 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.

Methods: Blood 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.

Results: The 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).

Conclusions: Our 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.

Prostate Cancer (PrCa) is one of the most common cancers worldwide and causes a significant healthcare burden. Recent predictions estimate the incidence of new cases of PrCa will double from 1.4 million in 2020 to 2.9 million by 2040.The known risk factors for PrCa are increasing age, family history, ancestry and genetics. PrCa is one of the most heritable of the more common cancers. The heritability of PrCa is due to both rare moderate to high-risk monogenic variants and more common variants known as single nucleotide polymorphisms (SNPs) which can be used to calculate a polygenic risk score (PRS) for PrCa, while there is some of the genetic risk as yet unexplained. In recent years more PrCa risk-associated SNPs have been identified, increasing over time with the inclusion of more persons of diverse ancestry in studies. The identification of germline variants known to be associated with increased PrCa risk and disease aggressiveness has led to targeted treatments for certain pathogenic variant carriers.This is a mini review of how the genetics of PrCa can impact on screening and early detection of the disease and the treatment and management of the disease when diagnosed.

There is an increasing recognition that comprehensive tumour profiling (CTP) represents an important adjunct to the diagnosis of malignancy providing not only an assessment of how many mutations there are in any given tumour which reflects the probability of immune checkpoint inhibitor success, but also which mutations are associated with targeted therapies, a signature that reflects environmental insult and potentially the identification of cancers of unknown origin.This short review describes an approach to assaying tumour mutational burden (TMB), what the difficulties are in the assessment of the TMB and what it can be applied to in regards to improving patient outcomes. A final section of the review delves into some examples of colorectal cancer studies that identify findings that suggest there remains much to learn about tumour development.

Background: Germline genetic susceptibilities of rare cancers of the esophagus, stomach, small intestine, testis, (nonmedullary) thyroid gland and bone with high familial risks are not well known. Here, we use familial risk data from the Swedish Family-Cancer Database which contains records of cancers in Swedish families obtained over a century. We compare familial risks for offspring diagnosed with any of these cancers when their parent had or had not that cancer. We review the global literature of the reported constitutional variants that may explain part of the familial risk.

Main body: Familial risks for esophageal and stomach cancers are about 2.0 and apart from early-onset stomach cancer few high-risk variants are known. Genetic studies may be hampered by dominant environmental risk factors for these cancers. Small intestinal carcinoids have a very high familial risk (28 between siblings) but no high-risk genes have been identified to explain this. Low-risk polygenic variants have been identified. Small intestinal adenocarcinoma is a manifestation in Lynch syndrome. Testicular and thyroid cancers are characterized by high familial risk (about 5) which may be explained largely by a polygenic background, although thyroid cancer is a component in a number of rare cancer syndromes. Several predisposing genes have been identified for bone cancer (familial risk 7).

Conclusions: The discussed cancers are rare and they present with a relatively high familial risk, in spite of lacking identified high-penetrant constitutional variants. It is possible that the polygenic component, already recognized for testis cancer, is stronger than previously expected. Thus polygenic models with rare high/moderate- and low-risk variants could fit the familial risk and shape the germline genetic landscape of these cancers. Polygenic background may have clinical implications.

Background: The widespread application of colonoscopy screening and genetic testing in colorectal cancer (CRC) treatment has led to the identification of a subset of familial adenomatous polyposis (FAP) patients who lack a family history of the disease but harbor germline gene mutations. Moreover, distinct genotypes may be associated with varied clinical presentations and therapeutic options. This case report describes a male patient with de novo FAP who harbored germline double heterozygosity (GDH) for APC and BRCA2 mutations. The patient underwent total colectomy, and genetic testing enabled personalized surveillance and management strategies for his family members.

Case presentation: A 43-year-old male with no family history of cancer presented to the outpatient clinic of the Colorectal Surgery Department with complaints of constipation and hematochezia. Colonoscopy revealed hundreds of polyps throughout the colon and a rectal adenocarcinoma located 5 cm from the anal verge. Gastroduodenal endoscopy did not detect any upper gastrointestinal adenomas. The patient underwent laparoscopic total colectomy with abdominoperineal resection of the rectum and end ileostomy. With the consent of the patient and his family, genetic testing was performed. The index patient was found to carry an APC splicing site mutation (exon 15: c.1744-1G > A) and a BRCA2 missense mutation (exon 17: c.7976G > A: p.R2659K). His daughter was found to have inherited the same germline BRCA2 variant. Additionally, the rectal cancer exhibited proficient DNA mismatch repair (pMMR) status, ERBB2 copy number amplification, and a missense mutation, while the KRAS, NRAS, and BRAF genes were wild-type. Based on the genetic testing results and clinical manifestations, the index patient was diagnosed with familial adenomatous polyposis (FAP) and rectal cancer. Personalized surveillance and management strategies were implemented for the patient and his family, focusing on the risks of extra-colonic diseases and potential malignancies in the prostate, pancreas, breast, and ovaries.

Conclusion: De novo FAP with double germline mutations in APC and BRCA2, along with somatic ERBB2 mutations, is exceptionally rare among hereditary cancer cases. With the rapid advancements in genomics, the detection of multiple gene variants in individuals or families has become increasingly common. Additionally, the application of artificial intelligence (AI) in medical research may provide powerful tools for genetic analysis and clinical decision-making. Consequently, a comprehensive evaluation of family history, a deep understanding of hereditary cancer syndromes, and precise interpretation of genetic mutations are essential for personalized clinical management in the era of precision medicine. However, these tasks pose significant challenges for clinicians and genetic counselors alike.

Background: The Swedish Family-Cancer Database (FCD) is the largest source of data on familial cancer in the world, including practically complete family structures and individual cancer diagnoses from the high-quality cancer registry. We present a novel application of FCD by analyzing age-specific familial risks and interpreting them through likely causes, such as germline pathogenic variants and/or environmental exposures.

Main body: The basic assumption for this approach is that a discrete familial clustering in a narrow age-interval is not random but may provide causal clues. For this analysis we selected reasonably common cancers to meaningfully scrutinize familial risk through adulthood in which cancers are diagnosed, that included colorectal (CRC) and endometrial cancers, prostate and kidney cancers and breast and lung cancers. The interpretation is based on the literature. The highest familial relative risks for CRC and endometrial cancers were found at ages 40-44 years, matching the peak impact of mismatch repair gene mutations. However endometrial cancer showed also a small early onset component which could not be explained. Age-related familial risks for breast, prostate and kidney cancers also matched data from large-scale sequencing; these included the early onset component in kidney cancer which was likely due to VHL mutations. Age distribution of familial lung cancer was unique in showing a wide peak extending from middle to old ages, which would be consistent with a combination of direct genetic effects and indirect influence on inheritance of smoking dependence.

Conclusions: The present review of age-specific familial risks and age-of-onset data from the literature may allow an interpretation that the familial and germline landscapes are reasonably harmonious for relatively early onset cancers but at higher ages no discrete peaks can be found which may implicate attenuated impact of high-risk genes and polygenic influence.

Background: The Department of Clinical Cancer Genetics at the Institute of Oncology Ljubljana offers genetic counselling and testing to cancer patients and their relatives. Before undergoing genetic testing, patients sign the informed consent form. In addition to giving consent for collection of biological material and genetic testing, patients decide about storage of biological material and participation in international databases. Furthermore, patients decide whether the information regarding their test results may be revealed to their blood relatives and whether they want to be informed about secondary findings.

Methods: Using the signed consent forms, we investigated the effect of selected factors on patients' decisions. Using different statistical methods, we tried to determine the proportion of patients who opted for different items and the effect of gender, age and cancer diagnoses on their decisions.

Results: Nearly all (99.6%) patients, regardless of gender, age, and presence of oncological diagnosis, consented to the storage of their biological material, 98.4% of patients, regardless of gender, age, and presence of oncological diagnosis, wanted to be included in international databases in a pseudo-anonymised form, 98.8% of patients, irrespective of gender, age, and presence of oncological diagnosis, allowed blood relatives to see their results, and 98.4% of patients, irrespective of gender, age and presence of oncological diagnosis, wanted to know whether secondary findings were detected when genetic analysis of their biological material was performed. Men are, on average, more likely to consent but the difference between genders is not statistically significant. Patients without oncological disease were more likely to agree to be included in international databases than patients with a confirmed oncological diagnosis.

Conclusions: Our results show that the vast majority of patients were in favour of the options they were offered. Most importantly, the majority of them allow their genetic test results be revealed to their blood relatives when needed and would participate in international databases. Research in rare diseases, including rare cancer genetic predisposition syndromes, is crucial for optimal diagnostic, prevention and treatment options for patients with rare genetic disorders. The results are also important for refining the approach to pre-and post-test cancer genetic counselling.