The increasing knowledge of the molecular pathogenesis of cancer and the rapid development of new molecular techniques are promoting the study of early molecular alterations involved in cancer development in body fluids. Specific genetic and epigenetic alterations could be found in plasma, serum, and urine cell-free DNA (cfDNA) and could potentially be used as diagnostic biomarkers for several types of cancers. This review focuses on the role of cfDNA in diagnosis: a PubMed search was performed by selecting papers according to journal impact factor and robustness of statistical analysis. A comprehensive evaluation of “liquid biopsy”, including cfDNA analysis, will be one of the critical challenges to better understand the early mechanisms of cancer development.

Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li–Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz–Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer Multiple-gene panel analysis in a case series of 255 women with Hereditary Breast and Ovarian Cancer

Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer

To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome–associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.