Mini review: Molecular pathology of personalized medicine in cancer susceptibility syndromes
How to cite this article: Kaler AK, Bora NS, Kavyashree P, Nikam A, Rane S, Tiwarekar Y, et al. Mini review: Molecular pathology of personalized medicine in cancer susceptibility syndromes. Int J Mol Immuno Oncol 2023;8:81-8.
In current times, medical oncology is increasingly incorporating cancer genetics and genetic testing into its practice. About 5–10% of all cancers are caused due to inherited genetic mutation that increases susceptibility to a particular malignancy. There is an increasing practice of incorporation of genetic testing and results with potential benefits that have been seen in current-day oncology practice. The American College of Medical Genetics and Genomics highly advises conducting clinical molecular genetic testing within a laboratory that has received CLIA approval with results accurately interpreted by molecular geneticists. The patient is highly recommended to talk to a genetic specialist to explain about the risk, document the family history, and also explain the limitations and outcomes of the genetic testing. Nonetheless, significant discussions and ambiguity persist regarding the optimal approach for providing genetic testing services. These include considerations such as which tests should be employed, which patients should undergo testing, the order and timing of the tests, who should administer them, and the appropriate course of action for follow-up.
Cancer susceptibility syndromes
Familial cancers can occur in multiple individuals within the same family but are not caused due to single gene mutation.[1,2] These type of cancers cluster within families but are not hereditary in nature and result from a combination of various factors, such as multiple genes, and lifestyle factors such as diet and exercise, which collectively increases the risk of developing cancers. Hereditary cancers are caused due to germline mutations in specific genes that are inherited from either one or both parents and are associated with susceptibility to particular cancers. Mostly autosomal dominant in nature, meaning the probability of 50% passing on this mutation or change to the next generation. An individual who tested positive on a hereditary cancer test has more than one pathogenic variant in 3.1% of cases. While germline mutations occur in all the cells of the body, cancers that are non-hereditary or sporadic are caused due to genetic mutations in the tumor cells or tissues concerned. These mutations are known as somatic mutations and are not inherited by the next generation.
A few of the cancers follow autosomal recessive patterns of inheritance, such as MUTYH-associated polyposis (MAP). MAP is associated with germline mutations in both the copies of the MUTYH gene, one copy of each mutated allele inherited from the maternal and paternal sides. Patients developing colon cancer at an early age and having healthy parents and/ or the presence of 15–20 colonic adenomas are indications of the possibility of MAP in an individual.
Hereditary basis of breast cancer was first described by Broca more than a century ago in 1866 when he reported breast cancer in multiple family members. Warthin and Henry Lynch reported distinct patterns of early age onset and multiple primary tumors in the same individual with colon cancer.[8,9] Li and Fraumeni described the clinical characteristics of families with p53 germline mutations as Li-Fraumeni syndrome (LFS) in the subsequent years. In 1971 Knudson propound the two-hit hypothesis in Retinoblastoma (RB), where he suggested that the patients who had bilateral RB carried an inherited gene mutation along with an acquired second mutation. Later, Friend SH et al. also confirmed the same hypothesis by and reported a high incidence of 2nd non-ocular tumor which was believed to be caused by the same mutation.
There have been more than 100 distinct syndromes found, and the majority are rare. About 5–10% of all cancers are caused due to inherited genetic mutation that increases susceptibility to a particular malignancy.[4,14] Being familiar with the more-prevalent syndromes, such as hereditary breast and ovarian cancer, Li-Fraumeni, Lynch Syndrome (HPNCC), familial adenomatous polyposis (FAP), RB, multiple endocrine neoplasia, and Von Hippel-Lindau (VHL) can help health-care professionals recognize different signs and symptoms in a patient as potentially having a genetic component, allowing for appropriate diagnostic testing and referrals.
There has been a tremendous advancement in next-generation sequencing (NGS) technologies in the last 30 years. The application of massively parallel sequencing in germline and somatic cancers has become clinically important. Germline testing assists in identifying the risk of inherited cancer in an individual and at-risk family members and benefit in risk-reducing measures and cancer surveillance. While somatic testing helps in therapeutic options for targeted therapies and immunotherapies. Although germline and somatic testing are carried out independently oftentimes in diagnostic laboratories, integrating both approaches to provide optimal care for individuals affected with diverse forms of cancer.[16-18]
PENETRANCE AND EXPRESSIVITY
Penetrance is a measurement of the proportion of individuals in a population who carry a particular pathogenic mutation and exhibit the disease phenotype. For example, Mutations in the RB1, APC, BRCA1 and 2, PTEN genes as mentioned in [Table 1]. But in some syndromes, the association between the gene and its expressivity is reduced, like incomplete penetrance shown in Wilms tumor.
|Cancer syndrome||Gene||Main tumor type||Penetrance||Patterns of inheritance|
|FAP||APC||Colorectal carcinoma||70–100%||Autosomal dominant|
|Cowden’s syndrome||PTEN||Breast, endometrium, follicular thyroid tumor||90–95%||Autosomal dominant|
|HBOC||BRCA1 and BRCA2||Breast/ovary||Up to 85%||Autosomal dominant|
|LFS||TP53||AML, sarcoma, adrenocortical Carcinoma||90–100%||Autosomal dominant|
|Lynch syndrome/HNPCC||MLH1, MSH2, MSH6, PMS1, PMS2||Colorectal, endometrium, brain||90%||Autosomal dominant|
|RB||RB||Eye, bone||90%||Autosomal dominant|
|Wilms’ tumor syndromes||WT1||Nephroblastoma||30% incomplete||Autosomal dominant|
|Gorlin syndrome/NBCC||PTCH1||Basal cell carcinoma/medulloblastoma||90%||Autosomal dominant|
|ATS||ATM||Lymphomas, leukemia||100%||Autosomal recessive|
|FA||FANCA, FANCB, FANCC, FANCD, FANCE, FANCF, FANCG, FANCL||Acute myeloid leukemia||100%||Autosomal recessive|
|BS||BLM||Wilms tumor, colorectal cancers, Leukemia||100%||Autosomal recessive|
The degree to which a genotype manifests its phenotypic expression is measured by expressivity. Different levels of expression in different people may result from variations in the allelic makeup of the rest of the genome or from environmental influences. Thus, expressivity quantifies the degree to which a genotype is phenotypically expressed in individuals, as opposed to penetrance measurements that concentrate on whether or not a disease is expressed in a population.[19,20]
Understanding the penetrance and expressivity of cancer-predisposing genes is significant in understanding the complexity of hereditary cancers and improving genetic counseling for patients as well as family members.
INDICATIONS FOR GERMLINE CANCER TESTING INCLUDES
Breast cancer diagnosis in ≤50 years age: Triple negative subtype or Lobular Carcinoma; Male Bilateral/multiple primary, Ashkenazi Jewish Ancestry, Breast cancer and one additional tumor (LFS, ≥1 PJ polyp, Cowden syndrome).
Colorectal cancer (CRC) diagnosed at age <50: Mismatch repair deficient; multiple primary synchronous or metachronous CRC; ≥10 adenomatous or >5 hamartomatous gastrointestinal polyps; association with other cancers – endometrial, LFS, Cowden syndrome criteria.
All women are diagnosed with ovarian cancer whether it is a single case present in the patient or a first-degree relative. BRCA1 and BRCA2 pathogenic germline variants are detected in the vast majority of ovarian cancer patients, specifically with high-grade serous histology.
Prostate cancer diagnosed at any age: Intraductal/ cribriform histology, Gleason score ≥7; metastatic, regional (node-positive) or very-high-risk localized prostate; Ashkenanzi Jewish ancestry.
Pancreatic cancer diagnosed at any age: Intraductal papillary mucinous neoplasm histopathology.
Patients diagnosed with renal cancer, having age of diagnosis <50; Bilateral or multifocal tumors; ≥1 close relative renal cell carcinoma (RCC) with clear cell, papillary type 1, papillary type 2, collecting duct, tubulopapillary and Birt-Hogg-Dubé (BHD)-related histology, Fumarate hydratase (FH) associated RCC.
Thyroid cancers with Medullary subtype, a cribriform morular subtype of papillary thyroid cancer Papillary/ follicular thyroid cancer, and additional carney complex or Cowden syndrome.
Gastric cancers: Diffuse type, signet ring cell type, and mismatch repair deficient.
Melanoma: Melanoma and pancreatic cancer/ Astrocytoma in the same person.
Lynch syndrome-related cancer (i.e., colorectal, endometrial, gastric, ovarian, pancreatic, ureter and renal pelvic, brain (usually glioblastoma), biliary tract, small intestinal, sebaceous adenoma, sebaceous carcinoma, or keratoacanthoma) and the tumor shows evidence of mismatch repair (MMR) deficiency (either by microsatellite instability or loss of MMR protein expression).
CATEGORIZATION OF GENETIC SYNDROMES BASED ON MOLECULAR PATHWAYS
The syndromes are supposed to be activate pathways that lead to uncontrolled proliferation, increased angiogenesis, or defective repair.
Defect in PI3K/AKT/mTOR pathway: This is the most common pathway activated in cancer, which leads to the formation of hamartomas/overgrowth syndromes. Cowden syndrome (PTEN gene), Proteus syndrome (AKT1), Tuberous sclerosis complex (TSC1/2), Von Recklinghausen disease (NF1 and NF2).
Defect in the RAS/RAF/MEK/ERK pathway: RASopathies, Von Recklinghausen disease (NF1 and NF2).
Defect in angiogenesis: VHL
Defects DNA repair mechanism: Hereditary breast and ovarian cancer syndrome, Lynch syndrome, LFS
Defect in growth factor regulation: Gorlin syndrome (PTCH1)
Others: FAP (APC).
NGS-based methods are used to rapidly sequence known cancer-associated genes for identifying germline mutations at once or identify novel germline variants linked to cancer. NGS platforms allow researchers to sequence millions of DNA fragments in parallel, greatly accelerating the process and reducing the cost per base. The high-throughput data generated through NGS make them particularly valuable for understanding complex diseases, including cancers. Among different cancers, there is significant interest in studying those with a familial predisposition, as they offer opportunities to identify novel genes or gene variants that contribute to cancer development and can be detected at the germline level, thus playing a role in cancer pathogenesis.[24,25]
Multiplex-Ligation Dependent Probe Amplification is another technique that identifies large deletions/duplications in genes. It combines aspects of both polymerase chain reaction and hybridization techniques to analyze the copy number of specific DNA sequences. Sanger sequencing chain termination sequencing technology is a method used to determine the nucleotide sequence of DNA. It can be used for mutation confirmation among at-risk family members, siblings, and next generations. It has its limitations in sequencing a single gene as compared to massively parallel sequencing millions of fragments sequenced in NGS.
REPORTING OF VARIANTS ACCORDING TO AMERICAN COLLEGE OF MEDICAL GENETICS AND GENOMICS (ACMG) GUIDELINES
The ACMG guidelines assist in the evaluation and accurate interpretation of genetic variants and have laid down specific criteria for variant classification and reporting based on their association with genetic and clinical presentation. It outlines a systematic approach to evaluating genetic variants based on multiple lines of evidence, such as population frequency, functional studies, computational, predictive, segregation data, clinical observations, and multiple databases [Table 2]. The guidelines also define standardized terms and criteria for variant interpretation, including pathogenic, likely pathogenic, uncertain significance, likely benign, and benign, based on the available evidence. The collective evidence from all the criteria evaluated, is then used to assign the appropriate variant classification.
|Population data||MAF is too high for disorder BA1/BS1 OR observation in controls inconsistent with disease penetrance BS2||Absent in population databases PM2||Prevalence in affected statistically increased over controls PS4|
|Computational and predictive data||Multiple lines of computational evidence suggest no impact on gene/gene product BP4
Missense in gene where only truncating cause disease BP1
Silent variant with non predicted splice impact BP7
|Multiple lines of computational evidence support a deleterious effect on the gene/gene product PP3||Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before PM5
Protein length changing variant PM4
|Same amino acid change as an established pathogenic variant PS1||Predicted null variant in a gene where LOF is a known mechanism of disease PVS1|
|Functional data||Well-established functional studies show no deleterious effect BS3||Missense in gene with low rate of benign missense variants and path. Missenses common PP2||Mutational hotspot or well-studied functional domain without benign variation PM1||Well-established functional studies show a deleterious effect PS3|
|Segregation data||Non-segregation with disease BS4||N≤1/8 if 1 family||N≤1/4 if >1 family||N≤1/16 if 1 family|
|N≤1/8 if >1 family||N≤1/32 if 1 family||N≤1/16 if >1 family|
|De novo data||De novo (without paternity and maternity confirmed) PM6||De novo (paternity and maternity confirmed) PS2|
|Allellic data||Observed in trans with a dominant variant BP2
Observed in cis with a pathogenic variant BP2
|For recessive disorders, detected in trans with a pathogenic variant PM3|
|Other database||Reputablesource without shared data=benign BP6||Reputablesource=pathogenic PP5|
|Other data||Found in case with an alternate cause BP5||Patient’s phenotype or FH highly specific for gene PP4|
Professional societies’ consensus statements recommend pre-test and post-test genetic counseling to patients for Germline hereditary cancer genetic testing. Taking into account the clinical and family history of the patient, informing the patient about indications of genetic testing, as well as addressing the patient’s concerns is an important aspect to consider before ordering a genetic test.[30,31] Constructing a pedigree chart for 3 generations is the best way to visualize risk assessment among patients.[32,33]
The process of obtaining consent for germline testing should comprise an explanation of the test’s rationale, potential outcomes, risks, and advantages. The results of a genetic test should be disclosed followed up with proper post-test genetic counseling.
Post-test genetic counseling involves providing patients and their families with an in-depth summary of the genetic testing results, helping them to comprehend the test outcomes and associated risks; co-ordinating comprehensive follow-up care to plan for cancer prevention, timely surveillance, and offering individuals personalized treatment strategies. If an individual is tested “positive” for a germline variant associated with hereditary cancer, other at-risk family members should be encouraged to follow up for genetic counseling.
Personalized approaches to cancer genetic syndrome
Individuals who test positive for cancer-associated germline mutations require a comprehensive approach to cancer management. Compared to the general population, individuals with cancer germline mutations may necessitate preventive and specialized screening options tailored to the specific associated cancer risks. In certain cases [Table 3], risk reduction surgery options may be recommended to minimize the likelihood of cancer development. For instance, patients consider prophylactic surgeries like mastectomy/oophorectomy/ colectomy to decrease the risk of respective cancer.
|TSC1/2 (mTOR Pathway)||Estrogen-based medications, including oral contraceptives
Everolimus, mTOR inhibitor
|Shared risk outcome of progression to lymphangioleiomyomatosis
TSC-associated Subependymal giant Astrocytoma and renal angiomyolipoma
|FDA Approved 2018|
|VHL (Hypoxia induced factor-a)||WELIREG, HIF-2a inhibitors||Sensitivity
VHL - RCC, CNS Hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery.
|FDA approval in 2021|
|Increased risk of breast cancer
Complete pathological response
Disease free survival
|Hahnen et al. 2017
Caramelo et al. 2019
|FDA 2018 (Breast), 2020 (Ovary), 2023 (Prostate)[44-46]|
|Aspirin and NSAIDs||Sensitivity||10-years follow-up of randomized controlled trial|
|Phase 1 clinical trial|
|TP53||Genotoxic agents like etoposide and radiotherapy||Resistance||Review|
|Carboplatin and Breast Cancer||Sensitivity||Cohort Study|
|Aspirin and NSAIDs||Shared risk outcome||FDA approved in 2018|
|RET||Tyrosine Kinase Inhibitors
Pralsetinib and selpercatinib
RET mutation-positive medullary thyroid cancer
|FDA approved in 2010|
|SDHA||Tyrosine kinase inhibitors||Resistance (GISTs)||Observational study|
|Sensitivity (Metastatic PGG and PCC)||Phase 2 clinical trial|
|SDHB||Temozolomide||Sensitivity||Retrospective population study|
|Tyrosine Kinase Inhibitors||Resistance (GISTs)||Observational study|
|Sensitivity (Metastatic PGG and PCC)||Phase 2 clinical trial|
|SDHC||Tyrosine kinase inhibitors||Sensitivity (RCC)||Case Report|
Genetic risk predictions models
It has become increasingly common to use computational models in genetic risk prediction models in recent years. A number of risk assessment tools and models are available to evaluate the probability that an individual carries a genetic mutation or their risk to develop cancer. These tools assess the risk based on the presence or absence of gene mutations, personal or family history of cancer. BRCAPRO is an important risk model, developed based on the statistical R package, BayesMendel. It calculates the individual’s probability of carrying a pathogenic BRCA1 or BRCA2 gene mutation, the risk of developing contralateral breast cancer and ovarian cancer at different ages. Users can input clinical information such as age, tumor marker information, mastectomy, and oophorectomy information, family race, and ethnicity. BRCAPRO serves as a helpful tool for guiding individuals on whether to pursue genetic testing.
Another breast cancer risk assessment tool is the Breast Cancer Risk Assessment Tool: Gail Model, named after Gail et al., is a statistical model that uses clinical information such as age, menstruation age, age at first live childbirth, and family history of cancer to estimate the risk of developing cancer.[61,62]
While these models may help in understanding the risk of an individual, this alone should not be used as a deciding factor to undergo genetic testing as they have certain limitations. Use of the tools might support decisions for a requirement for genetic testing, but it could also lead to stress and anxiety for patients and their family members if the patient is not guided and explained about the risk-assessment model and its implications.
Genetic testing for cancer may help in the estimation of an individual’s lifetime risk of developing cancer by identifying specific genetic changes or mutations. Germline testing is a powerful tool for early detection and cancer prevention not only in proband cases but also in family members. Understanding the indications for germline testing is a responsibility for coordinating this care between the patient and clinician. Choosing the right test with the right technology will help in the correct interpretation of the results and guide the patient and their family in disease prognosis and awareness of preventative screening options, if available.
We thank all the clinicians for their participation in this study and all co-workers in the laboratory for their excellent technical assistance.
Declaration of patient consent
Patient’s consent not required as there are no patients in this study.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The author(s) confirms that there was no use of Artificial Intelligence (AI)-Assisted Technology for assisting in the writing or editing of the manuscript and no images were manipulated using the AI.
Financial support and sponsorship
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