Genetics of Breast and Gynecologic Cancers (PDQ®)—Health Professional Version - National Cancer Institute

Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version

Pathology of breast cancer

BRCA1 pathology

Several studies evaluating pathologic patterns seen in BRCA1-associated breast cancers have suggested an association with adverse pathologic and biologic features. These findings include higher than expected frequencies of medullary histology, high histologic grade, areas of necrosis, trabecular growth pattern, aneuploidy, high S-phase fraction, high mitotic index, and frequent TP53 variants.[226-233] In a large international series of 3,797 carriers of BRCA1 pathogenic variants, the median age at breast cancer diagnosis was 40 years.[233] Of breast tumors arising in BRCA1 carriers, 78% were ER-negative; 79% were PR-negative; 90% were HER2-negative; and 69% were triple-negative. These findings were consistent with multiple smaller series.[90,229,234-236] In addition, the proportion of ER-negative tumors significantly decreased as the age at breast cancer diagnosis increased.[233]

There is considerable, but not complete, overlap between the triple-negative and basal-like subtype cancers, both of which are common in BRCA1-associated breast cancer,[237,238] particularly in women diagnosed before age 50 years.[90-92] A small proportion of BRCA1-related breast cancers are ER-positive, which are associated with later age of onset.[239,240] These ER-positive cancers have clinical behavior features that are intermediatebetween ER-negative BRCA1 cancers and ER-positive sporadic breast cancers, raising the possibility that there may be a unique mechanism by which they develop.

The prevalence of germline BRCA1 pathogenic variants in women with triple-negative breast cancer is significant, both in women undergoing clinical genetic testing (and thus selected in large part for family history) and in unselected triple-negative patients, with pathogenic variants reported in 9% to 35%.[92,93,234,241-244] Notably, studies have demonstrated a high rate of BRCA1 pathogenic variants in unselected women with triple-negative breast cancer, particularly in those diagnosed before age 50 years. A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 14.6% with a pathogenic variant in an inherited cancer susceptibility gene.[244] BRCA1 pathogenic variants accounted for the largest proportion (8.5%), followed by BRCA2 (2.7%); PALB2 (1.2%); and BARD1, RAD51D, RAD51C and BRIP1(0.3%–0.5% for each gene). In this study, those with pathogenic variants in BRCA1/BRCA2 or other inherited cancer genes were diagnosed at an earlier age and had higher grade tumors than those without pathogenic variants. Specifically, among carriers of BRCA1pathogenic variants, the average age at diagnosis was 44 years, and 94% had high-grade tumors. One study examined 308 individuals with triple-negative breast cancer; BRCA1pathogenic variants were present in 45. Pathogenic variants were seen both in women unselected for family history (11 of 58; 19%) and in those with family history (26 of 111; 23%).[245] A meta-analysis based on 2,533 patients from 12 studies was conducted to assess the risk of a BRCA1 pathogenic variant in high-risk women with triple-negative breast cancer.[246] Results indicated that the RR of a BRCA1 pathogenic variant among women with versus without triple-negative breast cancer is 5.65 (95% CI, 4.15–7.69), and approximately two in nine women with triple-negative disease harbor a BRCA1 pathogenic variant. Interestingly, a study of 77 unselected patients with triple-negative breast cancer in which 15 (19.5%) had a germline or somatic BRCA1/BRCA2 pathogenic variant demonstrated a lower risk of relapse in those with BRCA1 pathogenic variant–associated triple-negative breast cancer than in those with non-BRCA1-associated triple-negative breast cancer; this study was limited by its size.[242] A second study examining clinical outcomes in BRCA1-associated versus non-BRCA1-associated triple-negative breast cancer showed no difference, although there was a trend toward more brain metastases in those with BRCA1-associated breast cancer. In both of these studies, all but one carrier of BRCA1pathogenic variants received chemotherapy.[247] In contrast, HER2 positivity and young age alone in the absence of family history or a second primary cancer does not increase the likelihood of a pathogenic variant in BRCA1, BRCA2, or TP53.[248]

It has been hypothesized that many BRCA1 tumors are derived from the basal epithelial layer of cells of the normal mammary gland, which account for 3% to 15% of unselected invasive ductal cancers. If the basal epithelial cells of the breast represent the breast stem cells, the regulatory role suggested for wild-type BRCA1 may partly explain the aggressive phenotype of BRCA1-associated breast cancer when BRCA1 function is damaged.[249] Further studies are needed to fully appreciate the significance of this subtype of breast cancer within the hereditary syndromes.

The most accurate method for identifying basal-like breast cancers is through gene expression studies, which have been used to classify breast cancers into biologically and clinically meaningful groups.[235,250,251] This technology has also been shown to correctly differentiate BRCA1- and BRCA2-associated tumors from sporadic tumors in a high proportion of cases.[252-254] Notably, among a set of breast tumors studied by gene expression array to determine molecular phenotype, all tumors with BRCA1 alterations fell within the basal tumor subtype;[235] however, this technology is not in routine use due to its high cost. Instead, immunohistochemical markers of basal epithelium have been proposed to identify basal-like breast cancers, which are typically negative for ER, PR, and HER2, and stain positive for cytokeratin 5/6, or epidermal growth factor receptor.[255-258] Based on these methods to measure protein expression, a number of studies have shown that the majority of BRCA1-associated breast cancers are positive for basal epithelial markers.[90,229,257]

There is growing evidence that preinvasive lesions are a component of the BRCAphenotype. The Breast Cancer Linkage Consortium initially reported a relative lack of an in situ component in BRCA1-associated breast cancers,[227] also seen in two subsequent studies of BRCA1/BRCA2 carriers.[259,260] However, in a study of 369 ductal carcinoma in situ (DCIS) cases, BRCA1 and BRCA2 pathogenic variants were detected in 0.8% and 2.4%, respectively, which is only slightly lower than previously reported prevalence in studies of invasive breast cancer patients.[261] A retrospective study of breast cancer cases in a high-risk clinic found similar rates of preinvasive lesions, particularly DCIS, among 73 BRCA-associated breast cancers and 146 pathogenic variant–negative cases.[262,263] A study of AJ women, stratified by whether they were referred to a high-risk clinic or were unselected, showed similar prevalence of DCIS and invasive breast cancers in referred patients compared with one-third lower DCIS cases among unselected subjects.[264] Similarly, data about the prevalence of hyperplastic lesions have been inconsistent, with reports of increased [265,266] and decreased prevalence.[260] Similar to invasive breast cancer, DCIS diagnosed at an early age and/or with a family history of breast and/or ovarian cancer is more likely to be associated with a BRCA1/BRCA2 pathogenic variant.[267]

Overall evidence suggests DCIS is part of the BRCA1/BRCA2 spectrum, particularly BRCA2; however, the prevalence of pathogenic variants in DCIS patients, unselected for family history, is less than 5%.[261,264]

BRCA2 pathology

The phenotype for BRCA2-related tumors appears to be more heterogeneous and is less well-characterized than that of BRCA1, although they are generally positive for ER and PR.[227,268,269] A large international series of 2,392 carriers of BRCA2 pathogenic variants found that only 23% of tumors arising in carriers of BRCA2 pathogenic variants were ER-negative; 36% were PR-negative; 87% were HER2-negative; and 16% were triple-negative.[233] A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 2.7% with a BRCA2 pathogenic variant.[244] (Refer to the BRCA1 pathology section of this summary for more information about this study.) A report from Iceland found less tubule formation, more nuclear pleomorphism, and higher mitotic rates in BRCA2-related tumors than in sporadic controls; however, a single BRCA2 founder pathogenic variant (999del5) accounts for nearly all hereditary breast cancer in this population, thus limiting the generalizability of this observation.[270] A large case series from North America and Europe described a greater proportion of BRCA2-associated tumors with continuous pushing margins (a histopathologic description of a pattern of invasion), fewer tubules and lower mitotic counts.[271] Other reports suggest that BRCA2-related tumors include an excess of lobular and tubulolobular histology.[228,268] In summary, histologic characteristics associated with BRCA2 pathogenic variants have been inconsistent.

Role of BRCA1 and BRCA2 in sporadic breast cancer

Given that germline pathogenic variants in BRCA1 or BRCA2 lead to a very high probability of developing breast cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic pathogenic variants in BRCA1 and BRCA2 are not common in sporadic breast cancer tumors,[272-275] there is increasing evidence that hypermethylation of the gene promoter (BRCA1) and loss of heterozygosity (LOH) (BRCA2) are frequent events. In fact, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter.[276-278] Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER negative, PR negative, HER2 negative, and cytokeratin 5/6 positive) more commonly have BRCA1 dysregulation than other tumor types.[279-281] BRCA1-related tumor characteristics have also been associated with constitutional methylation of the BRCA1 promoter. In a study of 255 breast cancers diagnosed before age 40 years in women without germline BRCA1pathogenic variants, methylation of BRCA1 in peripheral blood was observed in 31% of women whose tumors had multiple BRCA1-associated pathological characteristics (e.g., high mitotic index and growth pattern including multinucleated cells) compared with less than 4% methylation in controls.[282] (Refer to the BRCA1 pathology section for more information.) Although hypermethylation has not been reported for BRCA2 pathogenic variants, the BRCA2 locus on chromosome 13q is the target of frequent LOH in breast cancer.[283,284] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[285]

Pathology of ovarian cancer

Ovarian cancers in women with BRCA1 and BRCA2 pathogenic variants are more likely to be high-grade serous adenocarcinomas and are less likely to be mucinous or borderline tumors.[286-290] Fallopian tube cancer and peritoneal carcinomas are also part of the BRCA-associated disease spectrum.[70,291]

Histopathologic examinations of fallopian tubes removed from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that suggest a premalignant phenotype.[292,293] Occult carcinomas have been reported in 2% to 11% of adnexa removed from carriers of BRCA pathogenic variants at the time of risk-reducing surgery.[294-296] Most of these occult lesions are seen in the fallopian tubes, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tubes. Specifically, the distal segment of the fallopian tubes (containing the fimbriae) has been implicated as a common origin of the high-grade serous cancers seen in BRCA pathogenic variant carriers, based on the close proximity of the fimbriae to the ovarian surface, exposure of the fimbriae to the peritoneal cavity, and the broad surface area in the fimbriae.[297] Because of the multicentric origin of high-grade serous carcinomas from Müllerian-derived tissue, staging of ovarian, tubal, and peritoneal carcinomas is now considered collectively by the International Federation of Gynecology and Obstetrics. The term high-grade serous ovarian carcinoma may be used to represent high-grade pelvic serous carcinoma for consistency in language.[298]

High-grade serous ovarian carcinomas have a higher incidence of somatic TP53 pathogenic variant.[286,299] DNA microarray technology suggests distinct molecular pathways of carcinogenesis between BRCA1, BRCA2, and sporadic ovarian cancer.[300] Furthermore, data suggest that BRCA-related ovarian cancers metastasize more frequently to the viscera, while sporadic ovarian cancers remain confined to the peritoneum.[301]

Unlike high-grade serous carcinomas, low-grade serous ovarian cancers are less likely to be part of the BRCA1/BRCA2 spectrum.[302,303]

Role of BRCA1 and BRCA2 in sporadic ovarian cancer

Given that germline variants in BRCA1 or BRCA2 lead to a very high probability of developing ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic pathogenic variants in BRCA1 and BRCA2 are not common in sporadic ovarian cancer tumors,[272-275] there is increasing evidence that hypermethylation of the gene promoter (BRCA1) and LOH (BRCA2) are frequent events. Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer,[304] and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease.[305,306] Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.[285]

Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancers

Lynch syndrome

Lynch syndrome is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer.[307] The condition is caused by germline variants in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch variants.[308] The MLH1 and MSH2 genes are the most common susceptibility genes for Lynch syndrome, accounting for 80% to 90% of observed pathogenic variants,[309,310] followed by MSH6 and PMS2.[311-316] (Refer to the Lynch Syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)

After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer,[317] in 1999, the Amsterdam criteria were revised to include endometrial cancer as extracolonic tumors associated with Lynch syndrome to identify families at risk.[318] In addition, the Bethesda guidelines in 1997 (revised in 2004) did include endometrial and ovarian cancers as Lynch syndrome–related cancers to prompt tumor testing for Lynch syndrome.[319,320]

The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected Lynch syndrome.[321-326] Characteristics of Lynch syndrome–associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages I and II at diagnosis (reported as 81.5%), underrepresentation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in carriers of BRCA pathogenic variants.[327,328]

The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[329-332] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[332] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [333] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[333] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[334] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1carriers but not in carriers of other MMR variants.[335] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[336]

A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[337-340] although this has not been consistently observed.[341] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[337] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2pathogenic variants.[338] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 105).[339] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[340] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.[95]

Refer to the Lynch Syndrome section of the Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes section of this summary for information about clinical management of Lynch syndrome.

Li-Fraumeni syndrome (LFS)

Breast cancer is also a component of the rare LFS, in which germline variants of the TP53gene on chromosome 17p have been documented. Located on chromosome 17p, TP53encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death.[342] Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells.[343,344] Widely used clinical diagnostic criteria for LFS were originally developed by Chompret et al. in 2001 (called the Chompret Criteria) [345] and revised in 2009 based on additional emerging data.[346]

LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[343,347,348]

Germline variants in TP53 are thought to account for fewer than 1% of breast cancer cases.[349] TP53-associated breast cancer is often HER2/neu-positive, in addition to being ER-positive, PR-positive, or both.[350-352] Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy.

Historical criteria for defining LFS

The term Li-Fraumeni syndrome was used for the first time in 1982,[353] and the following criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in 1988 [354]:

Sarcoma before age 45 years;
An FDR with cancer before age 45 years; AND
Another close relative (FDR or second-degree relative [SDR]) with either cancer before age 45 years or a sarcoma at any age.

Subsequently in 2001, Chompret et al. [345] systematically developed clinical criteria for recommending TP53 genetic testing, with the narrow LFS tumor spectrum defined as sarcoma, brain tumors, breast cancer, and adrenocortical carcinoma. The criteria were as follows:

A proband affected by a narrow-spectrum tumor before age 36 years AND at least one FDR or SDR affected by a narrow-spectrum tumor (other than breast cancer if the proband is affected by breast cancer) before age 46 years or multiple primary tumors; OR
A proband with multiple primary tumors, two of which belong to the narrow spectrum and the first of which occurred before age 36 years, irrespective of family history; OR
A proband with adrenocortical carcinoma irrespective of the age at onset and family history.

These criteria were revised in 2009 [346] based on additional emerging data [344,355] as follows:

A proband with a tumor belonging to the LFS tumor spectrum* before age 46 years AND at least one FDR or SDR with a LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
A patient with adrenocortical carcinoma or choroid plexus, irrespective of family history.

*The 2009 Chompret criteria defined the LFS tumor spectrum as including the following cancers: soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer.

In 2015, Bougeard et al. [348] revised the criteria based on data from 415 carriers of pathogenic variants, to include the presence of childhood anaplastic rhabdomyosarcoma and breast cancer before age 31 years as an indication for testing, similar to what is recommended for choroid plexus carcinoma and adrenocortical carcinoma. The criteria were revised as follows:

A proband with a tumor belonging to the LFS tumor spectrum** before age 46 years AND at least one FDR or SDR with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
A patient with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR
Breast cancer before age 31 years.

**The 2015 Chompret criteria defined the LFS tumor spectrum as including the following cancers: premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, and adrenocortical carcinoma.

Clinical characteristics of LFS

Germline TP53 pathogenic variants were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing.[344] All families with a TP53pathogenic variant had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 pathogenic variant, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 variants were found.

Subsequently, a large clinical series of patients from France who were tested primarily based on the 2009 version of the Chompret criteria [346] included 415 carriers of pathogenic variants from 214 families.[348] In this study, 43% of carriers had multiple malignancies, and the mean age at first tumor onset was 24.9 years. The childhood tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas, CNS tumors, and soft tissue sarcomas (present in 23%–30% collectively), whereas the adult tumor spectrum primarily encompassed breast cancer (79% of females) and soft tissue sarcomas (27% of carriers). The TP53 pathogenic variant detection rate was 6% among females younger than 31 years with breast cancer and no additional features suggestive of LFS. Evaluation of genotype-phenotype correlations indicated a gradient of clinical severity, with a significantly lower mean age at onset among those with dominant-negative missense variants (21.3 years), compared with those with all types of loss-of-function variants (28.5 years) or genomic rearrangements (35.8 years). With the exception of adrenocortical carcinoma, affected children mostly harbored dominant-negative missense pathogenic variants. Among 127 female carriers of pathogenic variants with breast cancer, 31% developed CBC. Receptor status information was available for 40 tumors, which indicated 55% were HER2-positive, and 37% were triple-positive (i.e., ER-positive, PR-positive, and HER2-positive). There was an exceptionally high rate of multiple malignancies (43%) among carriers of pathogenic variants, of which 83% were metachronous. Treatment records were available for 64 carriers who received radiation therapy for treatment of their first tumor; of these, 19 (30%) developed 26 secondary tumors within a radiation field, with a latency of 2 to 26 years (mean, 10.7 y).

Similarly, results of 286 TP53 pathogenic variant–positive individuals in the National Cancer Institute’s LFS Study indicated a cumulative cancer incidence of almost 100% by age 70 years for both males and females.[356] They reported substantial variations by sex, age, and cancer type. Specifically, cumulative cancer incidence reached 50% by age 31 years in females and age 46 years in males, although male risks were higher in childhood and late adulthood. Cumulative cancer incidence by sex for the top four cancers is included in Table 8. Of those with one cancer, 49% developed at least one additional cancer after a median of 10 years. Age-specific risks for developing first and second cancers were comparable.

Table 8. Cumulative Cancer Risks for the Most Common Li-Fraumeni Syndrome (LFS)-Associated Cancersa,b

	Cumulative Cancer Risk by Age 70 Years
aAdapted from Mai et al.[356]
bOther cancers, such as adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer, have been considered part of the LFS cancer spectrum.[346,348]
Cancer Type	Females (%)	Males (%)
Breast cancer	54	–
Soft tissue sarcoma	15	22
Brain cancer	6	19
Osteosarcoma	5	11

With the increasing use of multigene (panel) tests, it is important to recognize that pathogenic variants in TP53 are unexpectedly being identified in individuals without a family history characteristic of LFS.[357] The clinical significance of finding an isolated TP53pathogenic variant in an individual or family who does not meet the Chompret criteria is uncertain. Consequently, it remains important to interpret cancer risks and determine optimal management strategies for individuals who are unexpectedly found to have a germline TP53 pathogenic variant, while taking into account their personal and family histories.

One cohort study evaluated 116 individuals with a germline TP53 pathogenic variant yearly at the National Institutes of Health Clinical Center using multimodality screening with and without gadolinium. Baseline screening identified a cancer in eight patients (6.9%) with a false-positive rate of 34.5% for MRI (n = 40).[358] Screening for breast cancer with annual breast MRI is recommended;[95] additional screening for other cancers has been studied and is evolving.[359,360]

PTEN hamartoma tumor syndromes (including Cowden syndrome)

Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable PTEN pathogenic variant.[361] In addition, PTEN pathogenic variants have been identified in patients with very diverse clinical phenotypes.[362] The term PTEN hamartoma tumor syndromes refers to any patient with a PTEN pathogenic variant, irrespective of clinical presentation.

PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. Pathogenic variants of PTEN are diverse, including nonsense, missense, frameshift, and splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif, and several recurrent pathogenic variants have been observed.[363] Individuals with variants in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[364]

Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[365,366] These included major, minor, and pathognomonic criteria consisting of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested [367] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[95] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multigene panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTENpathogenic variants who do not meet these criteria. Until then, whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.[97] Detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[95,97] Additionally, a predictive model that uses clinical criteria to estimate the probability of a PTEN pathogenic variant is available; a cost-effectiveness analysis suggests that germline PTEN testing is cost effective if the probability of a variant is greater than 10%.[368]

Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTENtesting in the United States, Europe, and Asia.[369] Most individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline PTEN pathogenic variants. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline PTEN pathogenic variants. A second study of approximately 100 patients with a germline PTEN pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.[370]

Although PTEN pathogenic variants, which are estimated to occur in 1 in 200,000 individuals,[365] account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.[365,371] Lifetime breast cancer risk is estimated to be between 25% and 50% among women with Cowden syndrome.[372] Other studies have reported risks as high as 85%;[369,370,373,374] however, there are concerns regarding selection bias in these studies. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral.[375] Lifetime risk of endometrial cancer is estimated to be between 19% and 28%, depending on the cohort studied, with an increased risk of premenopausal onset.[369,370,376] Because of the low prevalence of PTEN pathogenic variants in the population, the proportion of endometrial cancer attributable to Cowden syndrome is small. There are no data that link PTEN pathogenic variants to an increased risk of ovarian cancer. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. CNS manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.[377,378] (Refer to the PDQ summaries on Genetics of Colorectal Cancer and Genetics of Skin Cancer for more information about PTENhamartoma tumor syndromes [including Cowden syndrome].)

Diffuse gastric and lobular breast cancer syndrome

The E-cadherin gene CDH1 was first described in 1998 in three Maori families with multiple cases of diffuse gastric cancer (DGC), leading to the designation of hereditary diffuse gastric cancer (HDGC). There have been multiple subsequent reports of an excess of lobular breast cancer in HDGC families.[379] CDH1 is located on chromosome 16q22.1 and encodes the E-cadherin protein, a calcium-dependent homophilic adhesion molecule that plays a key role in cellular adhesion, cell polarity, cell signaling, and maintenance of cellular differentiation and tissue morphology.[380] E-cadherin binds to various catenins to stabilize the cytoplasmic cell adhesion complex and to maintain the E-cadherin interaction with actin filament.[381] Loss of CDH1 can occur as a result of somatic variants, LOH, or hypermethylation, and can result in dedifferentiation and invasiveness in human cancers.[382,383] Classic histopathologic findings in gastrectomy specimens include in situ signet ring cells and/or pagetoid spread of signet ring cells. Of all gastric cancers, 1% to 3% are attributed to inherited gastric cancer syndromes.[384]

HDGC is an autosomal dominant syndrome associated with poorly differentiated invasive adenocarcinoma of the stomach presenting as linitis plastica. It is a highly penetrant and highly fatal syndrome, with a risk of clinical DGC ranging from 40% to 83%.[379] The risk of lobular breast cancer, which is characterized by small uniform cells that tend to invade in “single files,” is also increased in HDGC. Although invasive lobular breast cancer represents only 10% to 15% of all breast cancers, the lifetime risk of lobular breast cancer in carriers of CDH1 pathogenic variants ranges from 30% to 50%.[381,382] Guidelines for screening for CDH1 vary but include multiple cases of DGC in a family, early age of DGC, or lobular breast cancer in a family with DGC. Approximately 25% of families meeting these criteria are found to have a pathogenic variant in CDH1.[384] CDH1 pathogenic variants have been found in some families with lobular breast cancer but no gastric cancer.[385] The management of individuals with CDH1 pathogenic variants without a family history of gastric cancer is unclear.[385]

Peutz-Jeghers syndrome (PJS)

PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[386-388] Germline pathogenic variants in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[389-393] The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancies. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer [394-396] and 21% for ovarian cancer.[394] A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[397] Table 9 shows the cumulative risk of these tumors.

Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[398] In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;[399] although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.

Table 9. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea

Site	Age (y)	Cumulative Risk (%)b	Reference(s)
GI = gastrointestinal.
aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology [397], copyright 2010.
bAll cumulative risks were increased compared with the general population (P < .05), with the exception of cervix and testes.
cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.
dWesterman et al.: GI cancer does not include pancreatic cancer.[400]
eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.
Any cancer	60–70	37–93	[393-396,400,401]
GI cancerc,d	60–70	38–66	[395,396,400,401]
Gynecological cancer	60–70	13–18	[395,396]
Per origin
Stomach	65	29	[394]
Small bowel	65	13	[394]
Colorectum	65	39	[394,395]
Pancreas	65–70	11–36	[394,395]
Lung	65–70	7–17	[394-396]
Breast	60–70	32–54	[394-396]
Uterus	65	9	[394]
Ovary	65	21	[394]
Cervixe	65	10	[394]
Testese	65	9	[394]

Peutz-Jeghers gene(s)

PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[390,391] Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (LOH) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[402,403] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS.[404] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[405] indeed, compound mutant mice heterozygous for pathogenic variants in STK11 +/- and homozygous for pathogenic variants in TP53 -/- have accelerated development of both hamartomas and cancers.[406]

Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[389,395] Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein, and no germline variants have been reported in exon 9. No strong genotype-phenotype correlations have been identified.[395]

STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in STK11, studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS.[389,397,407] Given the results of these studies, it is unlikely that other major genes cause PJS.

Clinical management

The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.

PALB2

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic pathogenic variants in PALB2 have also been shown to cause Fanconi anemia.[408]

PALB2 pathogenic variants have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[14,409-426] Pathogenic variant prevalence has ranged from 0.4% to 3.9%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 pathogenic variants in families with hereditary breast cancer.[409] Among 559 cases with CBC and 565 matched controls with unilateral breast cancer, pathogenic (truncating) PALB2 pathogenic variants were identified in 0.9% of cases and in none of the controls (RR, 5.3; 95% CI, 1.8–13.2).[420]

Data based on 154 families with loss-of-function PALB2 variants suggest that this gene may be an important cause of hereditary breast cancer, with risks that overlap with BRCA2.[427] In this study, analysis of 362 family members from 154 families with PALB2 pathogenic variants indicated that the absolute risk of female breast cancer by age 70 years ranged from 33% (95% CI, 24%–44%) for those with no family history of breast cancer to 58% (95% CI, 50%–66%) for those with two or more FDRs with early-onset breast cancer. Furthermore, among 63 breast cancer cases in which HER2 status was known, 30% had triple-negative disease. An earlier Finnish study reported on a PALB2 founder pathogenic variant (c.1592delT) that confers a 40% risk of breast cancer to age 70 years [410] and is associated with a high incidence (54%) of triple-negative disease and lower survival.[411] Pathogenic variants have been observed in early-onset and familial breast cancer in many populations.[412,413] A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 1.2% with a PALB2pathogenic variant.[244] (Refer to the BRCA1 pathology section of this summary for more information about this study.)

In a later Polish study of more than 12,529 unselected women with breast cancer and 4,702 controls, PALB2 pathogenic variants were detected in 116 cases (0.93%; 95% CI, 0.76%–1.09%) and 10 controls (0.21%; 95% CI, 0.08%–0.34%), with an OR for breast cancer of 4.39 (95% CI, 2.30–8.37).[428] The study findings confirm a substantially elevated risk of breast cancer (24%–40%) among women with a PALB2 pathogenic variant up to age 75 years. The 5-year cumulative incidence of CBC was 10% among those with a PALB2 pathogenic variant, compared with 17% among those with a BRCA1 pathogenic variant and 3% among those without a variant in either gene. Furthermore, the 10-year survival for women with a PALB2pathogenic variant and breast cancer was 48% (95% CI, 36.5%–63.2%), compared with 72.0% among those with a BRCA1 pathogenic variant and 74.7% among those without a variant in either gene. Among PALB2 carriers, breast tumors 2 cm or larger had substantially worse outcomes (32.4% 10-year survival), compared with tumors smaller than 2 cm (82.4% 10-year survival). Approximately one-third of those with a PALB2 pathogenic variant had triple-negative breast cancer, and the average age at breast cancer diagnosis was 53.3 years.

Male breast cancer has been observed in PALB2 pathogenic variant–positive breast cancer families.[14,414,427] In a study of 115 male breast cancer cases in which 18 men had BRCA2pathogenic variants, an additional two men had either a pathogenic or predicted pathogenic PALB2 variant (accounting for about 10% of germline variants in the study and 1%–2% of the total sample).[14] The RR of breast cancer for male carriers of PALB2pathogenic variants compared with that seen in the general population was estimated to be 8.30 (95% CI, 0.77–88.56; P = .08) in the study of 154 families.[427]

After the identification of PALB2 pathogenic variants in pancreatic tumors and the detection of germline pathogenic variants in 3% of 96 familial pancreatic patients,[429] numerous studies have pointed to a role for PALB2 in pancreatic cancer. PALB2 pathogenic variants were detected in 3.7% of 81 familial pancreatic cancer families [430] and in 2.1% of 94 BRCA1/BRCA2 pathogenic variant–negative breast cancer patients who had either a personal or family history of pancreatic cancer.[431] Two relatively small studies—one of 77 BRCA1/BRCA2 pathogenic variant–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of AJ descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer—failed to detect any PALB2 pathogenic variants.[432,433] A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/BRCA2-negative, PALB2 pathogenic variant–positive breast cancer probands.[414]

Overall, the observed prevalence of PALB2 pathogenic variants in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed pathogenic variant rate was lower than 4%. Data suggest that the RR of breast cancer may overlap with that of BRCA2, particularly in those with a strong family history; thus, it remains important to refine cancer risk estimates in larger studies. Furthermore, the risk of other cancers (e.g., pancreatic) is poorly defined. Given the low PALB2 pathogenic variant prevalence in the population, additional data are needed to define best candidates for testing and appropriate management.

De Novo Pathogenic Variant Rate

Until the 1990s, the diagnosis of genetically inherited breast and ovarian cancer syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, PJS, PTEN hamartoma syndromes, and LFS are all thought to have high rates of spontaneous pathogenic variants, in the 10% to 30% range,[434-437] while estimates of de novo pathogenic variants in the BRCA genes are thought to be low, primarily on the basis of the few case reports published.[438-446] Additionally, there has been only one case series of breast cancer patients who were tested for BRCA pathogenic variants in which a de novo variant was identified. Specifically, in this study of 193 patients with sporadic breast cancer, 17 pathogenic variants were detected, one of which was confirmed to be a de novo pathogenic variant.[438] As such, the de novo pathogenic variant rate appears to be low and fall into the 5% or less range, based on the limited studies performed.[438-446] Similarly, estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[447-449] However, these estimates of spontaneous pathogenic variant rates in the BRCA genes and Lynch syndrome genes seem to overlap with the estimates of nonpaternity rates in various populations (0.6%–3.3%),[450-452] making the de novo pathogenic variant rate for these genes relatively low.

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